1995 年度実績報告書

シナプス伝達受容分子と可塑性

研究課題

研究課題/領域番号	07278102
研究種目	重点領域研究
研究機関	東京大学
研究代表者	三品昌美東京大学, 医学部(医), 教授 (80144351)
研究分担者	崎村建司新潟大学, 脳研究所, 助教授 (40162325) 渡辺雅彦北海道大学, 医学部, 助教授 (70210945) 杉山博之九州大学, 理学部, 教授 (20124224) 高橋智幸東京大学, 医学部(医), 教授 (40092415) 二木宏明東京大学, 大学院・人文・社会系研究科, 教授 (10073074)
キーワード	グルタミン酸受容体 / NMDA受容体 / ノックアウトマウス / シナプス可塑性 / シナプス形成 / 記憶 / 学習 / 運動失調
研究概要	本研究班は、シナプス伝達の長期増強および長期抑圧の機構を解明することならびに中枢シナプス可塑性と記憶・学習をはじめとする脳の高次機能との関係を実験的に検証することを目的とする。とくに、中枢における神経情報伝達とシナプス可塑性の鍵を握るグルタミン酸受容体を実体として明らかにした成果を基盤に、遺伝子ノックアウトを重視した。シナプス可塑性を担うと推論したNMDA受容体チャネルのε1サブユニットを欠損したマウスを標的遺伝子組換え法により作製した。ε1サブユニット欠損マウスは普通に発育し、脳神経系は形態学的にも組織化学的にも正常であった。海馬スライス標本にパッチクランプ法を適用し、NMDA受容体チャネル電流を測定した結果、ε1サブユニット欠損マウスではAMPA受容体チャネル電流に対するNMDA受容体チャネル電流の相対的な比率が約半分に低下していることを示した。さらに、ε1サブユニット欠損マウスでは高頻度刺激により誘発される海馬シナプスの長期増強の程度も低下していること、すなわちシナプスの可塑性が減少していることを見い出した。最後に、モリスの水迷路学習法を用いてε1サブユニット欠損マウスは低い学習能力しか示さないことを明らかにした。この結果は、ある種の記憶・学習はシナプス可塑性に基づいているとの考えを支持するものである。また、小脳プルキニエ細胞に特異的に発現するδ2サブユニット欠損マウスは運動失調を示し、平行線維とプルキニエ細胞間のシナプス長期抑圧が観察されないことを見い出した。さらに、平行線維とプルキニエ細胞間のシナプス数の減少ならびに登上線維によるプルキニエ細胞の多重支配を電子顕微鏡および電気生理学解析により明らかにした。これらの結果は、小脳においてシナプス可塑性とシナプス形成の分子基盤に密接な関連のあることを示唆している。本成果は、多くの計画班員の協同研究で達成されたものであり、Nature、Cell誌に発表した。

研究成果
(44件)

すべてその他

すべて文献書誌 (44件)

