2021/09/24 更新

写真a

タケイ ノブユキ
武井 延之
TAKEI Nobuyuki
所属
脳研究所 准教授
医歯学総合研究科 分子細胞医学専攻 准教授
職名
准教授
外部リンク

学位

  • 理学博士 ( 1989年1月   上智大学 )

  • 理学修士 ( 1985年3月   上智大学 )

研究分野

  • ライフサイエンス / 神経科学一般

経歴(researchmap)

  • 新潟大学   脳研究所 基礎神経科学部門   准教授

    2007年4月 - 現在

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  • 新潟大学   医歯学総合研究科 医科学専攻   准教授

    2007年4月 - 現在

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  • 新潟大学   医歯学総合研究科 分子細胞医学専攻   准教授

    2007年4月 - 現在

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  • 新潟大学   脳研究所 基礎神経科学部門   助教授

    1999年4月 - 2007年3月

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  • 新潟大学   脳研究所   講師

    1998年7月 - 1999年3月

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経歴

  • 新潟大学   医歯学総合研究科 医科学専攻   准教授

    2007年4月 - 現在

  • 新潟大学   脳研究所 基礎神経科学部門   准教授

    2007年4月 - 現在

  • 新潟大学   医歯学総合研究科 分子細胞医学専攻   准教授

    2007年4月 - 現在

  • 新潟大学   脳研究所 基礎神経科学部門   助教授

    1999年4月 - 2007年3月

  • 新潟大学   脳研究所   講師

    1998年7月 - 1999年3月

所属学協会

委員歴

  • 国際放射線神経生物学会   理事  

    2013年1月 - 現在   

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    団体区分:学協会

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  • 日本神経化学会   評議員  

    2001年 - 現在   

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    団体区分:学協会

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論文

  • mTORC1 is involved in DGKβ-induced neurite outgrowth and spinogenesis. 査読 国際誌

    Hiroko Nakai, Ryosuke Tsumagari, Kenta Maruo, Akio Nakashima, Ushio Kikkawa, Shuji Ueda, Minoru Yamanoue, Naoaki Saito, Nobuyuki Takei, Yasuhito Shirai

    Neurochemistry international   134   104645 - 104645   2020年3月

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    記述言語:英語  

    Diacylglycerol kinase β (DGKβ) is an enzyme converting DG to phosphatidic acid (PA) and is specifically expressed in neurons, especially those in the cerebral cortex, hippocampus and striatum. We previously reported that DGKβ induces neurite outgrowth and spinogenesis, contributing to higher brain function including emotion and memory, and plasma membrane localization of DGKβ via the C1 domain and a cluster of basic amino acids at the C-terminus is necessary for its function. To clarify the mechanisms involved in neuronal development by DGKβ, we investigated whether DGKβ activity induces neurite outgrowth using human neuroblastoma SH-SY5Y cells. DGKβ induced neurite outgrowth by activation of mammalian target of rapamycin complex 1 (mTORC1) through a kinase-dependent pathway. In addition, in primary cultured cortical and hippocampal neurons, inhibition of mTORC1 abolished DGKβ induced-neurite outgrowth, branching and spinogenesis. These results indicated that DGKβ induces neurite outgrowth and spinogenesis by activating mTORC1 in a kinase-dependent pathway.

    DOI: 10.1016/j.neuint.2019.104645

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  • AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks. 査読

    Yamada S, Kamata T, Nawa H, Sekijima T, Takei N

    Scientific reports   9 ( 1 )   11904   2019年8月

  • Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases. 査読

    Kobayashi Y, Iwakura Y, Sotoyama H, Kitayama E, Takei N, Someya T, Nawa H

    Translational psychiatry   9 ( 1 )   181   2019年8月

  • Characterization of Functional Primary Cilia in Human Induced Pluripotent Stem Cell-Derived Neurons. 査読

    Miki D, Kobayashi Y, Okada T, Miyamoto T, Takei N, Sekino Y, Koganezawa N, Shirao T, Saito Y

    Neurochemical research   44 ( 7 )   1736 - 1744   2019年7月

  • Pathological alterations of chondroitin sulfate moiety in postmortem hippocampus of patients with schizophrenia. 査読

    Yukawa T, Iwakura Y, Takei N, Saito M, Watanabe Y, Toyooka K, Igarashi M, Niizato K, Oshima K, Kunii Y, Yabe H, Matsumoto J, Wada A, Hino M, Iritani S, Niwa SI, Takeuchi R, Takahashi H, Kakita A, Someya T, Nawa H

    Psychiatry research   270   940 - 946   2018年12月

  • BDNF reduces eEF2 phosphorylation and enhances novel protein synthesis in growth cones of dorsal root ganglia neurons. 査読

    Hoshi O, Sugizaki A, Cho Y, Takei N

    Neurochem.Res.   43   1242 - 1249   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s11064-018-2541-8.

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  • Epidermal growth factor singals attenuate phenotypic and functional development of neocortical GABA neurons 査読

    Hisaaki Namba, Tadasato Nagano, Eiichi Jodo, Satoshi Eifuku, Masao Horie, Hirohide Takebayashi, Yuriko Iwakura, Hidekazu Sotoyama, Nobuyuki Takei, Hiroyuki Nawa

    JOURNAL OF NEUROCHEMISTRY   142 ( 6 )   886 - 900   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Phenotypic development of neocortical GABA neurons is highly plastic and promoted by various neurotrophic factors such as neuregulin-1. A subpopulation of GABA neurons expresses not only neuregulin receptor (ErbB4) but also epidermal growth factor (EGF) receptor (ErbB1) during development, but the neurobiological action of EGF on this cell population is less understood than that of neuregulin-1. Here, we examined the effects of exogenous EGF on immature GABA neurons both in culture and in vivo and also explored physiological consequences in adults. We prepared low density cultures from the neocortex of rat embryos and treated neocortical neurons with EGF. EGF decreased protein levels of glutamic acid decar-boxylases (GAD65 and GAD67), and EGF influences on neuronal survival and glial proliferation were negligible or limited. The EGF treatment also diminished the frequency of miniature inhibitory postsynaptic currents (mIPSCs). In vivo administration of EGF to mouse pups reproduced the above GABAergic phenomena in neocortical culture. In EGF-injected postnatal mice, GAD- and parvalbumin-immunoreactivities were reduced in the frontal cortex. In addition, postnatal EGF treatment decreased mIPSC frequency in, and the density of, GABAergic terminals on pyramidal cells. Although these phenotypic influences on GABA neurons became less marked during development, it later resulted in the reduced beta- and gamma-powers of sound-evoked electroencephalogram in adults, which is regulated by parvalbumin-positive GABA neurons and implicated in the schizophrenia pathophysiology. These findings suggest that, in contrast to the ErbB4 ligand of neuregulin-1, the ErbB1 ligand of EGF exerts unique maturation-attenuating influences on developing cortical GABAergic neurons.

    DOI: 10.1111/jnc.14097

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  • Striatal hypodopamine phenotypes found in transgenic mice that overexpress glial cell line-derived neurotrophic factor 査読

    Hidekazu Sotoyama, Yuriko Iwakura, Kanako Oda, Toshikuni Sasaoka, Nobuyuki Takei, Akiyoshi Kakita, Hideki Enomoto, Hiroyuki Nawa

    NEUROSCIENCE LETTERS   654   99 - 106   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Glial cell line-derived neurotrophic factor (GDNF) positively regulates the development and maintenance of in vitro dopaminergic neurons. However, the in vivo influences of GDNF signals on the brain dopamine system are controversial and not fully defined. To address this question, we analyzed dopaminergic phenotypes of the transgenic mice that overexpress GDNF under the control of the glial Gfap promoter. Compared with wild-type, the GDNF transgenic mice contained higher levels of GDNF protein and phosphorylated RET receptors in the brain. However, there were reductions in the levels of tyrosine hydroxylase (TH), dopamine, and its metabolite homovanillic acid in the striatum of transgenic mice. The TH reduction appeared to occur during postnatal development. Immunohistochemistry revealed that striatal TH density was reduced in transgenic mice with no apparent signs of neurodegeneration. In agreement with these neurochemical traits, basal levels of extracellular dopamine and high K+-induced dopamine efflux were decreased in the striatum of transgenic mice. We also explored the influences of GDNF overexpression on lomomotor behavior. GDNF transgenic mice exhibited lower stereotypy and rearing in a novel environment compared with wild-type mice. These results suggest that chronic overexpression of GDNF in brain astrocytes exerts an opposing influence on nigrostriatal dopamine metabolism and neurotransmission. (C) 2017 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.neulet.2017.06.005

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  • Advanced glycation end products induce brain-derived neurotrophic factor release from human platelets through the Src-family kinase activation 査読

    Kazuo Furukawa, Ichiro Fuse, Yuriko Iwakura, Hidekazu Sotoyama, Osamu Hanyu, Hiroyuki Nawa, Hirohito Sone, Nobuyuki Takei

    CARDIOVASCULAR DIABETOLOGY   16 ( 1 )   20   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Brain-derived neurotrophic factor (BDNF) exerts beneficial effects not only on diabetic neuropathies but also on cardiovascular injury. There is argument regarding the levels of serum BDNF in patients with diabetes mellitus (DM). Because BDNF in peripheral blood is rich in platelets, this may represent dysregulation of BDNF release from platelets. Here we focused on advanced glycation end products (AGEs), which are elevated in patients with DM and have adverse effects on cardiovascular functions. The aim of this study is to elucidate the role of AGEs in the regulation of BDNF release from human platelets.
    Methods: Platelets collected from peripheral blood of healthy volunteers were incubated with various concentrations of AGE (glycated-BSA) at 37 degrees C for 5 min with or without BAPTA-AM, a cell permeable Ca2+ chelator, or PP2, a potent inhibitor of Src family kinases (SFKs). Released and cellular BDNF were measured by ELISA and calculated. Phosphorylation of Src and Syk, a downstream kinase of SFKs, in stimulated platelets was examined by Western blotting and immunoprecipitation.
    Results: AGE induced BDNF release from human platelets in a dose- dependent manner, which was dependent on intracellular Ca2+ and SFKs. We found that AGE induced phosphorylation of Src and Syk.
    Conclusions: AGE induces BDNF release from human platelets through the activation of the Src- Syk-(possibly phospholipase C)-Ca2+ pathway. Considering the toxic action of AGEs and the protective roles of BDNF, it can be hypothesized that AGE-induced BDNF release is a biological defense system in the early phase of diabetes. Chronic elevation of AGEs may induce depletion or downregulation of BDNF in platelets during the progression of DM.

    DOI: 10.1186/s12933-017-0505-y

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  • Glutamate-Dependent Ectodomain Shedding of Neuregulin-1 Type II Precursors in Rat Forebrain Neurons. 査読

    Iwakura Y, Wang R, Inamura N, Araki K, Higashiyama S, Takei N, Nawa N

    PLoS One   12   e0174780   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1371/journal.pone.0174780.

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  • Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb 査読

    Mitsuko Nakashima, Hirotomo Saitsu, Nobuyuki Takei, Jun Tohyama, Mitsuhiro Kato, Hiroki Kitaura, Masaaki Shiina, Hiroshi Shirozu, Hiroshi Masuda, Keisuke Watanabe, Chihiro Ohba, Yoshinori Tsurusaki, Noriko Miyake, Yingjun Zheng, Tatsuhiro Sato, Hirohide Takebayashi, Kazuhiro Ogata, Shigeki Kameyama, Akiyoshi Kakita, Naomichi Matsumoto

    ANNALS OF NEUROLOGY   78 ( 3 )   375 - 386   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    ObjectiveFocal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb.
    MethodsWe collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments.
    ResultsWe identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase.
    InterpretationWe found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb. Ann Neurol 2015;78:375-386

    DOI: 10.1002/ana.24444

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  • Neuropathologic implication of peripheral neuregulin-1 and EGF Signals in dopaminergic dysfunction and behavioral deficits relevant to Schizophrenia: Their target cells and time window 招待 査読

    Nawa H, Sotoyama H, Iwakura Y, Takei N, Namba H

    Biomed Res Int.   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1155/2014/697935

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  • rnTOR signaling and its roles in normal and abnormal brain development 招待 査読

    Nobuyuki Takei, Hiroyuki Nawa

    FRONTIERS IN MOLECULAR NEUROSCIENCE   7   28 - 28   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FRONTIERS RESEARCH FOUNDATION  

    Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mammalian TOR (mTOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system, the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development.

    DOI: 10.3389/fnmol.2014.00028

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  • A possible link between BDNF and mTOR in control of food intake. 招待 査読

    Takei N, Furukawa K, Hanyu O, Sone H, NawaH

    Front. Psychol.   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3389/fpsyg.201401093

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  • AMP-activated protein kinase counteracts brain-derived neurotrophic factor-induced mammalian target of rapamycin complex 1 signaling in neurons 査読

    Yuta Ishizuka, Naomasa Kakiya, Lee A. Witters, Noriko Oshiro, Tomoaki Shirao, Hiroyuki Nawa, Nobuyuki Takei

    Journal of Neurochemistry   127 ( 1 )   66 - 77   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Growth factors and nutrients, such as amino acids and glucose, regulate mammalian target of rapamycin complex 1 (mTORC1) signaling and subsequent translational control in a coordinated manner. Brain-derived neurotrophic factor (BDNF), the most prominent neurotrophic factor in the brain, activates mTORC1 and induces phosphorylation of its target, p70S6 kinase (p70S6K), at Thr389 in neurons. BDNF also increases mammalian target of rapamycin-dependent novel protein synthesis in neurons. Here, we report that BDNF-induced p70S6K activation is dependent on glucose, but not amino acids, sufficiency in cultured cortical neurons. AMP-activated protein kinase (AMPK) is the molecular background to this specific nutrient dependency. Activation of AMPK, which is induced by glucose deprivation, treatment with pharmacological agents such as 2-Deoxy-d-glucose, metformin, and 5-aminoimidazole-4-carboxamide ribonucleoside or forced expression of a constitutively active AMPKα subunit, counteracts BDNF-induced phosphorylation of p70S6K and enhanced protein synthesis in cortical neurons. These results indicate that AMPK inhibits the effects of BDNF on mTORC1-mediated translation in neurons. Here, we report that growth factor-induced mTORC1 activity is dependent on glucose sufficiency, but not on amino acids in neurons. The mechanism underlying this phenomenon is AMP-activated protein kinase (AMPK) activation. AMPK activation inhibits BDNF-induced mTORC1 activity through TSC2 and raptor. Here, we report that growth factor-induced mTORC1 activity is dependent on glucose sufficiency, but not on amino acids in neurons. The mechanism underlying this phenomenon is AMP-activated protein kinase (AMPK) activation. AMPK activation inhibits BDNF-induced mTORC1 activity through TSC2 and raptor. © 2013 International Society for Neurochemistry.

    DOI: 10.1111/jnc.12362

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  • ErbB2 dephosphorylation and anti-proliferative effects of neuregulin-1 in erbb2-overexpressing cells; Re-evaluation of their low-affinity interaction

    Ran Wang, Yuriko Iwakura, Kazuaki Araki, Kazuko Keino-Masu, Masayuki Masu, Xue-Yi Wang, Nobuyuki Takei, Shigeki Higashiyama, Hiroyuki Nawa

    Scientific Reports   3   1402 - 1402   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuregulin-1 binds to ErbB3 and ErbB4 and regulates cancer proliferation and differentiation. Neuregulin-1 had been suggested to also react with ErbB2, but this argument becomes controversial. Here, we re-evaluated the cellular responses and ErbB2 interaction of neuregulin-1 in ErbB2 overexpressing cell lines. In a competitive ligand-binding assay, we detected significant replacement of [ 35 S]-labeled neuregulin-1 with nano molar ranges of cold neuregulin-1 in L929 cells expressing ErbB2 alone and SKOV3 cells carrying sulf-1 cDNA but not in these parental cells. The concentration of neuregulin-1 significantly decreased thymidine incorporation and phosphorylation of ErbB2 (Tyr877, Tyr1396, and Tyr1121) in ErbB2-overexpressing cancer cells as well as in L929 cells expressing ErbB2. A crosslinking assay ascertained the presence of neuregulin-1 immunoreactivity in the ErbB2 immune complexes of L929 expressing ErbB2 alone. These results suggest that the higher concentrations of neuregulin-1 exert an anti-oncogenic activity to attenuate ErbB2 auto-phosphorylation potentially through its low-affinity interaction with ErbB2.

    DOI: 10.1038/srep01402

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  • AMP-activated protein kinase counteracts BDNF-induced mammalian target of rapamycin complex1 signaling and protein synthesis in neurons 査読

    Y. Ishizuka, T. Shirao, H. Nawa, N. Takei

    JOURNAL OF NEUROCHEMISTRY   123   11 - 12   2012年10月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

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  • Cell surface expression of the major amyloid-β peptide (Aβ)-degrading enzyme, neprilysin, depends on phosphorylation by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and dephosphorylation by protein phosphatase 1a. 査読

    Kakiya N, Saito T, Nilsson P, Matsuba Y, Tsubuki S, Takei N, Nawa H, Saido TC, The Journal of, biological chemistry

    The Journal of biological chemistry   287 ( 35 )   29362 - 29372   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Kakiya N, Saito T, Nilsson P, Matsuba Y, Tsubuki S, Takei N, Nawa H, Saido TC, The Journal of biological chemistry, 2012, vol. 287, no. 35, pp. 29362-29372

    DOI: 10.1074/jbc.M112.340372

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    その他リンク: http://orcid.org/0000-0002-9659-9251

  • Periventricular nodular heterotopia functionally couples with the overlying hippocampus 査読

    Hiroki Kitaura, Makoto Oishi, Nobuyuki Takei, Yong-Juan Fu, Tetsuya Hiraishi, Masafumi Fukuda, Hitoshi Takahashi, Katsuei Shibuki, Yukihiko Fujii, Akiyoshi Kakita

    EPILEPSIA   53 ( 7 )   e127 - e131   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated.

    DOI: 10.1111/j.1528-1167.2012.03509.x

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  • AMPK REGULATES BDNF-INDUCED ACTIVATION OF MTOR SIGNALING AND ENHANCEMENT OF TRANSLATION IN CORTICAL NEURONS 査読

    Ishizuka Y, Nawa H, Takei N

    JOURNAL OF NEUROCHEMISTRY   118   74   2011年8月

  • Qualitative and quantitative re-evaluation of epidermal growth factor-ErbB1 action on developing midbrain dopaminergic neurons in vivo and in vitro: target-derived neurotrophic signaling (Part 1) 査読

    Yuriko Iwakura, Yingjun Zheng, Maria Sibilia, Yuichi Abe, Ying-shan Piao, Daisaku Yokomaku, Ran Wang, Yuta Ishizuka, Nobuyuki Takei, Hiroyuki Nawa

    JOURNAL OF NEUROCHEMISTRY   118 ( 1 )   45 - 56   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Although epidermal growth factor (EGF) receptor (ErbB1) is implicated in Parkinson's disease and schizophrenia, the neurotrophic action of ErbB1 ligands on nigral dopaminergic neurons remains controversial. Here, we ascertained colocalization of ErbB1 and tyrosine hydroxylase (TH) immunoreactivity and then characterized the neurotrophic effects of ErbB1 ligands on this cell population. In mesencephalic culture, EGF and glial-derived neurotrophic factor (GDNF) similarly promoted survival and neurite elongation of dopaminergic neurons and dopamine uptake. The EGF-promoted dopamine uptake was not inhibited by GDNF-neutralizing antibody or TrkB-Fc, whereas EGF-neutralizing antibody fully blocked the neurotrophic activity of the conditioned medium that was prepared from EGF-stimulated mesencephalic cultures. The neurotrophic action of EGF was abolished by ErbB1 inhibitors and genetic disruption of erbB1 in culture. In vivo administration of ErbB1 inhibitors to rat neonates diminished TH and dopamine transporter (DAT) levels in the striatum and globus pallidus but not in the frontal cortex. In parallel, there was a reduction in the density of dopaminergic varicosities exhibiting intense TH immunoreactivity. In agreement, postnatal erbB1-deficient mice exhibited similar decreases in TH levels. Although neurotrophic supports to dopaminergic neurons are redundant, these results confirm that ErbB1 ligands contribute to the phenotypic and functional development of nigral dopaminergic neurons.

    DOI: 10.1111/j.1471-4159.2011.07287.x

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  • Dopamine-dependent ectodomain shedding and release of epidermal growth factor in developing striatum: target-derived neurotrophic signaling (Part 2) 査読

    Yuriko Iwakura, Ran Wang, Yuichi Abe, Ying-shan Piao, Yuji Shishido, Shigeki Higashiyama, Nobuyuki Takei, Hiroyuki Nawa

    JOURNAL OF NEUROCHEMISTRY   118 ( 1 )   57 - 68   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Epidermal growth factor (EGF) and structurally related peptides promote neuronal survival and the development of midbrain dopaminergic neurons; however, the regulation of their production has not been fully elucidated. In this study, we found that the treatment of striatal cells with dopamine agonists enhances EGF release both in vivo and in vitro. We prepared neuron-enriched and non-neuronal cell-enriched cultures from the striatum of rat embryos and challenged those with various neurotransmitters or dopamine receptor agonists. Dopamine and a dopamine D(1)-like receptor agonist (SKF38393) triggered EGF release from neuron-enriched cultures in a dose-dependent manner. A D(2)-like agonist (quinpirole) increased EGF release only from non-neuronal cell-enriched cultures. The EGF release from striatal neurons and non-neuronal cells was concomitant with ErbB1 phosphorylation and/or with the activation of a disintegrin and metalloproteinase and matrix metalloproteinase. The EGF release from neurons was attenuated by an a disintegrin and metalloproteinase/matrix metalloproteinase inhibitor, GM6001, and a calcium ion chelator, BAPTA/AM. Transfection of cultured striatal neurons with alkaline phosphatase-tagged EGF precursor cDNA confirmed that dopamine D(1)-like receptor stimulation promoted both ectodomain shedding of the precursor and EGF release. Therefore, the activation of striatal dopamine receptors induces shedding and release of EGF to provide a retrograde neurotrophic signal to midbrain dopaminergic neurons.

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  • In vitro production of an active neurotrophic factor, neuregulin-1: Qualitative comparison of different cell-free translation systems 査読

    Ran Wang, Yuriko Iwakura, Kazuaki Araki, Hidekazu Sotoyama, Nobuyuki Takei, Hiroyuki Nawa

    NEUROSCIENCE LETTERS   497 ( 2 )   90 - 93   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    The individual biological activities of many neurotrophic factors and their variants, which are produced by alternative splicing and proteolytic processing, often remain to be characterized. Bacterial protein production combined with protein refolding and purification is a conventional procedure to obtain active neurotrophic factors; however, the procedure is time consuming and appropriate protein refolding in vitro is sometimes unpredictable. Here we examined three distinct cell-free translation systems: reticulocyte lysate, Hela cell lysate and wheat germ extract, which may allow us to produce biologically active factors in a single tube. Taking type-I neuregulin-1 beta3 as an example, we produced neuregulin-1 protein from its mRNAs flanked by Cap nucleotide and/or internal ribosome entry site (IRES) and compared the yields and biological activity of translation products from these systems. The protein yield from IRES+ mRNA was highest in the Hela cell-free system, while background translation was lowest in the wheat germ system. The biological activity of both translation products was modest or negligible, however. Neuregulin-1 protein was produced in reticulocyte lysate at yields of 19 pmol/mL (similar to 500 ng/mL); furthermore, it was potent at phosphorylating ErbB4 receptor and able to bind to heparin sulfate. These results demonstrate that the reticulocyte lysate translation system produces active neurotrophic factors in vitro and is useful for radiolabeling or preliminary assessment of novel neurotrophic factors and their variants. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

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  • Activation of mammalian target of rapamycin signaling in spatial learning 査読

    Sihua Qi, Makoto Mizuno, Kazuyoshi Yonezawa, Hiroyuki Nawa, Nobuyuki Takei

    NEUROSCIENCE RESEARCH   68 ( 2 )   88 - 93   2010年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Novel protein synthesis is an essential element of various learning paradigms. Although pharmacological and genetic strategies have indicated the importance of translational activation in learning, the specific signaling pathways that are activated in the brain remain unclear. Here, we show that mammalian target of rapamycin (mTOR), a key serine/threonine protein kinase in translational control, is activated in hippocampus of the learning rat as revealed by in vitro kinase assay, Western blotting and immunohistochemistry. The substrates of mTOR, eukaryotic initiation factor 4E-binding protein (4EBP) and p70S6 kinase (p70S6K) are phosphorylated, and total protein synthesis is enhanced, in the learning hippocampus. Furthermore, the inhibition of mTOR by chronic infusion of rapamycin, a specific inhibitor of mTOR, into the ventricle retards the establishment of spatial learning. Thus, mTOR signaling is activated during learning, enhances translation, and plays a crucial role in the spatial learning. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/j.neures.2010.06.008

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  • Downregulation of NF-κB signaling by mutant huntingtin proteins induces oxidative stress and cell death

    Sami Reijonen, Jyrki P. Kukkonen, Alise Hyrskyluoto, Jenny Kivinen, Minna Kairisalo, Nobuyuki Takei, Dan Lindholm, Laura Korhonen

    Cellular and Molecular Life Sciences   67 ( 11 )   1929 - 1941   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Accumulation of abnormal proteins and endoplasmic reticulum stress accompany neurodegenerative diseases including Huntington's disease. We show that the expression of mutant huntingtin proteins with extended polyglutamine repeats differentially affected endoplasmic reticulum signaling cascades linked to the inositol-requiring enzyme-1 (IRE1) pathway. Thus, the p38 and c-Jun N-terminal kinase pathways were activated, while the levels of the nuclear factor-κB-p65 (NF-κB-p65) protein decreased. Downregulation of NF-κB signaling was linked to decreased antioxidant levels, increased oxidative stress, and enhanced cell death. Concomitantly, calpain was activated, and treatment with calpain inhibitors restored NF-κB-p65 levels and increased cell viability. The calpain regulator, calpastatin, was low in cells expressing mutant huntingtin, and overexpression of calpastatin counteracted the deleterious effects caused by N-terminal mutant huntingtin proteins. These results show that calpastatin and an altered NF-κB-p65 signaling are crucial factors involved in oxidative stress and cell death mediated by mutant huntingtin proteins. © 2010 Springer Basel AG.

    DOI: 10.1007/s00018-010-0305-y

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  • Cyclooxygenase-2 plays a critical role in retinal ganglion cell death after transient ischemia: Real-time monitoring of RGC survival using Thy-1-EGFP transgenic mice 査読

    Yasuhiro Sakai, Takayuki Tanaka, Masaaki Seki, Shinya Okuyama, Takeo Fukuchi, Kanato Yamagata, Nobuyuki Takei, Hiroyuki Nawa, Haruki Abe

    NEUROSCIENCE RESEARCH   65 ( 4 )   319 - 325   2009年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    The exact role of cyclooxygenase-2 (COX-2) in neurodegeneration of retinal ganglion cells (RGCs) in vivo following ischemia-reperfusion injury of the retina was unknown. We made transgenic mice in which the Thy-1.2 promoter drives the expression of EGFP cDNA (Thy-1-EGFP) in RGCs to monitor RGC survival and death in retinal whole mount preparations and in live animals. We show that celecoxib, a selective COX-2 inhibitor, blocks RGC death after ischemic injury. Furthermore, in COX-2 knockout (COX-2(-/-)) mice, RGCs are resistant to ischemia-reperfusion injury. Finally, we performed time-lapse monitoring of RGC death after ischemia in Thy-1-EGFP; COX-2(-/-) mice. Our data show that COX-2 plays a crucial role in ischemia-reperfusion injury-induced RGC death. Inhibition of COX-2 activity may therefore be an effective therapy for neurodegenerative diseases of the retina and optic nerve. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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  • Brain-derived Neurotrophic Factor Enhances the Basal Rate of Protein Synthesis by Increasing Active Eukaryotic Elongation Factor 2 Levels and Promoting Translation Elongation in Cortical Neurons 査読

    Nobuyuki Takei, Mihoko Kawamura, Yuta Ishizuka, Naomasa Kakiya, Naoko Inamura, Hisaaki Namba, Hiroyuki Nawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 39 )   26340 - 26348   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The constitutive and activity-dependent components of protein synthesis are both critical for neural function. Although the mechanisms controlling extracellularly induced protein synthesis are becoming clear, less is understood about the molecular networks that regulate the basal translation rate. Here we describe the effects of chronic treatment with various neurotrophic factors and cytokines on the basal rate of protein synthesis in primary cortical neurons. Among the examined factors, brain-derived neurotrophic factor (BDNF) showed the strongest effect. The rate of protein synthesis increased in the cortical tissues of BDNF transgenic mice, whereas it decreased in BDNF knock-out mice. BDNF specifically increased the level of the active, unphosphorylated form of eukaryotic elongation factor 2 (eEF2). The levels of active eEF2 increased and decreased in BDNF transgenic and BDNF knock-out mice, respectively. BDNF decreased kinase activity and increased phosphatase activity against eEF2 in vitro. Additionally, BDNF shortened the ribosomal transit time, an index of translation elongation. In agreement with these results, overexpression of eEF2 enhanced protein synthesis. Taken together, our results demonstrate that the increased level of active eEF2 induced by chronic BDNF stimulation enhances translational elongation processes and increases the total rate of protein synthesis in neurons.

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  • Leucine induces phosphorylation and activation of p70S6K in cortical neurons via the system L amino acid transporter 査読

    Yuta Ishizuka, Naomasa Kakiya, Hiroyuki Nawa, Nobuyuki Takei

    JOURNAL OF NEUROCHEMISTRY   106 ( 2 )   934 - 942   2008年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    p70S6 kinase is a multipotent kinase that phosphorylates substrates in response to extracellular stimuli. This kinase activity inhibits apoptosis, regulates cell size and controls translation. In the CNS, p70S6K also participates in synaptic plasticity. In this study, we report that leucine, a branched-chain amino acid, induces phosphorylation and activation of p70S6 kinase in cortical neurons. Leucine also induces phosphorylation of S6 protein, a substrate of p70S6K. These effects of leucine are completely inhibited by rapamycin, consistent with mammalian target of rapamycin mediating p70S6 phosphorylation. Finally, we demonstrate that the action of leucine on cortical neurons is mediated by the system L amino acid transporter. Neurons express components of system L amino acid transporter LAT1, LAT2, and CD98. Leucine uptake and its effect on p70S6 kinase are both inhibited by a specific inhibitor of system L amino acid transporter. We propose that leucine plays important roles in regulating signaling by p70S6 kinase by acting as an intercellular communicator in the CNS.

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  • The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia

    M. Mizuno, H. Kawamura, N. Takei, H. Nawa

    JOURNAL OF NEURAL TRANSMISSION   115 ( 3 )   521 - 530   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER WIEN  

    Abnormality in cytokine signaling is implicated in the neuropathology of schizophrenia. Previously, we established an animal model for schizophrenia by administering epidermal growth factor (EGF) to neonatal rats. Here we investigated effects of the anthraquinone derivatives emodin (3-methyl-1,6,8-trihydroxyanthraquinone) and sennoside (bis-[D-glucopyranosyl-oxy]-tetrahydro-4,4'-dihydroxy-dioxo[bianthracene]-2,2'-dicarboxylic acid) on behaviors of this model and EGF signaling. Subchronic oral administration of emodin (50 mg/kg) suppressed acoustic startle responses and abolished prepulse inhibition (PPI) deficits in this rodent model. ANCOVA revealed that emodin had distinct effects on PPI and startle responses. In contrast, sennoside (50 mg/kg) had no effects. Emodin attenuated weight gain initially during treatment but had no apparent effect on weight gain and locomotor activity thereafter. Application of emodin to neocortical cultures attenuated the phosphorylation of ErbB1 and ErbB2. We conclude that emodin can both attenuate EGF receptor signaling and ameliorate behavioral deficits. Therefore, emodin might be a novel class of a pro-drug for anti-psychotic medication.

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  • Neonatal exposure to epidermal growth factor induces dopamine D-2-like receptor supersensitivity in adult sensorimotor gating

    Hidekazu Sotoyama, Hisaaki Namba, Nobuyuki Takei, Hiroyuki Nawa

    PSYCHOPHARMACOLOGY   191 ( 3 )   783 - 792   2007年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Rational Abnormality in the neurotrophic factor for dopamine neurons, epidermal growth factor (EGF), is associated with schizophrenia. Thus, rats treated with EGF as neonates are used as a putative animal model for schizophrenia showing impaired prepulse inhibition (PPI) and other cognitive deficits in the adult stage.
    Objectives To elucidate the abnormal behavioral traits of this animal model, the EGF effects on the dopaminergic system were analyzed pharmacologically and biochemically at the adult stage.
    Results We examined the effects of subthreshold doses of dopamine agonists on PPI in this model. A non-selective dopamine agonist, apomorphine (0.1 mg/kg), decreased PPI in EGF-treated rats, but not in controls. Further, a D-2-like receptor agonist, quinpirole (0.01 and 0.03 mg/kg), similarly decreased PPI in EGF-treated rats but had no effect in the control animals. In contrast, a D-1-like receptor agonist, SKF38393 (3 and 10 mg/kg), had no effect on PPI in both groups. To explore the molecular mechanism underlying the change in sensorimotor gating, we assessed D-1 and D-2 receptors expression in the prefrontal cortex, striatum and hippocampus and their downstream signaling. Although there were no significant differences in basal receptor levels, quinpirole administration significantly enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in the striatum of EGF-treated rats.
    Conclusion These results suggest that circulating EGF in the early development substantially influences D-2 receptor-dependent regulation of sensorimotor gating.

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  • In vivo administration of epidermal growth factor and its homologue attenuates developmental maturation of functional excitatory synapses in cortical GABAergic neurons

    Tadasato Nagano, Hisaaki Namba, Yuichi Abe, Hiroyuki Aoki, Nobuyuki Takei

    EUROPEAN JOURNAL OF NEUROSCIENCE   25 ( 2 )   380 - 390   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    The ErbB1 ligand family includes epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha), heparin-binding EGF-like growth factor, amphiregulin and betacellulin. Previously, we demonstrated that TGFa decreases alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in cultured neocorticaly gamma-aminobutyric acid (GABA) neurons. In the present study, we examined in vivo effects of EGF and TGF alpha in the mouse neocortex using electrophysiological and biochemical techniques. In mouse neonates, subcutaneously administered EGF penetrated the blood-brain barrier and activated ErbB1 in the neocortex. Daily administration of EGF or TGF alpha attenuates developmental increases in expression of the AMPA receptor subunits (GluR1 and GluR2/3) in the neocortex of postnatal mice. Immunolhistochemistry revealed that the reduction in AMPA receptor expression was significant in the GABAergic neurons, especially those positive for parvalbumin. Using cortical slices prepared from EGF-treated mice, we recorded miniature excitatory postsynaptic currents (mEPSCs) in both GABAergic and pyramidal neurons. Subchronic treatment with EGF decreased the amplitude and frequency of mEPSCs in GABAergic neurons, but its effects were negligible on pyramidal neurons. We conclude that EGF or other ErbB1 ligand(s) attenuates a developmental increase in AMPA receptor expression and function in cortical GABAergic neurons.

    DOI: 10.1111/j.1460-9568.2007.05297.x

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  • Possible involvement of BDNF release in long-lasting synapse formation induced by repetitive PKA activation

    Naoko Taniguchi, Yo Shinoda, Nobuyuki Takei, Hiroyuki Nawa, Akihiko Ogura, Keiko Tominaga-Yoshino

    NEUROSCIENCE LETTERS   406 ( 1-2 )   38 - 42   2006年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    For the analysis of the cellular mechanism underlying long-term synaptic plasticity, a model system that allows long-lasting pursuit is required. Previously we reported that, in hippocampal neurons under dissociated cell culture conditions, repeated (but not a single) transient activation of protein kinase A (PKA) led to an increase in the number of synapses that lasted > 3 weeks, and hence we proposed that this phenomenon should serve as an appropriate model system. Here we report that repeated pulsatile application of brain-derived neurotrophic factor (BDNF) leads to persistent synapse formation equivalent to that after the repeated transient activation of PKA. A BDNF-scavenging substance applied concomitantly with PKA activation abolished the synapse formation. The release of BDNF upon PKA activation was confirmed by phosphorylation of TrkB. These results indicate that the release of BDNF is involved in the putative signaling cascade connecting PKA activation and synapse formation. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2006.06.071

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  • Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons

    Yuji Shishido, Takayuki Tanaka, Ying-Shan Piao, Kazuaki Araki, Nobuyuki Takei, Shigeki Higashiyama, Hiroyuki Nawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   348 ( 3 )   963 - 970   2006年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is initially produced as a membrane-anchored precursor (proHB-EGF) and subsequently liberated from the cell membrane through ectodomain shedding. Here, we characterized the molecular regulation of pro-HB-EGF shedding in the central nervous system. Cultured neocortical or hippocampal neurons were transfected with the alkaline-phosphatase-tagged pro-HB-EGF gene and stimulated with various neurotransmitters. Both kainate and N-methlyl-D-aspartate, but not agonists for metabotropic glutamate receptors, promoted pro-HB-EGF shedding and HB-EGF release, which were attenuated by an exocytosis blocker and metalloproteinase inhibitors. In the brain of transgenic mice over-expressing human pro-HB-EGF, kainate-induced seizure activity decreased content of pro-HB-EGF-like immuno reactivity and conversely increased levels of soluble HB-EGF. There was concomitant phosphorylation of EGF receptors (ErbB1) following seizures, suggesting that seizure activities liberated HB-EGF and activated neighboring ErbB1 receptors. Therefore, we propose that glutamatergic neurotransmission in the central nervous system plays a crucial role in regulating ectodomain shedding of pro-HB-EGF. (c) 2006 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2006.07.129

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  • Transforming growth factor alpha attenuates the functional expression of AMPA receptors in cortical GABAergic neurons

    H Namba, T Nagano, Y Iwakura, H Xiong, H Jourdi, N Takei, H Nawa

    MOLECULAR AND CELLULAR NEUROSCIENCE   31 ( 4 )   628 - 641   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    In the developing neocortex, brain-derived neurotrophic factor (BDNF) exerts a trophic activity to increase the expression and channel activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunits. Here, we demonstrate that the epidermal growth factor (EGF) receptor (ErbB1) ligands exert the opposite biological activity in cultured neocortical neurons. Subchronic stimulation of ErbB1 with transforming growth factor alpha (TGF alpha) EGF, or heparin-binding EGF (HB-EGF) down-regulated protein expression of the GluR1 AMPA receptor subunit in cultured neocortical neurons. In agreement, TGF alpha treatment decreased the B-max of [H-3] AMPA binding and GluR1 mRNA levels. Immunocytochemistry revealed that the decrease in GluR1 was most pronounced in multipolar GABAergic neurons. To examine the physiological consequences, we recorded AMPA-evoked currents as well as miniature excitatory postsynaptic currents in morphologically identified putative GABAergic neurons in culture. Suhchronic TGF alpha treatment decreased AMPA-triggered currents as well as the amplitude and frequency of miniature excitatory postsynaptic currents. An ErbB1 tyrosine kinase inhibitor, PD153035, inhibited the TGF alpha effect. Moreover, TGF alpha counteracted the neurotrophic activity of BDNF on AMPA receptor expression. Co-application of TGF alpha with BDNF blocked the BDNF-triggered up-regulation of AMPA receptor expression and currents. These observations reveal a negative regulatory activity of the ErbB1 ligand, TGF alpha, which reduces the input sensitivity of cortical GABAergic neurons to attenuate their inhibitory function. (c) 2005 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.mcn.2005.12.002

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  • Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: Implications for mammalian target of rapamycin signaling

    N Inamura, H Nawa, N Takei

    JOURNAL OF NEUROCHEMISTRY   95 ( 5 )   1438 - 1445   2005年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    The effects and signaling mechanisms of brain-derived neurotrophic factor (BDNF) on translation elongation were investigated in cortical neurons. BDNF increased the elongation rate approximately twofold, as determined by measuring the ribosomal transit time. BDNF-accelerated elongation was inhibited by rapamycin, implicating the mammalian target of rapamycin (mTOR). To explore the mechanisms underlying these effects, we examined the protein phosphorylation cascades that lead to the activation of translation elongation in neurons. BDNF increased eukaryote elongation factor 1A (eEF1A) phosphorylation and decreased eEF2 phosphorylation. Whereas eEF2 phosphorylation levels altered by BDNF were inhibited by rapamycin, eEF1A phosphorylation was not affected by rapamycin or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. BDNF induced phosphorylation of eEF2 kinase (Ser366), as well as decreased its kinase activity. All these events were inhibited by rapamycin. Furthermore, mTOR siRNA, which reduced mTOR levels up to 50%, inhibited the BDNF-induced enhancement in elongation rate and decrease in eEF2 phosphorylation. These results strongly suggest that BDNF enhances translation elongation through the activation of the mTOR-eEF2 pathway.

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  • Differential distributions of peptides in the epidermal growth factor family and phosphorylation of ErbB1 receptor in adult rat brain

    YS Piao, Y Iwakura, N Takei, H Nawa

    NEUROSCIENCE LETTERS   390 ( 1 )   21 - 24   2005年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Using two-site enzyme immunoassays, we measured protein levels of epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), and heparin-binding epidermal growth factor (HB-EGF) in adult rat brain, and compared them with the phosphorylation levels of their receptor (ErbB 1). There were significant variations in the brain distributions of each ErbB I ligand. Among these ErbB1 ligands, HB-EGF protein levels were higher than those of TGF alpha and those of EGF were the lowest. TGF alpha protein was relatively enriched in the midbrain regions, while HB-EGF levels were most abundant in the cerebellum. Protein distributions of the EGF family members were discordant with previously reported mRNA distributions. In addition, there was significant basal ErbB I phosphorylation detected with the largest amount of activation in the midbrain. These observations suggest that the activation of brain ErbB1 involves post-translational regulation of multiple EGF family members in a region-specific manner. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

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  • Distinct influences of neonatal epidermal growth factor challenge on adult neurobehavioral traits in four mouse strains

    M Tohmi, N Tsuda, M Mizuno, N Takei, PW Frankland, H Nawa

    BEHAVIOR GENETICS   35 ( 5 )   615 - 629   2005年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Epidermal growth factor (EGF) receptor (ErbB1) signals regulate dopaminergic development and function and are implicated in schizophrenia. We evaluated genetic effects on neurobehavioral changes induced by neonatal EGF administration, using four mouse strains. Subcutaneous EGF administration increased phosphorylation of brain ErbB1 in all strains, although DBA/2 and C57BL/6 mice had lower basal phosphorylation. Neonatal EGF treatment differentially influenced physical and behavioral/cognitive development, depending on mouse strain. Prepulse inhibition was decreased in DBA/2 and C57BL/6 mice but not C3H/He and ddY mice. Locomotor activity was accelerated in DBA/2 mice, but reduced in ddY mice. EGF treatment enhanced fear-learning performance with a tone cue in DBA/2 mice, but decreased performance with tone and context cues in C3H/He and ddY mice, respectively. The strain-dependent behavioral sensitivity was correlated with basal ErbB1 phosphorylation. Genetic components regulating brain ErbB1 signaling strongly influence the direction and strength of behavioral responses stemming from the neonatal neurotrophic perturbation.

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  • Muller cells as a source of brain-derived neurotrophic factor in the retina: Noradrenaline upregulates brain-derived neurotrophic factor levels in cultured rat Muller cells

    M Seki, T Tanaka, Y Sakai, T Fukuchi, H Abe, H Nawa, N Takei

    NEUROCHEMICAL RESEARCH   30 ( 9 )   1163 - 1170   2005年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    Muller cells, the predominant glial cells in the retina, are thought to play important roles in the survival of retinal neurons. Previous studies have demonstrated that Muller cells express brain-derived neurotrophic factor (BDNF), which has a pronounced neurotrophic effect on retinal ganglion cells. In this study, we investigated whether Muller cells express and release BDNF in culture. Reverse transcriptase-PCR, immunocytochemistry and Western blotting revealed that Muller cells produce BDNF mRNA and protein. Using the enzyme-linked immunosorbant assay, BDNF protein levels in Muller cells and their conditioned medium were quantified, demonstrating that Muller cells produce and release high levels of BDNF. Noradrenaline administration caused an upregulation of BDNF mRNA and protein expression by cultured Muller cells. These results suggest that Muller cells may act as an endogenous source of BDNF in the retina. Furthermore, induction of BDNF expression by adrenergic agonists may provide a therapeutic approach to retinal neurodegenerative disorders.

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  • Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson's disease and its model: neurotrophic implication in nigrostriatal neurons

    Y Iwakura, YS Piao, M Mizuno, N Takei, A Kakita, H Takahashi, H Nawa

    JOURNAL OF NEUROCHEMISTRY   93 ( 4 )   974 - 983   2005年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING LTD  

    Epidermal growth factor (EGF) is a member of a structurally related family containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGF alpha) that exerts neurotrophic activity on midbrain dopaminergic neurons. To examine neurotrophic abnormality in Parkinson's disease (PD), we measured the protein content of EGF, TGF alpha, and HB-EGF in post-mortem brains of patients with Parkinson's disease and age-matched control subjects. Protein levels of EGF and tyrosine hydroxylase were decreased in the prefrontal cortex and the striatum of patients. In contrast, HB-EGF and TGF alpha levels were not significantly altered in either region. The expression of EGF receptors (ErbB1 and ErbB2, but not ErbB3 or ErbB4) was down-regulated significantly in the same forebrain regions. The same phenomenon was mimicked in rats by dopaminergic lesions induced by nigral 6-hydroxydopamine infusion. EGF and ErbB1 levels in the striatum of the PD model were markedly reduced on the lesioned side, compared with the control hemisphere. Subchronic supplement of EGF in the striatum of the PD model locally prevented the dopaminergic neurodegeration as measured by tyrosine hydroxylase immunoreactivity. These findings suggest that the neurotrophic activity of EGF is maintained by afferent signals of midbrain dopaminergic neurons and is impaired in patients with Parkinson's disease.

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  • ErbB1 receptor ligands attenuate the expression of synaptic scaffolding proteins, GRIP1 and SAP97, in developing neocortex

    D Yokomaku, H Jourdi, A Kakita, T Nagano, H Takahashi, N Takei, H Nawa

    NEUROSCIENCE   136 ( 4 )   1037 - 1047   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Scaffolding proteins containing postsynaptic density-95/discs large/zone occludens-1 (PDZ) domains interact with synaptic receptors and cytoskeletal components and are therefore implicated in synaptic development and plasticity. Little is known, however, about what regulates the expression of PDZ proteins and how the levels of these proteins influence synaptic development. Here, we show that ligands for epidermal growth factor receptors (ErbB1) decrease a particular set of PDZ proteins and negatively influence synaptic formation or maturation. In short-term neocortical cultures, concentrations of epidermal growth factor and amphiregulin (2-9 pM) decreased the expression of glutamate receptor interacting protein 1 (GRIP1) and synapse-associated protein 97 kDa (SAP97) without affecting postsynaptic density-95 (PSD-95) levels and glial proliferation. In long-term cultures, epidermal growth factor treatment resulted in a decrease in the frequency of pan-PDZ-immunoreactive aggregates on dendritic processes. A similar activity on the same PDZ proteins was observed in the developing neocortex following epidermal growth factor administration to rat neonates. Immunoblotting revealed that administered epidermal growth factor from the periphery activated brain ErbB1 receptors and decreased GRIP1 and SAP97 protein levels in the neocortex. Laser-confocal imaging indicated that epidermal growth factor administration suppressed the formation of pan-PDZ-immunoreactive puncta and dispersed those structures in vivo as well. These findings revealed a novel negative activity of ErbB1 receptor ligands that attenuates the expression of the PDZ proteins and inhibits postsynaptic maturation in developing neocortex. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.

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  • ニュートロフィンによる脳機能の調節 査読

    武井延之, 那波宏之

    生化学   76 ( 2 )   111 - 123   2004年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites.

    Takei Nobuyuki, Inamura Naoko, Kawamura Mihoko, Namba Hisaaki, Hara Kenta, Yonezawa Kazuyoshi, Nawa Hiroyuki

    J Neurosci   24 ( 44 )   9760 - 9769   2004年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In neurons, perisynaptic or dendritic translation is implicated in synapse-wide alterations of function and morphology triggered by neural activity. The molecular mechanisms controlling local translation activation, however, have yet to be elucidated. Here, we show that local protein synthesis and translational activation in neuronal dendrites are upregulated by brain-derived neurotrophic factor (BDNF) in a rapamycin and small interfering RNA specific for mammalian target of rapamycin (mTOR)-sensitive manner. In parallel, BDNF induced the phosphorylation of tuberin and the activation of mTOR in dendrites and the synaptoneurosome fraction. mTOR activation stimulated translation initiation processes involving both eIF4E/4E-binding protein (4EBP) and p70S6 kinase/ribosomal S6 protein. BDNF induced phosphorylation of 4EBP in isolated dendrites. Moreover, local puff application of BDNF to dendrites triggered S6 phosphorylation in a restricted area. Taken together, these data indicate that mTOR-dependent translation activation is essential for the upregulation of local protein synthesis in neuronal dendrites.

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  • Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites 査読

    N Takei, N Inamura, M Kawamura, H Namba, K Hara, K Yonezawa, H Nawa

    JOURNAL OF NEUROSCIENCE   24 ( 44 )   9760 - 9769   2004年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    In neurons, perisynaptic or dendritic translation is implicated in synapse-wide alterations of function and morphology triggered by neural activity. The molecular mechanisms controlling local translation activation, however, have yet to be elucidated. Here, we show that local protein synthesis and translational activation in neuronal dendrites are upregulated by brain-derived neurotrophic factor (BDNF) in a rapamycin and small interfering RNA specific for mammalian target of rapamycin (mTOR)-sensitive manner. In parallel, BDNF induced the phosphorylation of tuberin and the activation of mTOR in dendrites and the synaptoneurosome fraction. mTOR activation stimulated translation initiation processes involving both eIF4E/4E-binding protein (4EBP) and p70S6 kinase/ribosomal S6 protein. BDNF induced phosphorylation of 4EBP in isolated dendrites. Moreover, local puff application of BDNF to dendrites triggered S6 phosphorylation in a restricted area. Taken together, these data indicate that mTOR-dependent translation activation is essential for the upregulation of local protein synthesis in neuronal dendrites.

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  • Quantitative analyses of mRNA and protein levels of neurotrophin-3 in the rat retina during postnatal development and aging

    M Seki, T Fukuchi, T Tanaka, H Nawa, N Takei, H Abe

    JAPANESE JOURNAL OF OPHTHALMOLOGY   48 ( 5 )   460 - 464   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Purpose: In this study, we sought to elucidate changes in the levels of neurotrophin-3 (NT-3) in the rat retina throughout postnatal development and aging.
    Methods: We demonstrated NT-3 localization in the retina by immunohistochemistry. Protein and mRNA levels of NT-3 were quantified by enzyme-linked immunosorbant assay and semiquantitative reverse transcriptase-polymerase chain reaction, respectively. NT-3 protein levels were assayed in the various regions of the central nervous system. Age-associated changes in protein and mRNA levels of NT-3 in the retinas were assessed.
    Results: NT-3-immunoreactivity localized in the ganglion cell layer, inner nuclear layer, and outer nuclear layer. NT-3 content in the retina was relatively high in the examined regions of the central nervous system. Retinal NT-3 protein levels decreased after eye opening, whereas mRNA levels were constant. Both mRNA and protein levels of NT-3 in the retinas of aged animals remained constant.
    Conclusions: Our observations suggest that NT-3 regulation in the retina is independent of increasing visual stimuli after eye opening. Stable expression of NT-3 in the adult retina suggests a possible role in the maintenance of the retinal environment throughout later life. (C) Japanese Ophthalmological Society 2004.

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  • Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats - Therapeutic potential of brain-derived neurotrophic factor for dopaminergic amacrine cells

    M Seki, T Tanaka, H Nawa, T Usui, T Fukuchi, K Ikeda, H Abe, N Takei

    DIABETES   53 ( 9 )   2412 - 2419   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER DIABETES ASSOC  

    Although neurotrophins have been assessed as candidate therapeutic agents for neural complications of diabetes, their involvement in diabetic retinopathy has not been fully characterized. We found that the protein and mRNA levels of brain-derived neurotrophic factor (BDNF) in streptozotocin-induced diabetic rat retinas were reduced to 49% (P<0.005) and 74% (P<0.05), respectively, of those of normal control animals. In addition, dopaminergic amacrine cells appeared to be degenerating in the diabetic rat retinas, as revealed by tyrosine hydroxylase (TH) immunoreactivity. Overall TH protein levels in the retina were decreased to one-half that of controls (P<0.01), reflecting reductions in the density of dopaminergic amacrine cells and the intensity of TH immunoreactivity within them. To confirm the neuropathological implications of BDNF reduction, we administered BDNF protein into the vitreous cavities of diabetic rats. Intraocular administration of BDNF rescued dopaminergic amacrine cells from neurodegeneration and counteracted the downregulation of TH expression, demonstrating its therapeutic potential. These findings suggest that the early retinal neuropathy of diabetes involves the reduced expression of BDNF and can be ameliorated by an exogenous supply of this neurotrophin.

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  • Regulated release of EGF-like molecules from rat striatal culture: Their trophic activity on midbrain dopaminergic neurons. 査読

    Y Iwakura, YS Piao, N Takei, H Nawa

    FASEB JOURNAL   18 ( 8 )   C255 - C255   2004年5月

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    記述言語:英語   出版者・発行元:FEDERATION AMER SOC EXP BIOL  

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  • Modulation of brain function by neurotrophins 査読

    N Takei, H Nawa

    SEIKAGAKU   76 ( 2 )   111 - 123   2004年2月

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    記述言語:日本語   出版者・発行元:JAPANESE BIOCHEMICAL SOC  

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  • Characterization of novel bicistronic Sindbis virus vectors, SinEGdsp and SinIRES-EG, in cultured neurons 査読

    Kawamura M, Namba H, Otsu Y, Hayashi Y, Takei N, Nawa H

    Recent Res. Devel. Neurochem.   6   105 - 120   2003年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptor-associated PDZ proteins in developing cortical neurons

    H Jourdi, Y Iwakura, M Narisawa-Saito, K Ibaraki, HB Xiong, M Watanabe, Y Hayashi, N Takei, H Nawa

    DEVELOPMENTAL BIOLOGY   263 ( 2 )   216 - 230   2003年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Postsynaptic molecules with PDZ domains (PDZ proteins) interact with various glutamate receptors and regulate their subcellular trafficking and stability. In rat neocortical development, the protein expression of AMPA-type glutamate receptor GluR1 lagged behind its mRNA expression and rather paralleled an increase in PDZ protein levels. One of the neurotrophins, brain-derived neurotrophic factor (BDNF), appeared to contribute to this process, regulating the PDZ protein expression. In neocortical cultures, BDNF treatment upregulated SAP97, GRIP1, and Pick1 PDZ proteins. Conversely, BDNF gene targeting downregulated these same PDZ molecules. The BDNF-triggered increases in PDZ proteins resulted in the elevation of their total association with the AMPA receptors GluR1 and GluR2/3, which led to the increase in AMPA receptor proteins. When Sindbis viruses carrying GluR1 or GluR2 C-terminal decoys disrupted their interactions, GluR2 C-terminal decoys inhibited both BDNF-triggered GluR1 and GluR2/3 increases, whereas GluR1 C-terminal decoys blocked only the BDNF-triggered GluR1 increase. In agreement, coexpression of SAP97 and GluR1 in nonneuronal HEK293 cells increased both proteins compared with their single transfection, implying mutual stabilization. This work reveals a novel function of BDNF in postsynaptic development by regulating the PDZ protein expression. (C) 2003 Elsevier Inc. All rights reserved.

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  • Brain-derived neurotrophic factor upregulates and maintains AMPA receptor currents in neocortical GABAergic neurons

    T Nagano, Y Yanagawa, K Obata, M Narisawa-Saito, H Namba, Y Otsu, N Takei, H Nawa

    MOLECULAR AND CELLULAR NEUROSCIENCE   24 ( 2 )   340 - 356   2003年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors is implicated in synaptic plasticity. Although we have found that brain-derived neurotrophic factor (BDNF) triggers surface translocation of AMPA receptor proteins, the physiological significance of the BDNF effect remained to be determined. The present immunohistochemical studies revealed that cortical GABAergic neurons exhibited the most striking response to BDNF. Accordingly, we monitored AMPA-triggered currents through GABAergic neurons: Chronic BDNF treatment increased the AMPA-triggered currents but not NMDA-triggered currents in culture. In parallel, the amplitude, but not frequency, of spontaneous miniature excitatory postsynaptic currents (mEPSCs) was elevated in GABAergic neurons. In agreement, BDNF enhanced GABA release triggered by AMPA compared to the amount triggered by high potassium. Conversely. there was a significant decrease in the mEPSC amplitude of GABAergic neurons in heterozygous BDNF-knockout trice. These findings indicate that the neurotrophin enhances the input sensitivity of GABAergic neurons to facilitate their inhibitory function in the neocortex. (C) 2003 Elsevier Science (USA). All rights reserved.

    DOI: 10.1016/S1044-7431(03)00172-6

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  • BDNF is upregulated by postnatal development and visual experience: Quantitative and immunohistochemical analyses of BDNF in the rat retina

    M Seki, H Nawa, T Fukuchi, H Abe, N Takei

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   44 ( 7 )   3211 - 3218   2003年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

    PURPOSE. This study sought to elucidate changes in the levels and distribution of brain-derived neurotrophic factor (BDNF) in the retina throughout aging and depending on visual experience.
    METHODS. Protein and mRNA levels of BDNF were quantified by enzyme-linked inummosorbent assay (ELISA) and semiquantitative reverse transcription-polymerase chain reaction (RTPCR), respectively. Levels were assayed in the retinas of rats on postnatal day (P)2, P7, and P14 (approximate time of eye opening) and at 1 month (M), 3M, 8M, and 18M of age. Changes in BDNF expression and localization in the retina were assessed by immunohistochemistry. The effect of monocular deprivation during infancy on retinal BDNF expression was also examined, by ELISA and immunohistochemistry.
    RESULTS. Both protein and mRNA levels of BDNF in the rat retina increased after P14. Immunohistochemical analyses revealed that the increase in BDNF protein levels occurred in retinal ganglion cells (RGCs) between P14 and 1M. BDNF immunoreactivity in Muller cell processes was observed in the inner nuclear layer at 1M, but not at P14. The levels of BDNF protein in the retinas of visually deprived eyes were lower than those of control eyes, as quantified by ELISA. Immunohistochemistry showed that BDNF immunoreactivity in RGCs was diminished by visual deprivation, whereas Muller cells were unaffected.
    CONCLUSIONS. These observations indicate that BDNF expression in RGCs is upregulated in an activity-dependent manner, whereas that in Muller cells is regulated only by development.

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  • Developmental changes of eukaryotic initiation factor 2B subunits in rat hippocampus

    N Inamura, H Nawa, N Takei

    NEUROSCIENCE LETTERS   346 ( 1-2 )   117 - 119   2003年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Regulated protein synthesis is critical for neural development, such as the formation of synapses and neural circuits and the modulation of synaptic plasticity. Protein synthesis is controlled by translation factors, including initiation, elongation and release factors. Here we investigated the developmental changes of eukaryotic initiation factor 213 (eIF2B) subunits in rat hippocampus. The eIF2B beta, gamma, delta and epsilon subunit protein levels were maximal at embryonic day 18 and then decreased during development. Aged hippocampus contained only trace amounts of these subunits. The finding that eIF2B subunit levels are high in developing hippocampus suggests that regulated protein synthesis is active in young, highly plastic brain. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

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  • A novel rat orthologue and homologue for the Drosophila crooked neck gene in neural stem cells and their immediate descendants

    N Amada, T Tezuka, A Mayeda, K Araki, N Takei, K Todokoro, H Nawa

    JOURNAL OF BIOCHEMISTRY   133 ( 5 )   615 - 623   2003年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE BIOCHEMICAL SOC  

    The crooked neck (crn) gene of Drosophila melanogaster encodes a scaffold protein carrying multiple tetratricopeptide repeat (TPR) motifs, and its mutation results in a reduction in the number of neuroblasts and lethality during larval stages. Here, we isolated two structurally related genes from a rat embryonic brain cDNA library. One gene is the rat orthologue of crn, which encodes 690 amino acids including 16 copies of TPR. The other gene, ATH55, encodes an 855 amino acid protein including 21 TPR motifs, which presumably represents a rat crn homologue and an orthologue of human XAB2. Both genes are highly expressed in embryonic brain but their expressions decrease during development. ATH55-like immunoreactivity is present in the ventricular zone and newly formed cortical plate, while CRN-like immunoreactivity is more abundant in a younger ventricular zone. In agreement, both proteins were found to be enriched in cultured neural stem cells and to decrease in response to cell differentiation signals. As indicated for the yeast CRN-like protein, ATH55 and CRN immunoreactivities were both recovered in the nuclear fraction and detected in the splicing complex carrying pre-mRNA. These findings suggest that both TPR-motif-containing proteins are involved in RNA processing of mammalian neural stem cells and their immediate descendants.

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  • Cellular and subcellular distributions of translation initiation, elongation and release factors in rat hippocampus

    N Inamura, S Hoshino, T Uchiumi, H Nawa, N Takei

    MOLECULAR BRAIN RESEARCH   111 ( 1-2 )   165 - 174   2003年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Novel protein synthesis in the brain has been suggested to contribute to the formation of synapses and neural circuits during development and the modulation of long-term synaptic plasticity through life. However, cellular and subcellular distribution of neuronal translation machinery and regulator molecules has not yet been extensively characterized in rat brain. In this report, the distribution of translation factors in the developing hippocampus, a region which is highly plastic, was analyzed by immunohistochemistry and Western blotting. Western blot analysis revealed that the hippocampus expresses the factors in all three steps of translation, initiation factors, elongation factors and a release factor. Immunochemical studies of hippocampal slices and culture showed that all translation factors were observed not only in cell bodies but also in dendrites of hippocampal neurons. In addition, the levels of the individual translation factors differed between hippocampal subregions. The differential distribution of translation factors was also confirmed by Western blotting. These results suggest that regulated protein synthesis occurs in the hippocampus, with differences existing between different subregions such as CA1, CA3 and dentate gyrus. (C) 2003 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0169-328X(03)00027-5

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  • PACAP and NGF cooperatively enhance choline acetyltransferase activity in postnatal basal forebrain neurons by complementary induction of its different mRNA species

    A Yuhara, K Ishii, C Nishio, Y Abiru, M Yamada, H Nawa, H Hatanaka, N Takei

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   301 ( 2 )   344 - 349   2003年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Both nerve growth factor (NGF) and pituitary adenylate cyclase activating polypeptide (PACAP) have neurotrophic effects on basal forebrain cholinergic neurons. They promote differentiation, maturation, and survival of these cholinergic neurons in vivo and in vitro. Here we report on the cooperative effects of NGF and PACAP on postnatal, but not embryonic, cholinergic neurons cultured from rat basal forebrain. Combined treatment with NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and PACAP induced an additive increase in choline acetyltransferase (ChAT) activity. There were no cooperative effects on the number of cholinergic neurons, suggesting that ChAT mRNA expression had been induced in each cholinergic neuron. Further analysis revealed that NGF and PACAP led to complementary induction of different ChAT mRNA species, thus enhancing total ChAT mRNA expression. These results explain the cooperative neurotrophic action of NGF and PACAP on postnatal cholinergic neurons. (C) 2003 Elsevier Science (USA). All rights reserved.

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  • Transforming growth factor-alpha changes firing properties of developing neocortical gabaergic neurons by down-regulation of voltage-gated potassium currents

    H Namba, N Takei, H Nawa

    NEUROSCIENCE   122 ( 3 )   637 - 646   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Transforming growth factor-alpha (TGFalpha), a member of the epidermal growth factor family, has neurotrophic actions on postmitotic neurons. We examined the chronic effects of TGFalpha on the electrophysiological properties of one type of GABAergic neuron, identified by its bipolar morphology, in neocortical primary culture. Approximately 85% of the bipolar neurons were GABA-immunoreactive. In response to depolarizing current injection, the bipolar neurons usually showed tonic firing of action potential under control conditions. After treatment with TGFalpha (20 ng/ml) for 2 days, these neurons failed to generate trains of action potentials. Furthermore, the treatment altered the action potential waveforms of the bipolar neurons, including the duration and amplitude of the fast after-hyperpolarization, which implies a reduction in voltage-gated potassium currents. In contrast, TGFalpha did not affect the firing properties of pyramidal-shaped non-GABAergic neurons. Voltage-clamp recordings from the bipolar neurons indicated that chronic treatment with TGFalpha markedly decreased the current densities of slow delayed rectifier (I-K) and transient voltage-gated potassium currents, whereas the treatment had no effect on voltage-gated sodium current and fast delayed rectifier potassium current densities. Reverse transcription-polymerase chain reaction analysis of potassium channel mRNA in the bipolar neurons revealed that the reduction in the I-K current density was caused by Kv2.2 mRNA down-regulation. Thus, chronic treatment with TGFalpha down-regulated slow delayed rectifier and transient voltage-gated potassium currents, and in parallel, suppressed repetitive generation of action potentials in the cortical GABAergic neurons. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.

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  • Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation

    M Mizuno, K Yamada, N Takei, MH Tran, J He, A Nakajima, H Nawa, T Nabeshima

    MOLECULAR PSYCHIATRY   8 ( 2 )   217 - 224   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidlylinositol 3-kinase (P13-K) and Akt, a target of P13-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with P13-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/P13-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.

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  • Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity

    R Hashimoto, N Takei, K Shimazu, L Christ, B Lu, DM Chuang

    NEUROPHARMACOLOGY   43 ( 7 )   1173 - 1179   2002年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Mechanisms underlying the therapeutic effects of lithium for bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults in vitro and in vivo. This study was undertaken to investigate the role of the brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway in mediating neuroprotection of lithium against glutamate excitotoxicity in cortical neurons. Pretreatment with either lithium or BDNF protected rat cerebral cortical neurons from glutamate excitotoxicity. The duration of treatment required to elicit maximal neuroprotection by BDNF (1 day) was much shorter than that by lithium (6 days). K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody suppressed the neuroprotective effect of lithium. Treatment of cortical neurons with lithium increased the cellular BDNF content in 3 days and the phosphorylation of TrkB at Tyr490 in 5 days, suggesting that long-term lithium administration enhances BDNF expression/secretion, leading to the activation of TrkB receptor. Lithium failed to protect against glutamate excitotoxicity in cortical neurons derived from homozygous and heterozygous BDNF knockout mice, although lithium fully protected cortical neurons prepared from wild type mice littermates. Taken together, these data suggest that the BDNF/TrkB pathway plays an essential role in mediating the neuroprotective effect of lithium. Published by Elsevier Science Ltd.

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  • Brain-derived neurotrophic factor regulates surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors by enhancing the N-ethylmaleimide-sensitive factor/GluR2 interaction in developing neocortical neurons

    M Narisawa-Saito, Y Iwakura, M Kawamura, K Araki, S Kozaki, N Takei, H Nawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 43 )   40901 - 40910   2002年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    In hippocampal neurons, the exocytotic process of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors is known to depend on activation of N-methyl-D-aspartate channels and its resultant Ca2+ influx from extracellular spaces. Here we found that brain-derived neurotrophic factor (BDNF) induced a rapid surface translocation of AMPA receptors in an activity-independent manner in developing neocortical neurons. The receptor translocation became evident within hours as monitored by [H-3]AMPA binding and was resistant against ionotropic glutamate receptor antagonists as evidenced with surface biotinylation assay. This process required intracellular Ca2+ and was inhibited by the blockers of conventional exocytosis, brefeldin A, botulinuin toxin B, and N-ethylmaleimide. To explore the translocation mechanism of individual AMPA receptor subunits, we utilized the human embryonic kidney (HEK) 293 cells carrying the BDNF receptor TrkB. After the single transfection of GluR2 cDNA or GluR1 cDNA into HEK/TrkB cells, BDNF triggered the translocation of GluR2 but not that of GluR1. Subsequent mutation analysis of GluR2 carboxyl-terminal region indicated that the translocation of GluR2 subunit in HEK293 cells involved its N-ethylmaleimide-sensitive factor-binding domain but not its PDZ-interacting site. Following co-transfection of GluR1 and GluR2 cDNAs, solid phase cell sorting revealed that GluR1 subunits were also able to translocate to the cell surface in response to BDNF. An immunoprecipitation assay confirmed that BDNF stimulation can enhance the interaction of GluR2 with N-ethylmaleimide-sensitive factor. These results reveal a novel role of BDNF in regulating the surface expression of AMPA receptors through a GluR2-NSF interaction.

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  • Nerve growth factor induces systemic hyperalgesia after thoracic burn injury in the rat

    Masashi Ueda, Munetaka Hirose, Nobuyuki Takei, Takae Ibuki, Yoshihisa Naruse, Fumimasa Amaya, Yasuhiko Ibata, Masaki Tanaka

    Neuroscience Letters   328 ( 2 )   97 - 100   2002年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Acute burn injury is usually associated with pain in the injured and nearby areas. However, we have recently reported that a thoracic scald induces hindpaw hyperalgesia during the healing stage in rats. The present study investigated the cause of the remotely occurring hyperalgesia. Behavioral testing using the von Frey test revealed that rats developed hyperalgesia in the neck and flank as well as the hindpaw 2-3 weeks after injury. The concentration of nerve growth factor (NGF) in the skin of the chest increased markedly during the healing stage. Moreover, rats injected daily with anti-NGF serum after burn injury did not develop hyperalgesia, suggesting that increased NGF in the tissue of the healing skin is a key factor causing systemic hyperalgesia during the recovery stage. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0304-3940(02)00456-1

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  • Establishment of a novel enzyme-linked immunosorbant assay for Thy-1; quantitative assessment of neuronal degeneration

    M Seki, H Nawa, T Morioka, T Fukuchi, T Oite, H Abe, N Takei

    NEUROSCIENCE LETTERS   329 ( 2 )   185 - 188   2002年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    In the central nervous system (CNS), Thy-1 is expressed predominantly on neurons and serves as a specific marker for neurons. In the present study, we established a two-site enzyme-linked immunosorbant assay (ELISA) that detects trace amounts of Thy-1 protein. Recombinant Thy-1 protein expressed in Escherichia coli was purified and used as a standard. Of the regions of the nervous system examined, the highest Thy-1 concentration was found in the striatum followed by the hippocampus, neocortex, cerebellum, spinal cord, retina and optic nerve. We found that injection of a neurotoxin, N-methyl-D-aspartate, into the vitreous cavity reduced the Thy-1 level in the retina. Thy-1 ELISA will be useful for quantitative assessment of neurodegeneration in the CNS. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

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  • Nerve growth factor enhances neurotransmitter release from PC12 cells by increasing Ca2+-responsible secretory vesicles through the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

    S Amino, M Itakura, H Ohnishi, J Tsujimura, S Koizumi, N Takei, M Takahashi

    JOURNAL OF BIOCHEMISTRY   131 ( 6 )   887 - 894   2002年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE BIOCHEMICAL SOC  

    Neurotrophins play important roles in the differentiation and survival of neurons during development, and in the regulation of synaptic transmission in adult brain. Brief treatment with nerve growth factor (NGF) enhances depolarization and ionomycin-induced dopamine and acetylcholine release from PC12 cells. The enhancing effect appears very quickly and reaches a plateau 10-15 min after application. NGF also enhances hypertonic solution-induced dopamine release, and increases the amount of dopamine released from membrane-permeabilized PC12 cells in the absence of MgATP, suggesting that NGF enhances neurotransmitter release by increasing the number of Ca2+-responsive secretory vesicles. The activation of Trk receptors is essential for NGF action, since K252a abolishes the NGF-induced potentiation of dopamine release and brain-derived neurotrophic factor enhanced ionomycin-induced release only in TrkB-expressing cells. NGF-mediated potentiation of dopamine release is completely abolished by wortmannin, a PI 3-kinase inhibitor, and by U0126 and PD98059, MAP kinase kinase inhibitors, indicating that the activation of PI 3-kinase and MAP kinase pathways is essential for NGF action. These findings suggest that NGF regulates neurotransmitter release through the activation of TrkA receptors, possibly by increasing the number of secretory vesicles in a readily releasable pool.

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  • Neurotrophins induce BDNF expression through the glutamate receptor pathway in neocortical neurons

    H Xiong, T Futamura, H Jourdi, H Zhou, N Takei, A Diverse-Pierluissi, S Plevy, H Nawa

    NEUROPHARMACOLOGY   42 ( 7 )   903 - 912   2002年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Neurotrophins jointly exert various functions in the nervous system, including neuronal differentiation. survival. and regulation of synaptic plasticity. However, the functional interactions of neurotrophins or mechanisms through which neurotrophins regulate each other are still not clear. In the present study, brain-derived neurotrophic factor (BDNF) mRNA expression is induced by neurotrophin-4/5 (NT-4/5) and by BDNF itself in neocortical neurons. K252a, a specific tyrosine kinase (Trk) inhibitor, completely suppresses BDNF- and NT-4/5-enhanced BDNF mRNA expression. NT-4/5 significantly augments BDNF protein production, which is also reversed by K252a. When neurons Lire incubated with neurotrophin-3 (NT-3) or nerve growth factor (NGF). there are no significant changes in BDNF mRNA or protein expression. Interestingly, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the N-methyl-D-aspartate (NMDA) receptor blocker AP-5 Completely Suppresses NT-4/5-enhanced BDNF protein production, while tetrodotoxin (TTX) only suppresses NT-4/5-enhanced BDNF production by 50%. Additionally, the mitogen activated protein (MAP) kinase inhibitor PD98059 enhances BDNF-induced glutamate receptor-1 (GluR1) protein expression. but a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 strongly reduces BDNF-induced GluR1 protein expression. Taken together, glutamate receptors are important for the regulation of BDNF expression by neurotrophins. and MAP and PI3K kinases differentially modulate AMPA receptor expression in the cortical neurons. (C) 2002 Elsevier Science Ltd. All rights reserved.

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  • Thy-1 protein measured by a novel enzyme immunoassay in rat retina 査読

    M Seki, T Fukuchi, J Ueda, K Hashimoto, T Tanaka, F Hayama, H Abe, N Takei, H Nawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   43   U162 - U162   2002年5月

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    記述言語:英語   出版者・発行元:ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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  • Mechanisms of local translation control by BDNF in neuronal dendrites 査読

    N Takei, N Inamura, H Nawa

    JAPANESE JOURNAL OF PHARMACOLOGY   88   14P - 14P   2002年

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    記述言語:英語   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • BDNF as an anterophin; a novel neurotrophic relationship between brain neurons.

    Nawa H, Takei N

    Trends Neurosci   24 ( 12 )   683 - 4; discussion 684   2001年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Studies of the peripheral nervous system have led to the concept of target-derived neurotrophic support. Neurotrophic factors such as nerve growth factor are now known to act as retrograde trophic factors--retrophins--that are produced in the target cells and released to presynaptic neurons. However, using brain-derived neurotrophic factor (BDNF) tagged with green-fluorescent protein to monitor the subcellular dynamics of BDNF in neurites, Tsumoto and colleagues have provided persuasive visual evidence that BDNF can be released at the synapses of brain neurons in an activity-dependent manner to act on postsynaptic neurons. Accordingly, BDNF serves as an anterophin to regulate postsynaptic development and plasticity in the central nervous system.

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  • Brain-derived neurotrophic factor enhances depolarization-evoked glutamate release in cultured cortical neurons

    T Matsumoto, T Numakawa, N Adachi, D Yokomaku, S Yamagishi, N Takei, H Hatanaka

    JOURNAL OF NEUROCHEMISTRY   79 ( 3 )   522 - 530   2001年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL SCIENCE LTD  

    Brain-derived neurotrophic factor (BDNF) has been reported to play an important role in neuronal plasticity. In this study, we examined the effect of BDNF on an activity-dependent synaptic function in an acute phase. First, we found that shortterm treatment (10 min) with BDNF enhanced depolarization-evoked glutamate release in cultured cortical neurons. The enhancement diminished gradually according to the length of BDNF treatment. The BDNF-enhanced release did not require the synthesis of protein and mRNA. Both tetanus toxin and bafilomycin abolished the depolarization-evoked glutamate release with or without BDNF, indicating that BDNF acted via an exocytotic pathway. Next, we investigated the effect of BDNF on intracellular Ca2+. BDNF potentiated the increase in intracellular Ca2+ induced by depolarization. The Ca2+ was derived from intracellular stores, because thapsigargin completely inhibited the potentiation. Furthermore, both thapsigargin and xestospongin C inhibited the effect of BDNF. These results suggested that the release of Ca2+ from intracellular stores mediated by the IP3 receptor was involved in the BDNF-enhanced glutamate release, Last, it was revealed that the enhancement of glutamate release by BDNF was dependent on the TrkB-PLC-gamma pathway. These results clearly demonstrate that short-term treatment with BDNF enhances an exocytotic pathway by potentiating the accumulation of intracellular Ca2+ through intracellular stores.

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  • PACAP has a neurotrophic effect on cultured basal forebrain cholinergic neurons from adult rats

    A Yuhara, C Nishio, Y Abiru, H Hatanaka, N Takei

    DEVELOPMENTAL BRAIN RESEARCH   131 ( 1-2 )   41 - 45   2001年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal polypeptide gene family (VIP) that was originally isolated from rat hypothalamus. The high affinity PACA-P receptor, PAC1, is expressed in the basal forebrain area of adult, as well as developing rat brain. Hippocampus, a targeting area of basal forebrain cholinergic neurons, contains PACAP Thus, hippocampal-derived PACAP may have an effect on basal forebrain cholinergic neurons. Indeed, we have reported that PACAP showed neurotrophic effects on these neurons in embryonic and early postnatal culture. Here we report that PACA-P has a neurotrophic effect on adult cholinergic neurons in culture. PACAP increases the number of choline acetyltransferase immunoreactive neurons about 2-fold. A similar effect was observed on treatment with cAMP analogue but not nerve growth factor. PACAP also improved the survival and neurite outgrowth of total neurons. These results indicate that PACAP acts as a neurotophic factor even on adult neurons in vitro. (C) 2001 Elsevier Science BY All rights reserved.

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  • Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes - Comparison with the effects of insulin

    N Takei, M Kawamura, K Hara, K Yonezawa, H Nawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 46 )   42818 - 42825   2001年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The effects of neurotrophic factors on translational activation were investigated in cortical neurons. Brain-derived neurotrophic factor (BDNF) increased protein synthesis within 30 min, whereas insulin produced a weaker enhancement of protein synthesis. BDNF-triggered protein synthesis was inhibited by LY294002, PD98059, and rapamycin, whereas the effect of insulin was unaffected by PD98059. To explore the mechanisms underlying this effect, the protein phosphorylation cascades that lead to the activation of translation initiation in neurons were examined. BDNF induced the phosphorylation of both eukaryote initiation factor (eIF) 4E and its binding protein (eIF4E-binding protein-1). The former reaction was inhibited by PD98059, whereas the latter was inhibited by LY294002 or rapamycin. In agreement, BDNF induced the phosphorylation of mammalian TOR ((t) under bar arget (o) under barf (r) under bar apamycin) and enhanced its kinase activity toward eIF4E-binding protein-1. In contrast, insulin failed to activate MAPK and did not induce the phosphorylation of eIF4E. Since BDNF and insulin increased the activity of eIF2B and eIF2, the only difference between them was eIF4E phosphorylation. Thus, this may explain the lower activity of insulin in potentiating neuronal protein synthesis. These results suggest strongly that BDNF simultaneously activates multiple signaling cascades consisting of phosphatidylinositol 3-kinase, mammalian TOR and MAPK to enhance translation initiation in neurons.

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  • N-methyl-D-aspartate-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor down-regulation involves interaction of the carboxyl terminus of GluR2/3 with Pick1. Ligand-binding studies using Sindbis vectors carrying AMPA receptor

    Iwakura Y, Nagano T, Kawamura M, Horikawa H, Ibaraki K, Takei N, Nawa H

    J Biol Chem   276 ( 43 )   40025 - 40032   2001年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The dynamics of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors, as represented by their exocytosis, endocytosis and cytoskeletal linkage, has often been implicated in N-methyl-d-aspartate (NMDA)-dependent synaptic plasticity. To explore the molecular mechanisms underlying the AMPA receptor dynamics, cultured hippocampal neurons were stimulated with 100 microm NMDA, and the biochemical and pharmacological changes in the ligand binding activity of AMPA receptor complexes and its subunits, GluR1 and GluR2/3, were investigated. The NMDA treatment reduced the total amount of bound [(3)H]AMPA on the surface of the neurons but not in their total membrane fraction. This process was mimicked by a protein kinase C activator, phorbol ester, but blocked by an inhibitor of the same kinase, calphostin C. The NMDA-induced down-regulation of the ligand binding activity was also reflected by the decreased AMPA-triggered channel activity as well as by the cells' reduced immunoreactivity for GluR1. In parallel, the NMDA treatment markedly altered the interaction between the AMPA receptor subunits and their associating molecule(s); the association of PDZ m

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  • N-methyl-D-aspartate-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor down-regulation involves interaction of the carboxyl terminus of GluR2/3 with Pick1 - Ligand-binding studies using sindbis vectors carrying AMPA receptor decoys 査読

    Y Iwakura, T Nagano, M Kawamura, H Horikawa, K Ibaraki, N Takei, H Nawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 43 )   40025 - 40032   2001年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The dynamics of alpha -amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid (AMPA)-type glutamate receptors, as represented by their exocytosis, endocytosis and cytoskeletal linkage, has often been implicated in N-methyl-D-aspartate (NMDA)-dependent synaptic plasticity. To explore the molecular mechanisms underlying the AMPA receptor dynamics, cultured hippocampal neurons were stimulated with 100 mum NMDA, and the biochemical and pharmacological changes in the ligand binding activity of AMPA receptor complexes and its subunits, GluR1 and GluR2/3, were investigated. The NMDA treatment reduced the total amount of bound [H-3]AMPA on the surface of the neurons but not in their total membrane fraction. This process was mimicked by a protein kinase C activator, phorbol ester, but blocked by an inhibitor of the same kinase, calphostin C. The NMDA-induced down-regulation of the ligand binding activity was also reflected by the decreased AMPA-triggered channel activity as well as by the cells' reduced immunoreactivity for GluR1. In parallel, the NMDA treatment markedly altered the interaction between the AMPA receptor subunits and their associating molecule(s); the association of PDZ molecules, including Pick1, with GluR2/3 was enhanced in a protein-kinase-C-dependent manner. Viral expression vectors carrying GluR1 and GluR2 C-terminal decoys, both fused to enhanced green fluorescent protein, were transfected into hippocampal neurons to disrupt their interactions. The overexpression of the C-terminal decoy for GluR2 specifically and significantly blocked the NMDA-triggered reduction in [H-3]AMPA binding, whereas that for GluR1 had no effects. Co-immunoprecipitation using anti-Pick1 antibodies revealed that the overexpressed GluR2 C-terminal decoy indeed prevented Pick1 from interacting with the endogenous GluR2/3. Therefore, these observations suggest that the NMDA-induced down-regulation of the functional AMPA receptors involves the interaction between GluR2/3 subunits and Pick1.

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  • Brain-derived neurotrophic factor triggers a rapid glutamate release through increase of intracellular Ca2+ and Na+ in cultured cerebellar neurons

    T Numakawa, T Matsumoto, N Adachi, D Yokomaku, M Kojima, N Takei, H Hatanaka

    JOURNAL OF NEUROSCIENCE RESEARCH   66 ( 1 )   96 - 108   2001年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    We reported previously that BDNF induced glutamate release was dependent on intracellular Ca2+ but not extracellular Ca2+ in cerebellar neurons (Numakawa et al., 1999). It was revealed that the release was through a non-exocytotic pathway (Takei et al., 1998; Numakawa et al., 1999). In the present study, we monitored the dynamics of intracellular Ca2+ and Na+ in cerebellar neurons, and investigated the possibility of reverse transport of glutamate mediated by BDNF. As reported, BDNF increased the intracellular Ca2+ level. We found that the Ca2+ increase induced by BDNF was completely blocked by xestospongin C, an IP3 receptor antagonist, and U-73122, a PLC-gamma inhibitor. Xestospongin C and U-73122 also blocked the BDNF-dependent glutamate release, suggesting that the BDNF-induced transient increase of Ca2+ through the activation of the PLC-gamma/ IP3 pathway was essential for the glutamate release. We found that BDNF induced a Na+ influx. This was blocked by treatment with TTX. U-73122 and xestospongin C blocked the BDNF-induced Na+ influx, suggesting that the Na+ influx required the BDNF-induced Ca2+ increase. Next, we examined the possibility that a co-transporter of Na+ and glutamate was involved in the BDNF-induced glutamate release. BDNF-induced glutamate release was blocked by L-trans-pyrollidine-2,4-dicalboxylic acid (t-PDC), a glutamate transporter inhibitor, whereas neither the 4-aminopyridine (4AP)- nor high potassium (HK+)induced release was blocked by t-PDC. In addition, DL-threo-beta -benzyloxyaspartate (DL-TBOA) also blocked the BDNF-mediated glutamate release, suggesting that reverse transport of glutamate may be involved. All the results therefore suggest that Na+-dependent reverse transport contributes to BDNF-mediated transmitter release through the PLC-gamma /IP3-mediated Ca2+ signaling. (C) 2001 Wiley-Liss, Inc.

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  • Biological characterization and optical imaging of brain-derived neurotrophic factor-green fluorescent protein suggest an activity-dependent local release of brain-derived neurotrophic factor in neurites of cultured hippocampal neurons

    M Kojima, N Takei, T Numakawa, Y Ishikawa, S Suzuki, T Matsumoto, R Katoh-Semba, H Nawa, H Hatanaka

    JOURNAL OF NEUROSCIENCE RESEARCH   64 ( 1 )   1 - 10   2001年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    To visualize the release dynamics of the brain-derived neurotrophic factor (BDNF) involved in neural plasticity, we constructed a plasmid encoding green fluorescent protein (GFP) fused with BDNF. First, several biological studies confirmed that this fusion protein (BDNF-GFP) mimics the biological functions and the release kinetics of unfused (native) BDNF. Second, when BDNF-GFP was expressed in cultured hippocampal neurons, we observed that this protein formed striking clusters in the neurites of mature neurons and colocalized with the PSD-95 immunoreactivity. Such a clustered BDNF-GFP rapidly disappeared in response to depolarization with KCl, as revealed by confocal microscopic studies. These data suggest that BDNF is locally and rapidly released at synaptic sites in an activity-dependent manner. Optical studies using BDNF-GFP may provide important evidence regarding the participation of BDNF in synaptic plasticity. (C) 2001 Wiley-Liss, Inc.

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  • Quantitative analysis of neurotrophins in the retina of rats. 査読

    M Seki, N Takei, T Fukuchi, J Ueda, K Hashimoto, F Hayama, T Tanaka, H Matsuda, H Nawa, H Abe

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   42 ( 4 )   S659 - S659   2001年3月

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  • Expression of c-Met in developing rat hippocampus: evidence for HGF as a neurotrophic factor for calbindin D-expressing neurons

    L Korhonen, U Sjoholm, N Takei, MA Kern, P Schirmacher, E Castren, D Lindholm

    EUROPEAN JOURNAL OF NEUROSCIENCE   12 ( 10 )   3453 - 3461   2000年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL SCIENCE LTD  

    Hepatocyte growth factor-scatter factor (HGF) is expressed in different parts of the nervous system, and has been shown to exhibit neurotrophic activity. Here we show that c-Met, the receptor for HGF, is expressed in developing rat hippocampus, with the highest levels during the first postnatal weeks. To study the function of HGF, hippocampal neurons were prepared from embryonic rats and treated with different HGF concentrations. In these cultures, HGF increased the number of neurons expressing the 28-kDa calcium-binding protein (calbindin D) in a dose-dependent manner. The effect of HGF was larger than that observed with either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), and cotreatment of the cultures with HGF and the neurotrophins was additive with respect to calbindin D neurons. Besides affecting the number of neurons, HGF significantly increased the degree of sprouting of calbindin D-positive neurons, suggesting an influence on neuronal maturation. BDNF and NT-3 stimulated neurite outgrowth of calbindin D neurons to a much smaller degree. In contrast to calbindin D neurons, HGF did not significantly increase the number of neurons immunoreactive with the neurotransmitter gamma-aminobutyric acid (GABA) in the hippocampal cultures. Immunohistochemical studies showed that c-Met-, calbindin D- and HGF-immunoreactive cells are all present in the dentate gyrus and partly colocalize within neurons. These results show that HGF acts on calbindin D-containing hippocampal neurons and increases their neurite outgrowth, suggesting that HGF plays an important role for the maturation and function of these neurons in the hippocampus.

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  • Pituitary adenylate cyclase-activating polypeptide promotes the survival of basal forebrain cholinergic neurons in vitro and in vivo: comparison with effects of nerve growth factor

    N Takei, E Torres, A Yuhara, H Jongsma, C Otto, L Korhonen, Y Abiru, Y Skoglosa, G Schutz, H Hatanaka, MV Sofroniew, D Lindholm

    EUROPEAN JOURNAL OF NEUROSCIENCE   12 ( 7 )   2273 - 2280   2000年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL SCIENCE LTD  

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasointestinal polypeptide gene family for which neurotrophic activity has been postulated. PACAP mRNA is expressed in the developing and adult hippocampus, which is the principal target region of septal cholinergic neurons. We therefore studied the effects of PACAP on septal cholinergic neurons. In primary cultures from septum of embryonic and postnatal rats, PACAP increased the number of neurons immunohistochemically stained for the low-affinity nerve growth factor (NGF) receptor p75 and for the enzyme choline acetyltransferase (ChAT). PACAP also caused a corresponding increase in ChAT activity. In comparison, NGF had a greater effect than PACAP on the number of p75- and ChAT-positive neurons in these cultures. In vivo, following fimbria fornix transection, the number of immunohistochemically stained septal cholinergic neurons fell significantly to 18% in rats given continuous intracerebroventricular infusion of vehicle, whereas in rats given NGF the number of these neurons did not differ significantly from unoperated controls. In PACAP-treated rats the number was 48% of unoperated values, which represented a significant increase compared with vehicle-treated rats and a significant decrease compared with NGF-treated rats or unoperated controls. Double-staining experiments revealed that most ChAT-positive neurons in rat medial septum also express PACAP receptor 1. Together the results show that PACAP promotes the survival of septal cholinergic neurons in vitro, and after injury in vivo, suggesting that PACAP acts as a neurotrophic factor influencing the development and maintenance of these neurons.

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  • Molecular characterization of a novel gamma-glutamyl transpeptidase homologue found in rat brain

    T Yamaguchi, N Takei, K Araki, K Ishii, T Nagano, T Ichikawa, T Kumanishi, H Nawa

    JOURNAL OF BIOCHEMISTRY   128 ( 1 )   101 - 106   2000年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE BIOCHEMICAL SOC  

    A cDNA clone for a novel homologue to gamma-glutamyl transpeptidase (gamma-GTP), termed GTPH, was isolated from a rat brain expression cDNA library using antisera against total brain synaptosomal fractions. The cloned GTPH consists of 641 amino acid residues (78 kDa) and exhibits structural similarity with a conventional type of gamma-GTP that is predominantly expressed in the liver: They share significant amino acid homology (33% identity, 73% similarity) spanning over the entire sequence. RNA analyses revealed that GTPH mRNA expression is found only in the nervous system, including all brain regions, eyes and peripheral ganglia, and increases during development. Endogenous GTPH protein is a membrane-bound glycoenzyme and migrates as 90-100 kDa in polyacrylamide gels, Taken together, GTPH is a novel form of a gamma-GTP-like molecule expressed exclusively in the nervous system.

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  • BDNF rapidly induces aspartate release from cultured CNS neurons

    T Numakawa, N Takei, H Hatanaka

    NEUROSCIENCE RESEARCH   37 ( 1 )   59 - 65   2000年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    We investigated the effects of brain-derived neurotrophic factor (BDNF) on aspartate release from cultured cerebellar neurons. This release occurred within 1 min after the addition of 100 ng/ml BDNF. The amount of aspartate released was less than that of glutamate. Aspartate release induced by BDNF was rapid and transient, as in the case of glutamate. Although high potassium evoked the release of both excitatory (glutamate and aspartate) and inhibitory (GABA and glycine) amino acid transmitters, BDNF only induced glutamate and aspartate release. BDNF-induced aspartate release was completely blocked by pretreatment with K252a or TrkB-IgG. The aspartate release induced by BDNF was not dependent on the extracellular Ca2+, but required intracellular Ca2+ mobilization. These results showed that BDNF may be involved in excitatory transmission using aspartate as well as glutamate through TrkB-mediated signaling in cerebellum. (C) 2000 Elsevier Science ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/S0168-0102(00)00103-6

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  • Neurotrophin-elicited short-term glutamate release from cultured cerebellar granule neurons

    T Numakawa, N Takei, S Yamagishi, N Sakai, H Hatanaka

    BRAIN RESEARCH   842 ( 2 )   431 - 438   1999年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Brain-derived neurotrophic factor (BDNF) has been suggested to play an important role in neuronal plasticity. In this study, we investigated the effects of BDNF on short-term transmitter release from cultured CNS neurons. Rapid and transient glutamate and aspartate releases induced by BDNF were observed from cultured cortical, hippocampal, striatal and cerebellar neurons. We furthermore investigated the mechanism of release induced by neurotrophins from cerebellar granule cells, since granule cells represent a large homogeneous glutamatergic population. NGF and NT-3 elicited neurotrophin-induced release of glutamate as well as BDNF from the cerebellar granule neurons. The release was dependent on intracellular Ca2+ mobilization. Pretreatment with K252a and also TrkB-IgG completely blocked the glutamate and aspartate release elicited by BDNF, but not by NGF. The cerebellar granule neurons expressed trkB and p75 mRNAs at high levels, but not trkA mRNA. These results suggested that while BDNF induced release via TrkB, NGF-elicited release was not mediated by Trks. Furthermore, in the experiment using the styryl dye FM1-43, which selectively labels synaptic vesicles, neither BDNF nor NGF evoked dye loss, suggesting that neurotrophin-induced excitatory amino acid release occurs through a non-exocytotic pathway. (C) 1999 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0006-8993(99)01867-3

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  • Regulation of nerve growth factor release by nitric oxide through cyclic GMP pathway in cortical glial cells

    HB Xiong, K Yamada, H Jourdi, M Kawamura, N Takei, DK Han, T Nabeshima, H Nawa

    MOLECULAR PHARMACOLOGY   56 ( 2 )   339 - 347   1999年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    In the present study, we found that S-nitroso-N-acetyl-DL-penicillamine, a spontaneous nitric oxide (NO) generator, dose-dependently inhibited basal nerve growth factor (NGF) release from mixed glial cells. To elucidate the function of endogenous NO in the regulation of NGF release, the mixed glial cells were stimulated with lipopolysaccharide (LPS) or LPS plus interferon-gamma (IFN gamma). The results showed that LPS alone induced NGF release and moderate NO production. However, costimulation with LPS plus IFN gamma greatly enhanced NO production but significantly suppressed LPS-induced NGF release. When N-G-monomethyl-L-arginine, an NOS inhibitor, was added to the culture, the suppression of NGF release by IFN gamma was significantly reduced. Quantitative reverse transcription-polymerase chain reaction demonstrated S-nitroso-N-acetyl-DL-penicillamine was also able to inhibit the LPS-induced NGF mRNA expression. To understand the different contributions of astroglia and microglia to this phenomenon, both cell types were purified. We found purified astroglia produced high amounts of NGF but low amounts of NO. However, purified microglia produced a large amount of NO but very low amounts of NGF after stimulation with LPS or LPS plus IFN gamma. Our data also indicated the second messenger cyclic GMP, but not cyclic AMP, was able to inhibit basal NGF release. In vivo experiments confirmed that NGF protein level was significantly enhanced in rats treated with L-N-omega-nitro-arginine methyl ester and in endothelial NO synthase mutant mice. Taken together, we conclude NO derived mainly from microglia down-regulates NGF release from astroglia at the transcriptional level by stimulating cyclic GMP pathway.

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  • Distribution of pituitary adenylate cyclase activating polypeptide mRNA in the developing rat brain

    Y Skoglosa, N Takei, D Lindholm

    MOLECULAR BRAIN RESEARCH   65 ( 1 )   1 - 13   1999年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    PACAP is a member of the secretin/vasoactive intestinal peptide (VIP) family, isolated from hypothalamus. Recent studies have shown that PACAP is expressed in many parts of adult brain. We have studied the precise distribution of PACAP mRNA in developing rat brain, employing in situ hybridisation. PACAP mRNA is expressed in distinct parts of the embryonic rat brain from embryonic day 13, with a robust expression in developing cortex, hippocampus, amygdala and hypothalamus as well as in spinal cord and dorsal root ganglia. The expression in hippocampus and cortex diminishes towards adulthood, compared to new-born rat brain. In the mature brain, PACAP mRNA is located in alternating layers of cerebral cortex (layers I, III and V), in the dentate gyrus, in CA4 and CA1 regions, but not in CA2 or CA3 of the hippocampus. The presence of PACAP mRNA in different structures of developing rat brain suggests an important function for this peptide during brain development. (C) 1999 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0169-328X(98)00294-0

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  • BDNF and NT-3 but not CNTF counteract the Ca2+ ionophore-induced apoptosis of cultured cortical neurons: involvement of dual pathways

    N Takei, O Tanaka, Y Endo, D Lindholm, H Hatanaka

    NEUROPHARMACOLOGY   38 ( 2 )   283 - 288   1999年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    The effect of neurotrophic factors on apoptosis induced by ionomycin, a potent Ca2+ ionophore, was investigated using cultured cortical neurons from embryonic rats. Brain-derived neurotophic factor (BDNF) and neurotrophin-3 (NT-3) prevented the ionomycin-mediated cell death in a dose-dependent manner. In contrast to the neurotrophins, cilliary neurotrophic factor (CNTF) did not rescue neurons from cell death induced by ionomycin. The protective effect of BDNF was partially blocked by wortmannin, a phosphatidylinositol 3-kinase inhibitor, and by PD98059, a MAP kinase kinase inhibitor. However, the addition of both compounds together completely inhibited the survival promoting effect of BDNF. These results suggest that the neuroprotective effect of BDNF requires activation of both phosphatidylinositol-3 kinase and the Ras/MAP kinase cascade and that CNTF signaling through other pathways is without an effect in this system. (C) 1999 Elsevier Science Ltd. All rights reserved.

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  • Regulation of pituitary adenylate cyclase activating polypeptide and its receptor type 1 after traumatic brain injury: Comparison with brain-derived neurotrophic factor and the induction of neuronal cell death

    Y Skoglosa, A Lewen, N Takei, L Hillered, D Lindholm

    NEUROSCIENCE   90 ( 1 )   235 - 247   1999年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Neurotrophic factors are known to promote neuronal survival during development and after acute brain injury. Recent data suggest that some neuropeptides also exhibit neurotrophic activities, as shown for the pituitary adenylate cyclase activating polypeptide, which increases the survival of various neuronal populations in culture. Employing in situ hybridization techniques, we have studied the regulation of messenger RNA for pituitary adenylate cyclase activating polypeptide and its receptor type 1 after a moderate traumatic brain injury to rat brain cortex. We have further compared their messenger RNA expression to that of brain-derived neurotrophic factor and to the amount of cell death occurring in the brain at various times after the brain injury. Levels of brain-derived neurotrophic factor messenger RNA increased rapidly within 2 h after trauma in cortex and hippocampus, and returned to control levels thereafter. The levels of messenger RNA for pituitary adenylate cyclase activating polypeptide also increased with time in the injured brains and reached maximal expression at 72 h, i.e. the end of the observation period. The alterations in pituitary adenylate cyclase activating polypeptide messenger RNA levels were particularly pronounced in the perifocal region and in the ipsilateral dentate gyrus of the brain injury. In contrast, the messenger RNA levels encoding pituitary adenylate cyclase activating polypeptide receptor type 1 first decreased after trauma and were then normalized in the dentate gyrus. There was a large increase in the number of cells labelled for DNA breaks at 12 h past-trauma, indicative of enhanced cell death. The number of labelled cells, however, decreased at later stages concomitant with an increase in the expression of pituitary adenylate cyclase activating polypeptide messenger RNA. Pituitary adenylate cyclase activating polypeptide rescued cortical neurons in cultures against ionomycin-induced cell death, supporting the concept of a neuroprotective effect for the peptide.
    These results demonstrate a differential regulation of messenger RNA for brain-derived neurotrophic factor and the pituitary adenylate cyclase activating polypeptide and its receptor after brain trauma. The data also suggest that pituitary adenylate cyclase activating polypeptide might have a beneficial effect in brain injury by counteracting neuronal cell death. (C) 1999 IBRO. Published by Elsevier Science Ltd.

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  • Developmental regulation of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor 1 in rat brain: function of PACAP as a neurotrophic factor.

    Lindholm D, Skoglosa Y, Takei N

    Ann N Y Acad Sci   865   189 - 196   1998年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To function as a trophic factor PACAP and PACAP-R must be expressed in the nervous system during early development. We report here on the distribution of PACAP mRNA in the developing nervous system of the rat and compare its expression with that of PACAP-R. We discuss primary neuron culture experiments that study the neurotrophic activity of PACAP. Experimental results that indicate the presence of PACAP and its receptor in the developing nervous system, together with the observed neuropeptide activity on various populations of neurons, support the view that PACAP exhibits important neurotrophic activities comparable to those of the classical neurotrophic factors.

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  • Neurotrophic and neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on mesencephalic dopaminergic neurons

    N Takei, Y Skoglosa, D Lindholm

    JOURNAL OF NEUROSCIENCE RESEARCH   54 ( 5 )   698 - 706   1998年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is present in many regions of the adult and developing brain as are receptors for PACAP. PACAP stimulates different signalling cascades in neurons, involving cAMP, MAP kinase, and calcium. These characteristics suggest that PACAP may influence neuronal development. Here we have studied the effects of PACAP on mesencephalic dopaminergic neurons using primary cultures from embryonic rats. PACAP increased the number of tyrosine hydroxylase (TH)-immunoreactive neurons, elevated TH protein, and enhanced tritiated dopamine uptake in these cultures. Moreover, PACAP counteracted the effects of 6-hydroxydopamine treatments, which induce cell death of dopaminergic neurons. In situ hybridisation showed that both PACAP and PACAP receptor type 1 are present in developing and adult rat mesencephalon. These results show that PACAP has a neurotrophic action on dopaminergic neurons and partially protects them against 6-OHDA induced neurotoxicity. (C) 1998 Wiley-Liss, Inc.

    DOI: 10.1002/(SICI)1097-4547(19981201)54:5<698::AID-JNR15>3.0.CO;2-5

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  • Brain-derived neurotrophic factor induces rapid and transient release of glutamate through the non-exocytotic pathway from cortical neurons

    N Takei, T Numakawa, S Kozaki, N Sakai, Y Endo, M Takahashi, H Hatanaka

    JOURNAL OF BIOLOGICAL CHEMISTRY   273 ( 42 )   27620 - 27624   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    There is increasing interest in the involvement of neurotrophins in neural transmission and plasticity. Thus, Re investigated the effects of brain-derived neurotrophic factor (BDNF) on glutamate release from cortical neurons, Treatment of cultured cortical neurons with BDNF induced rapid and transient release of glutamate, This effect was suggested to be mediated by TrkB activation because R252a inhibited the release of glutamate and BDNF phosphorylated TrkB within 30 s, BDNF-induced glutamate release was observed even when using Ca2+-free assay buffer but was inhibited by BAPTA-AM, a cell-permeable Ca2+ chelator, Therefore, BDNF-induced glutamate release was independent of extracelluar Ca2+ but dependent on intracellular Ca2+. Because normal neurotransmitter release is exocytotic, the involvement of the exocytotic pathway in BDNF-induced glutamate release was examined. As botulinum toxin is known to cleave exocytosis-associated proteins, thereby inhibiting exocytosis, it was applied to neurons prior to the release assay. Although botulinum toxin B cleaved VAMP2 and inhibited Ca2+-triggered glutamate release, it did not inhibit the BDNF-induced release of glutamate. These results strongly suggested that BDNF induces rapid and transient release of glutamate from cortical neurons through a non-exocytotic pathway.

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  • Roles of neurotrophins on synaptic development and functions in the central nervous system.

    Takei N, Nawa H

    Hum Cell   11 ( 3 )   157 - 165   1998年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Evidence is emerging to suggest that in addition to their &quot;classical&quot; neurotrophic involvement in the regulation of the differentiation, maturation and survival of neurons, neurotrophins play crucial roles in neural transmission and succeeding activity-dependent plasticity of synapses. Here we discuss: 1) the regulated synthesis and secretion of neurotrophins in response to neural activity, 2) the short- and long-term effects of neurotrophins on neural transmission, and 3) the neurotrophin-induced rearrangement of synaptic networks.

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  • Pituitary adenylate cyclase-activating polypeptide (PACAP) protects dorsal root ganglion neurons from death and induces calcitonin gene-related peptide (CGRP) immunoreactivity in vitro

    M Lioudyno, Y Skoglosa, N Takei, D Lindholm

    JOURNAL OF NEUROSCIENCE RESEARCH   51 ( 2 )   243 - 256   1998年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a recently discovered neuropeptide which is present both in the central and peripheral nervous system of adult rats, Here we show that PACAP is also expressed by dorsal root ganglion sensory neurons of embryonic and newborn rats. To characterize the effects of PACAP on dorsal root ganglion (DRG) neurons, dissociated cultures were established and incubated in the absence or presence of this neuropeptide. The results show that PACAP increases the survival of cultured DRG neurons, and the effect was comparable to that of nerve growth factor (NGF). In DRG explants, PACAP induces the immunoreactivity for the neuropeptide calcitonin gene-related peptide (CGRP), PACAP also promoted the outgrowth of neurites in the DRG cultures. The present results show that PACAP acts as a trophic factor for DRG neurons and that it is able to modulate the expression of another neuropeptide in the ganglia, The presence of PACAP in normal DRG and after nerve lesions suggests that PACAP acts in a autocrine/paracrine manner possibly in conjunction with other neurotrophic factors such as nerve growth factor. (C) 1998 Wiley-Liss, Inc.

    DOI: 10.1002/(SICI)1097-4547(19980115)51:2<243::AID-JNR13>3.0.CO;2-9

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  • Involvement of phosphatidylinositol-3 kinase in prevention of low K+-induced apoptosis of cerebellar granule neurons

    K Shimoke, T Kubo, T Numakawa, Y Abiru, Y Enokido, N Takei, T Ikeuchi, H Hatanaka

    DEVELOPMENTAL BRAIN RESEARCH   101 ( 1-2 )   197 - 206   1997年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Cerebellar granule neurons obtained from 9-day-old rats die in an apoptotic manner when cultured in serum-free medium containing a low concentration of potassium (5 mM). A high concentration of potassium (26 mM) in the culture medium and BDNF can effectively prevent this apoptosis. The survival effects of high potassium and BDNF were additive, and the effect of high potassium was not blocked by addition of anti-BDNF antibody. These observations indicated that these survival effects were independent. To examine which molecules are involved in the survival pathway induced by BDNF or high K+, we used wortmannin, a specific inhibitor of PI-3 kinase. Wortmannin blocked the survival effects of both BDNF and high K+ on cerebellar granule neurons. Furthermore, in vitro PI-3 kinase assay showed that treatment with BDNF or high K+ induced PI-3 kinase activity, which was diminished by addition of wortmannin. These results indicate that different survival-promoting agents, BDNF and high K+, can prevent apoptosis in cerebellar granule neurons via a common enzyme, PI-3 kinase. (C) 1997 Elsevier Science B.V.

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  • NGF and BDNF increase the immunoreactivity of vesicular acetylcholine transporter in cultured neurons from the embryonic rat septum

    N Takei, H Kuramoto, Y Endo, H Hatanaka

    NEUROSCIENCE LETTERS   226 ( 3 )   207 - 209   1997年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The expression of vesicular acetylcholine transporter (VAChT), which transports ACh into synaptic vesicles, is coregulated with choline acetyltransferase (ChAT). Therefore, the effects of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) on the levels of VAChT in cultured neurons from the septum of embryonic rats were investigated by immunocytochemistry. NGF and BDNF increased the number of VAChT-immunoreactive neurons by approximately 1.5-fold and enhanced the immunoreactivity in each positive cell. These results suggest that the neurotrophins enhance not only synthesis but also storage of ACh in septal neurons. (C) 1997 Elsevier Science Ireland Ltd.

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  • Identification of NAP-22 and GAP-43 (neuromodulin) as major protein components in a Triton insoluble low density fraction of rat brain.

    Maekawa S, Kumanogoh H, Funatsu N, Takei N, Inoue K, Endo Y, Hamada K, Sokawa Y

    Biochim Biophys Acta   1323 ( 1 )   1 - 5   1997年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    NAP-22 is a membrane-localized brain enriched acidic protein having a Ca(2+)-dependent calmodulin binding activity. Further fractionation of the NAP-22 containing membrane showed the localization of NAP-22 in a Triton insoluble fraction of low density. Besides NAP-22, this fraction was found to contain GAP-43 (neuromodulin), trimeric G proteins, and some GPI-anchored proteins such as Thy-1 and N-CAM-120. Presence of some protein tyrosine kinases, such as src and fyn, was also shown.

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  • Brain-derived neurotrophic factor increases the stimulation-evoked release of glutamate and the levels of exocytosis-associated proteins in cultured cortical neurons from embryonic rats

    N Takei, K Sasaoka, K Inoue, M Takahashi, Y Endo, H Hatanaka

    JOURNAL OF NEUROCHEMISTRY   68 ( 1 )   370 - 375   1997年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    Differentiation and survival of neurons induced by neurotrophins have been widely investigated, but little has been reported about the long-term effect of brain-derived neurotrophic factor (BDNF) on synaptic transmission, Among many steps of neurotransmission, one important step is regulated release of transmitters. Therefore, the release of glutamate and GABA from cortical neurons cultured for several days with or without BDNF was measured by an HPLC-fluorescence method. Although BDNF had little effect on the basal release of glutamate, high K+-evoked release was greatly increased by BDNF. BDNF also tended to increase evoked release of GABA. Recently, several proteins involved in the step of ''regulated release'' have been identified. Thus, the effect of BDNF on the levels of these proteins was then investigated. Neurons were cultivated with or without BDNF, collected, and electrophoresed for western blotting. BDNF increased levels of synaptotagmin, synaptobrevin, synaptophysin, and rab3A, which were known as vesicle protein. Levels of syntaxin, SNAP-25, and beta-SNAP were also increased by BDNF. In addition, the numbers of cared and clear vesicles in nerve terminals or varicosities were also increased by BDNF. These results raise the possibility that BDNF increases regulated release of neurotransmitters through the up-regulation of secretary mechanisms.

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  • A role of peroxides in Ca2+ ionophore-induced apoptosis in cultured rat cortical neurons

    Y Hatanaka, K Suzuki, Y Kawasaki, Y Endo, N Taniguchi, N Takei

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   227 ( 2 )   513 - 518   1996年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    The implication of reactive oxygen species for the Ca2+ ionophore ionomycin-induced apoptosis was investigated in cultured cortical neurons from embryonic rats. Ionomycin increased the production of intracellular peroxides as measured by flow cytometric analysis with 6-carboxy-2'7'-dichlorodihydrofluorescein diacetate, di(acetoxymethyl ester). Low doses of ionomycin increased the level of manganese-superoxide dismutase (Mn-SOD). In addition, N-acetyl-L-cysteine prevented apoptotic neuronal death induced by ionomycin in a dose-dependent manner. Buthionine sulfoximine suppressed the effect of N-acetyl-L-cysteine. These results suggest that peroxides and redox-regulation play an important role in the apoptosis of neurons induced by elevation of intracellular Ca2+ concentration. (C) 1996 Academic Press, Inc.

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  • BDNF increases the expression of neuropeptide Y mRNA and promotes differentiation/maturation of neuropeptide Y-positive cultured cortical neurons from embryonic and postnatal rats

    N Takei, K Sasaoka, H Higuchi, Y Endo, H Hatanaka

    MOLECULAR BRAIN RESEARCH   37 ( 1-2 )   283 - 289   1996年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The effects of neurotrophic factor on the expression of neuropeptide Y (NPY) mRNA and on morphology of NPY-immunoreactive neurons were investigated. Brain-derived neurotrophic factor (BDNF) increased the expression of NPY mRNA in cultured cortical neurons from both embryonic and postnatal rats. BDNF also increased the number of NPY neurons. Furthermore, multipolar neurites from NPY neurons were observed in cultures treated with BDNF, whereas only monopolar and bipolar neurites were observed in control cultures. These results suggest that BDNF not only increases the expression of NPY mRNA but also promotes the differentiation/maturation of NPYergic neurons both in number and morphology. NPY expression was strongly increased by neurotrophin-4/5 similarly to BDNF and neurotrophin-3 evoked a slight increase. In contrast, basic fibroblast growth factor, cilliary neurotrophic factor and interferon-gamma had no effect on NPY expression.

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  • BASIC FIBROBLAST GROWTH-FACTOR INHIBITED CA2+ IONOPHORE-INDUCED APOPTOTIC CELL-DEATH OF CULTURED CORTICAL-NEURONS FROM EMBRYONIC RATS

    N TAKEI, H OGAKI, Y ENDO

    NEUROSCIENCE LETTERS   192 ( 2 )   124 - 126   1995年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI PUBL IRELAND LTD  

    The effect of basic fibroblast growth factor (bFGF) on apoptotic cell death of cultured cortical neurons from embryonic rats induced by ionomycin, a potent Ca2+ ionophore, was investigated. bFGF inhibited Ca2+ ionophore-induced neurotoxicity in a dose-dependent manner. bFGF also reduced the degree of fragmentation of DNA of Ca2+ ionophore-treated neurons. These findings strongly suggest that bFGF inhibited ionomycin-induced neurotoxicity by preventing apoptosis.

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  • NEUROTROPHIC AND NEUROPROTECTIVE EFFECTS OF NEURON-SPECIFIC ENOLASE ON CULTURED NEURONS FROM EMBRYONIC RAT-BRAIN

    T HATTORI, N TAKEI, Y MIZUNO, K KATO, S KOHSAKA

    NEUROSCIENCE RESEARCH   21 ( 3 )   191 - 198   1995年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI PUBL IRELAND LTD  

    We previously reported that the gamma gamma-isozyme of enolase (neuron-specific enolase, NSE), one of the glycolytic enzymes, promoted the survival of embryonic rat neocortical neurons in culture, but alpha alpha-isozyme (non-neuronal enolase) had no effect. In the present study, the neurotrophic effects of NSE on cultured mesencephalic and spinal neurons from rat embryo were examined. NSE promoted the survival of neurons not only in neocortical cultures but also in mesencephalic and spinal cord cultures. Furthermore, NSE showed neuroprotective action on cultured neocortical neurons in a low-oxygen atmosphere. By contrast, non-neuronal enolase did not show any neurotrophic or neuroprotective activities. To clarify the mechanism of the neurotrophic effect of NSE, the binding of NSE to cultured neurons was determined by radio-receptor assay using I-125-labelled NSE. The specific binding, which was dose-dependent, saturable, and calcium-dependent, could be detected. These results suggest that NSE has neurotrophic and neuroprotective effects on rather a broad spectrum of neurons in the central nervous system. The existence of specific binding of NSE to cultured neurons suggests the possibility that receptor-like or carrier-like molecules on the neuronal surface are involved in the neurotrophic activity of NSE.

    DOI: 10.1016/0168-0102(94)00849-B

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  • CA2+ IONOPHORE-INDUCED APOPTOSIS ON CULTURED EMBRYONIC RAT CORTICAL-NEURONS

    N TAKEI, Y ENDO

    BRAIN RESEARCH   652 ( 1 )   65 - 70   1994年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The neurotoxicity of ionomycin, a Ca2+ ionophore, was investigated in cultured cortical neurons from embryonic rats. While about 90% of neurons survived 2 h after exposure to ionomycin, the surviving neurons had decreased by about 30 to 40% at 16 h. Both RNA and protein synthesis inhibitors blocked this neurotoxicity. Furthermore, c-Fos immunoreactive neurons increased not only in number but also in the intensity of immunoreactivity. These results suggest that ionomycin-induced neuronal cell death is an active process which requires de novo transcription and translation. In addition, the ultrastructural changes, such as shrinkage of cell body, compaction of nucleus, condensation of chromatin, and membrane blebbing, were observed by electron microscopy. These morphological changes are indexes of apoptosis. Furthermore, DNA fragmentation, a biochemical marker of apoptosis, was also observed. All the results suggest that ionomycin-induced neuronal cell death is apoptotic.

    DOI: 10.1016/0006-8993(94)90317-4

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  • NEUROTROPHIC EFFECTS OF ANNEXIN-V ON CULTURED NEURONS FROM EMBRYONIC RAT-BRAIN

    N TAKEI, K OHSAWA, Y IMAI, H NAKAO, A IWASAKI, S KOHSAKA

    NEUROSCIENCE LETTERS   171 ( 1-2 )   59 - 62   1994年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Recombinant human annexin V showed survival promoting activity in embryonic rat neocortical and mesencephalic neurons in vitro. The neurotrophic effect was observed from a relatively low dose and in a dose-dependent manner. The neurotrophic activity of annexin V was completely blocked by anti-annexin V antibody. Northern blot analysis demonstrated that annexin V mRNA is expressed in non-neuronal cells in the CNS. These results suggest that annexin V plays certain roles in the CNS as a paracrine-type neurotrophic factor.

    DOI: 10.1016/0304-3940(94)90604-1

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  • MICROGLIAL CONDITIONED MEDIUM PROMOTES SURVIVAL AND DEVELOPMENT OF CULTURED MESENCEPHALIC NEURONS FROM EMBRYONIC RAT-BRAIN

    K NAGATA, N TAKEI, K NAKAJIMA, H SAITO, S KOHSAKA

    JOURNAL OF NEUROSCIENCE RESEARCH   34 ( 3 )   357 - 363   1993年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    We previously reported that microglial conditioned medium (Mic-CM) has a neurotrophic effect on cultured rat neocortical neurons [Nakajima et al. (1989): Biomed Res 10:411-423]. In order to investigate the interaction between microglia and neurons in more detail, we determined the effects of Mic-CM on the primary cultured mesencephalic neurons from 16-day embryonic rats. The addition of Mic-CM to the culture medium significantly enhanced the survivability of neurons and promoted neurite extension in a low cell-density culture condition. In a high cell-density culture condition, Mic-CM markedly increased dopamine uptake, which was quantified by assessing the specific [H-3]dopamine uptake, and also increased the dopamine content of cultured cells. Furthermore, the number of mesencephalic dopaminergic neurons, which was determined by quantitative analysis of tyrosine hydroxylase (TH)-immunoreactive cells, increased significantly in the presence of Mic-CM. These results suggest that Mic-CM enhances survival or maturation of TH-positive neurons present in cultures of the embryonic mesencephalon and that these neurotrophic effects may be due to a diffusible factor(s) from microglia.

    DOI: 10.1002/jnr.490340313

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  • NEURONAL SURVIVAL FACTOR FROM BOVINE BRAIN IS IDENTICAL TO NEURON-SPECIFIC ENOLASE

    N TAKEI, J KONDO, K NAGAIKE, K OHSAWA, K KATO, S KOHSAKA

    JOURNAL OF NEUROCHEMISTRY   57 ( 4 )   1178 - 1184   1991年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    Neuronal survival factors in the central nervous system were investigated by using a primary culture of embryonic rat neocortical neurons. Bovine hippocampus was homogenized, and the supernatant from high-speed centrifugation was used as the starting material. At the step of DE-52 ion-exchange chromatography, neuronal survival activity was recovered in two fractions, fraction 14 (F14) and fraction 23 (F23). Antisera to the crude F14 and F23 fractions were raised in rabbits. These two antisera completely inhibited the neurotrophic activity of both fractions. Western blotting analysis revealed that anti-F14 antiserum recognized mainly a 30-kDa protein in F14 and anti-F23 antiserum recognized mainly a 44-kDa protein in F23. After sodium dodecyl sulfatepolyacrylamide gel electrophoresis of F23, the 44-kDa protein was cut out from the gel and partial amino acid sequences of the protein fragments were determined. A GenBank data bank indicated that the amino acid sequence of the fragment was identical to that of neuron-specific enolase (NSE). In our assay system, commercially available NSE itself possessed neuronal survival activity for the cultured neocortical neurons. The effects of NSE and F23 were inhibited completely by anti-NSE polyclonal antibody. Furthermore, highly purified NSE supported the survival of cultured neurons in a dose-dependent manner, and the neurotrophic effect was inhibited by monoclonal antibody to the NSE. These results strongly suggest that NSE is one of the neuronal survival factors in the central nervous system.

    DOI: 10.1111/j.1471-4159.1991.tb08277.x

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  • PRODUCTION OF BASIC FIBROBLAST GROWTH-FACTOR IN CULTURED RAT-BRAIN MICROGLIA

    M SHIMOJO, K NAKAJIMA, N TAKEI, M HAMANOUE, S KOHSAKA

    NEUROSCIENCE LETTERS   123 ( 2 )   229 - 231   1991年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The production of basic fibroblast growth factor (bFGF) in cultured rat brain microglia was investigated. Rat brain microglia were found to express mRNA of bFGF in analysis by polymerase chain reaction (PCR) technique. Basic FGF was also detected in microglial cell lysate by Western blot analysis. These results indicate that microglia produce bFGF and possibly contribute to the regulation of neuronal development and regeneration.

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  • Interleukin-6 improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from postnatal, two-week-old rats in cultures.

    Hama T, Kushima Y, Miyamoto M, Kubota M, Takei N, Hatanaka H

    Neuroscience   40 ( 2 )   445 - 452   1991年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Interleukin-6 (human recombinant) supported the survival of cultured mesencephalic, catecholaminergic and septal cholinergic neurons from postnatal, two-week-old (P13-P15) rats. Significantly, more catecholaminergic neurons, stained by monoclonal anti-tyrosine hydroxylase antibody, were found in cultures supplemented with interleukin-6 at a concentration of 5 ng/ml than in cultures not treated with interleukin-6. The optimal dose used was 50 ng/ml. The survival effect of interleukin-6 on postnatal rat, tyrosine hydroxylase-positive neurons was observed both in cultures using serum-containing and serum-free medium. Contents of dopamine and noradrenaline in cultures with interleukin-6 were also larger than in control cultures. Interleukin-6 also increased the survival of cultured embryonic (E17) rat midbrain tyrosine hydroxylase-positive neurons. The effect on these neurons was, however, smaller, and the optimal dose of interleukin-6 was nearly 5 ng/ml. Interleukin-6 also supported the survival of cultured postnatal (P13) rat septal cholinergic neurons, visualized by acetylcholinesterase staining. The concomitant addition of mouse nerve growth factor (100 ng/ml) and interleukin-6

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  • MONITORING OF ACETYLCHOLINE RELEASED FROM POSTNATAL RAT BASAL FOREBRAIN CHOLINERGIC NEURONS CULTURED ON MEMBRANE-FILTER BY CELL BED PERFUSION SYSTEM AND HPLC ECD

    N TAKEI, H TSUKUI, K KUMAKURA, H HATANAKA

    EXPERIMENTAL NEUROLOGY   108 ( 3 )   229 - 231   1990年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    A method for the determination of release of endogenous neurotransmitter from cultured neurons has been developed. Basal forebrain cholinergic neurons from postnatal rats were cultured on polyethyleneimine-coated membrane filter with nerve growth factor. The membrane filter, on which the neurons lived and extended neurites, was packed in a cell bed chamber for a closed perfusion. The perfusate was fractionated and the content of acetylcholine released from cultured neurons was measured by high-performance liquid chromatography-electrochemical detection (HPLC-ECD). Acetylcholine release evoked by glutamate and high K+ was 1.5- and 3-fold greater than the spontaneous level. This method for the determination of the neurotransmitter released from cultured neurons is very advantageous for investigating regulation of transmitter release in central neurons.

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  • INTRACELLULAR STORAGE AND EVOKED RELEASE OF ACETYLCHOLINE FROM POSTNATAL RAT BASAL FOREBRAIN CHOLINERGIC NEURONS IN CULTURE WITH NERVE GROWTH-FACTOR

    N TAKEI, H TSUKUI, H HATANAKA

    JOURNAL OF NEUROCHEMISTRY   53 ( 5 )   1405 - 1410   1989年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    Cholinergic neurons from the septum area, the vertical limb of the diagonal band of Broca, and the nucleus basalis of Meynert of postnatal 13-day-old rats were cultured with or without nerve growth factor (NGF) conditions. Total choline acetyltransferase (ChAT) activities, acetylcholine (ACh) contents, and survival numbers of cholinergic neurons in culture from each of three distinct regions were increased by NGF treatment, but little difference was found in cellular ChAT activities and ACh contents obtained in cultures with or without NGF. The result shows that NGF promotes the survival of cholinergic neurons from 13-day-old rats. Furthermore, the release of ACh from cultured neurons was investigated. The cells cultured with NGF showed a larger increase of the high K+-evoked ACh release than those cultured without NGF. However, NGF had no effect on spontaneous release. This suggests that NGF could regenerate and sustain the stimulation-evoked release mechanisms of ACh in cultured cholinergic neurons from postnatal rats.

    DOI: 10.1111/j.1471-4159.1989.tb08531.x

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  • INCREASE IN CHOLINE-ACETYLTRANSFERASE ACTIVITY IN SEPTUM OF RATS AFTER TRANSIENT FOREBRAIN ISCHEMIA - A POSSIBLE ROLE OF FACTORS RELEASED IN THE HIPPOCAMPUS

    K HISANAGA, K KOGURE, H TSUKUI, N TAKEI, C NISHIO, H HATANAKA

    NEUROSCIENCE LETTERS   105 ( 3 )   321 - 325   1989年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Choline acetyltransferase (ChAT) activity increased in rat septum 2 weeks after a transient forebrain ischemia. Extracts were prepared from hippocampus in which CA1 pyramidal neurons had been selectively destroyed by the ischemic insult. ChAT activity in septal neuronal cultures treated with these extracts for 6 days was significantly higher than that in control cultures.

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  • TRANSPLANTATION OF SEPTAL CHOLINERGIC NEURONS TO THE HIPPOCAMPUS IMPROVES MEMORY IMPAIRMENTS OF SPATIAL-LEARNING IN RATS TREATED WITH AF64A

    S IKEGAMI, NIHONMATSU, I, H HATANAKA, N TAKEI, H KAWAMURA

    BRAIN RESEARCH   496 ( 1-2 )   321 - 326   1989年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Embryonic septal neurons were transplanted into damaged hippocampus in adult rats which had received lateral ventricular administration of AF64A, a cholinergic neurotoxin. About 3 months after transplantation, the rats with bilateral septal grafts showed significant improvement in the radial maze and T-maze tasks. Many ingrowths of acetylcholinesterase (AChE)-positive fibers originating from the grafts were observed in the hippocampus of the rats which showed good performance in these learning tasks. These results indicate that transplantation of septal cholinergic neurons into the AF64A-treated hippocampus may induce at least partial recovery in learning tasks believed to involve the hippocampus.

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  • AGE-RELATED DECLINE OF ACETYLCHOLINE-RELEASE EVOKED BY DEPOLARIZING STIMULATION

    N TAKEI, NIHONMATSU, I, H KAWAMURA

    NEUROSCIENCE LETTERS   101 ( 2 )   182 - 186   1989年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Release of endogenous acetylcholine (ACh) from the dorsal hippocampus in response to depolarizing stimulation with high-K+ infusion was examined in young and aged rats using the method of in vivo dialysis. ACh content in the dialysate was determined by high-performance liquid chromatography-electrochemical detection (HPCC-ECD). During the high-K+ stimulation, the concentration of ACh in the dialysate only slightly increased in aged rats in contrast with young rats where the ACh content during stimulation increased about 2-fold of the basal level. These results showed that ACh release evoked by depolarizing stimulation declined through aging in the hippocampus.

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  • RECOVERY OF HIPPOCAMPAL CHOLINERGIC ACTIVITY BY TRANSPLANTATION OF SEPTAL NEURONS IN AF64A TREATED RATS

    S IKEGAMI, NIHONMATSU, I, H HATANAKA, N TAKEI, H KAWAMURA

    NEUROSCIENCE LETTERS   101 ( 1 )   17 - 22   1989年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Embryonic septal neurons were transplanted into the hippocampus of adult rats which had received lateral-ventricular administration of AF64A, a cholinergic neurotoxin, and the effects on hippocampal cholinergic activity were studied. One week after AF64A administration, we injected dissociated septal cell suspension into the dorsal hippocampus, unilaterally. About 3 months after the transplantation, acetylcholine (ACh)-rich septal grafts formed extensive acetylcholinesterase (AChE)-positive fibers into the host hippocampus, recovering choline acetyltransferase (ChAT) level only in the grafted side. These results indicate that septal implants can produce a partial recovery of the cholinergic activity in the chemically damaged hippocampus.

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  • TRANSPLANTATION OF FETAL AND EARLY POSTNATAL RAT SEPTAL CHOLINERGIC NEURONS CULTURED IN SERUM-FREE AND SERUM-CONTAINING MEDIUM WITH NERVE GROWTH-FACTOR

    K HISANAGA, H TSUKUI, N TAKEI, H HATANAKA

    BRAIN RESEARCH   475 ( 2 )   349 - 355   1988年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Fetal rat (E17-E19) septal neurons were cultured in a defined, serum-free medium for 6-8 days with or without nerve growth factor (NGF) and transplanted into the hippocampus or the surrounding ventricle of 28 adult rats denervated of its septal input by a fimbria-fornix transection. The cholinergic septal neurons, which were visualized by acetylcholinesterase (AChE) histochemistry, always survived in transplantation to the adult brains from nearly pure neuronal cultures. Although choline acetyltransferase (ChAT) activity of septal neurons in culture was greatly increased (5.59-fold) by the addition of NGF to the defined medium, this ChAT induction appeared to have little effect on the subsequent survival or growth of the septal neurons after transplantation. These results demonstrate that survival of cultured fetal septal cholinergic neurons following transplantation is not dependent upon the presence of NGF or serum- or glia-derived factors during the preliminary culture. Postnatal rat (P4) septal neurons cultured for 5 days in serum-containing medium with NGF were also successfully transplanted in one of 3 cases.

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  • NERVE GROWTH-FACTOR INCREASES THE INTRACELLULAR CONTENT OF ACETYLCHOLINE IN CULTURED SEPTAL NEURONS FROM DEVELOPING RATS

    N TAKEI, H TSUKUI, H HATANAKA

    JOURNAL OF NEUROCHEMISTRY   51 ( 4 )   1118 - 1125   1988年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    The effects of nerve growth factor (NGF) on the intracellular content of acetylcholine (ACh) in cultured septal neurons from developing rats have been examined. The content of ACh could be measured by using HPLC and electrochemical detection (HPLC-ECD), coupled with an immobilized enzyme column. This method of determination is very simple and rapid, and is highly sensitive. The content of ACh and the activity of choline acetyltransferase (ChAT) in cultured postnatal day 1 (P1) septal neurons grown on an astroglial &quot;feeder&quot; layer was increased during the period of cultivation by the addition of NGF. The activities of ChAT and the content of ACh increased in a dose-dependent manner in direct relationship to the different amounts of NGF employed. These effects of NGF, i.e., elevating the intracellular content of ACh, accompanied by an increase in activity of ChAT, also were confirmed in the P1 septal organotypic cultures. Additionally, embryonic day 17 (E17) septal neurons in a serum-free medium displayed a similar responsiveness to NGF with respect to the elevation in the content of ACh and the increase in activity of ChAT. These results suggest that intracellular levels of ACh are

    DOI: 10.1111/j.1471-4159.1988.tb03076.x

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    担当ページ:pp272-275   記述言語:日本語 著書種別:学術書

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  • 「基礎の基礎」神経細胞特異的翻訳調節機構 招待

    武井延之

    細胞工学   31   642 - 645   2012年6月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(商業誌、新聞、ウェブメディア)   出版者・発行元:学研メディカル秀潤社  

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  • 「翻訳調節と脳高次機能」 神経特異的翻訳調節機構 招待

    武井延之

    細胞工学   31   687 - 691   2012年6月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(商業誌、新聞、ウェブメディア)   出版者・発行元:学研メディカル秀潤社  

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  • 統合失調症とマイクロRNA 招待

    渡部雄一郎, 武井延之, 那波宏之, 染矢俊幸

    分子精神医学   11   179 - 184   2011年7月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(商業誌、新聞、ウェブメディア)   出版者・発行元:先端医学社  

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  • 脳における神経栄養因子の働き 招待

    武井延之

    化学と生物   46   24 - 31   2008年

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)   出版者・発行元:日本農芸化学会  

    DOI: 10.1271/kagakutoseibutsu.46.24

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  • シナプスにおける局所的翻訳調節機構 招待 査読

    武井延之

    生化学   78 ( 10 )   939 - 948   2006年10月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)   出版者・発行元:日本生化学会  

    Web of Science

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  • 網膜における神経栄養因子の発現-実験緑内障眼における脳由来神経栄養因子の定量的解析ー

    関正明, 武井延之, 那波宏之, 福地健郎

    緑内障   14   21 - 24   2004年10月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(大学・研究所紀要)  

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  • 白血病阻害因子の脳内投与によるドパミン・シグナルおよび潜在制止の異常(Central Administration of Leukemia Inhibitory Factor Disrupts Dopaminergic Signaling and Latent Inhibition)

    渡部 雄一郎, 武井 延之, 柿田 明美, 染矢 俊幸, 那波 宏之

    神経化学   43 ( 2-3 )   490 - 490   2004年8月

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    記述言語:英語   出版者・発行元:日本神経化学会  

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講演・口頭発表等

  • Anticancer activity of antipsychotics on brain tumor 国際会議

    Kobayashi Y, Irie K, Kawase A, Takei N, Nawa H

    7th International Society of Radiation Neurobiology Conference  2017年2月  International Society of Radiation Neurobiology

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    記述言語:英語   会議種別:ポスター発表  

    開催地:Yuzawa, Niigata  

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  • 冬眠期のシマリス神経細胞におけるAMPKを上流とした翻訳の抑制

    山田新太郎, 関島恒夫, 那波宏之, 武井延之

    第59回日本神経化学会  2016年9月  日本神経化学会

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    記述言語:日本語   会議種別:ポスター発表  

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  • Epidermal growth factor downregulates presynaptic maturation and suppresses synapse formation in vitro and in vivo. 国際会議

    Takei N, Yokomaku D, Ushiki D, Nawa H

    7th ISN Special Conference  2016年6月  International Society for Neurochemistry

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    記述言語:英語   会議種別:ポスター発表  

    開催地:Coimbra, Portugal  

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  • mTORシグナル系と脳形成異常 招待

    武井延之

    BMB2015(日本生化学会/日本分子生物学会合同年会)  2015年12月  日本生化学会/日本分子生物学会

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    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    開催地:神戸国際会議場  

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  • EGF downregulates presynaptic maturation and suppresses synapse formation in vitro and in vivo. 国際会議

    Takei N, Yokomaku D, Ushiki T, Nawa H

    25th ISN Biennial Meeting  2015年8月  ISN (International Society for Neurochemistry)

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    記述言語:英語   会議種別:ポスター発表  

    開催地:Cairns, Australia  

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  • mTORシグナルと脳神経発達 招待

    武井延之

    第44回日本神経精神薬理学会大会  2014年11月  日本神経精神薬理学会

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    開催地:名古屋国際会議場  

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  • mTOR mediates neuronal maturation and cell size control 招待 国際会議

    Takei N

    ISN Satellite Symposium:Key molecules for neuronal maturation  2014年9月  ISN(International Society for Neurochemistry) /NIHS(National Institute of Health Sciences)

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    記述言語:英語   会議種別:口頭発表(招待・特別)  

    開催地:Yayoi Auditorium, The University of Tokyo, Tokyo Japan  

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共同研究・競争的資金等の研究

  • 成長円錐における局所蛋白合成と細胞骨格の動態との関係解析

    2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    星 治

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    資金種別:競争的資金

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  • mTOR阻害剤による口内炎の発症機序の解明」

    2016年4月 - 2019年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    北村信隆

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    資金種別:競争的資金

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  • 神経発達に伴う細胞サイズ制御機構の解明と病態モデルの確立

    2016年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    武井延之

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    担当区分:研究代表者  資金種別:競争的資金

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  • 冬眠特異的タンパク質HPの機能評価と受容体同定に向けたシマリスの繁殖と神経幹細胞培養系の確立

    2016年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業  挑戦的萌芽研究

    関島恒夫

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    資金種別:競争的資金

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  • 神経細胞のサイズ制御の機構とその破綻による病態の解析

    2013年4月 - 2016年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    武井延之

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    担当区分:研究代表者  資金種別:競争的資金

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  • 皮質異形成の病態機序:体細胞変異仮説の検証

    2013年4月 - 2014年3月

    日本学術振興会  科学研究費助成事業  挑戦的萌芽研究

    柿田明美

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    資金種別:競争的資金

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  • 成長円錐の動態の制御機構解析ー原子間力顕微鏡によるアプローチー

    2012年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    星治

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    資金種別:競争的資金

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  • 抗肥満と抗認知症作用を持つ機能性食品としてのアミノ酸誘導体、ペプチドの探索•開発

    2011年4月 - 2012年3月

    JST  A-STEP 

    武井延之

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    担当区分:研究代表者  資金種別:競争的資金

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  • 中枢神経細胞における軸索内局所的蛋白合成の分子メカニズム

    2010年4月 - 2013年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    武井延之, 難波寿明

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    担当区分:研究代表者  資金種別:競争的資金

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  • 局所的mRNA翻訳マシナリーの活性化と脳高次機能

    2005年4月 - 2007年3月

    文部科学省  科学研究費助成事業  特定領域研究

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    資金種別:競争的資金

    配分額:5600000円 ( 直接経費:5600000円 )

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  • 神経活動に依存した翻訳調節とその生理的意義に関する研究

    2003年4月 - 2006年3月

    日本学術振興会  科学研究費助成事業  基盤研究(B)

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    資金種別:競争的資金

    配分額:5600000円 ( 直接経費:5600000円 )

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  • 刺激に応答したmRNA翻訳マシナリーの神経突起への移動と活性化機構

    2003年4月 - 2004年3月

    文部科学省  科学研究費助成事業  特定領域研究

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    資金種別:競争的資金

    配分額:3200000円 ( 直接経費:3200000円 )

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  • 遺伝性精神遅滞症脆弱X症候群の分子機構解析とその治療への応用

    2001年4月 - 2003年3月

    厚生労働省  厚生労働科学研究費補助金 

    塩見春彦

      詳細を見る

    資金種別:競争的資金

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社会貢献活動

  • 新発田高校学校評議員

    役割:助言・指導

    新潟県  2018年4月 - 現在

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    対象: 高校生

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メディア報道

  • Frontiers in Molecular Neuroscience誌 Editorial Board Member

    2019年

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  • Scientific Reports 誌 Handling Editor

    2011年

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  • Neurochemical Research誌 編集委員

    2009年

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