[文献書誌] Mori, H.: "Structure and function of the NMDA receptor channel." Neuropharmacology. 34. 1219-1237 (1995)
[文献書誌] Morita, T.: "Differential expression of two zebrafish emx homeoprotein mRNAs in the developing brain." Neurosci. Lett.198. 131-134 (1995)
[文献書誌] Kawamoto, S.: "N-linked glycosylation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate(AMPA)-selective glutamate receptor channel α2 subunit is essential for the acquisition of ligand-bindingactivity." J. Neurochem.64. 1258-1266 (1995)
[文献書誌] Hirano, T.: "Suppression of LTD in cultured Purkinje cells deficient in the glutamate receptor δ2 subunit." NeuroReport. 6. 524-526 (1995)
[文献書誌] Kawamoto, S.: "Expression and characterization of the ζ1 subunit of the N-methyl-D-aspartate(NMDA)receptor channel in a Baculovirus system." Mol. Brain Res.30. 137-148 (1995)
[文献書誌] Ibaraki, K.: "Identification of four different forma of syntaxin3." Biochem. Biophys. Res. Commun.211. 997-1005 (1995)
[文献書誌] Sakimura, K.: "Upstream and intron regulatory regions for expression of the rat neuron-specific enolase gene" Molecular Brain Research. 28. 19-28 (1995)
[文献書誌] Yamakura, T.: "Effects of propofol on various AMPA-,kainate- and NMDA-selective glutamate receptor channels expressed in Xenopus oocytes" Neuroscience Letters.188. 187-190 (1995)
[文献書誌] Yamakura, T.: "The sensitivity of AMPA-selective glutamate receptor channels to pentobarbital is determined by a single amino residue of the α2 subunit" FEBS Letters.374. 412-414 (1995)
[文献書誌] Nagasawa, M.: "Gene structure and chromosomal localization of the mouse NMDA receptor channel subunits" Molecular Brain Research. (in press).
[文献書誌] Kutsuwada, T.: "Impairment of suckling response,trigeminal neuronal pattern formation and hippocampal LTD in NMDA receptor ε2 subunit mutant mice" Neuron. (in press).
[文献書誌] T. Tezuka: "Physical and functional association of the cbl proto-oncogene product with a Src-family protein tyrosine kinase, p53/56lyn" Journal of Experimental Medicine. (in press).
[文献書誌] Tsuyoshi Miyakawa: "Enhanced susceptibility of audiogenic seizures in Fyn-kinase deficient mice." Molecular Brain Research. 28. 349-352 (1995)
[文献書誌] Tsuyoshi Miyakawa: "Radial maze performance,open-field. and elevated plus maze behaviors in Fyn-kinase deficient mice." Molecular Brain Research. (in press).
[文献書誌] Nobuko Kashiwabuchi: "Impairment of motor coordination,Purkinje cell synaps formation, and cerebellar long-term depression in GluR d2 mutant" Cell. 81. 245-252 (1995)
[文献書誌] Kazuaki Ikeda: "Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel." Molecular Brain Research. 33. 61-71 (1995)
[文献書誌] Michio Yoshida: "A new strategy of gene trapping in ES cells using 3′RACE." Transgenic Research. 4. 277-287 (1995)
[文献書誌] Satoshi Watanabe: "Stable production of mutant mice from double gene converted ES cells with puromycin and neomycin." Biochemical and Biophysical Research Communications. 213. 130-137 (1995)
[文献書誌] Watanabe, M.: "Cerebellum of the adult reeler mutant mouse contains two Purkinje cell populations with respect to gene expression for the N-methyl-D-aspartate receptor channel." Neurosci. Res.22. 335-345 (1995)
[文献書誌] Watanabe, M.: "Mice deficient in cystathionine β-synthase:Aminal models for mild and severe homocyst(e)inemia." Proc. Natl. Acad. Sci. USA. 92. 1585-1589 (1995)
[文献書誌] Takayama, C.: "Light-and electron-microscopic localization of the glutamate receptor channel δ2 subunit in the mouse Purkinje cell." Neurosci. Lett.188. 89-92 (1995)
[文献書誌] Ono, Y.: "Developmental expression of APEX nuclease, a multifunctional DNA repair enzyme, in mouse brain." Dev. Brain Res.86. 1-6 (1995)
[文献書誌] Shibata, T.: "Dynamic changes in expression of glutamate transporter mRNAs in developing brain." Neuroreport. (in press).
[文献書誌] Takayama, C.: "Developmental changes in expression and distribution of the glutamate receptor channel δ2 subunit according to the Purkinje cell maturation." Dev. Brain Res.(in press).
[文献書誌] Tatanabe, M.: "Developmental regulation of ionotropic glutamate receptor gene expression and functional correlations." Receptor Dynamics in Neural Development. (ed. Shaw. C. ). CRC Press.(in press).
[文献書誌] 渡辺雅彦: "脳の発達とグルタミン酸受容体" 化学と生物. 34. 7-9 (1996)
[文献書誌] 渡辺雅彦: "NMDA型グルタミン酸受容体サブユニット" 細胞. 28. 7-12 (1996)
[文献書誌] Silver RA: "Non-NMDA receptor occupancy during transmission at rat cerebellar mossy fibre-granule cell synapses with only one functional release site." Journal of Physiology(London). 489. 16P (1995)
[文献書誌] Larkman PM: "Adenosine3′: 5′-cyclic monophosphate mediates a 5-HT-induced response in neonatal rat motoneurons." Pflugers Arch. 430. 763-769 (1995)
[文献書誌] Takei Y: "Synapsin I deficiency results in the structural change in the presynaptic terminals in the murine nervous system." Journal of Cell Biology. 131. 1789-1800 (1995)
[文献書誌] Minakami, R.: "The expression of two splice variants of metabotropic glutamate receptor subtype 5 in the rat brain and neuronal cells during development" J. Neurochem.65. 1536-1542 (1995)
[文献書誌] Sakimura, K.: "Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit" Nature. 373. 151-155 (1995)
[文献書誌] Ito, I.: "Age-dependent reductuion of hippocampal LTP in mice lacking NMDA receptor ε1 subuint" Neurosci. Lett.203. 69-71 (1996)
[文献書誌] 杉山博之: "メタボトロピック・グルタミン酸受容体の特性と海馬シナプスにおける役割" 日本生理学雑誌(J. Physiol. Soc. Jpn.). 57. 253-260 (1995)
[文献書誌] Hori Y: "Long-lasting synaptic facilitation induced by serotonin in superficial dorsal horn neurones of rat spinal cord." Journal of Physiology(London). (in press).
[文献書誌] Silver RA: "Non-NMDA glutamate receptor occupancy and open probability at a rat cerebellar synapse with single and multiple release sites." Journal of Physiology(London). (in press).
[文献書誌] Kano, M.: "Ryanodine receptor-mediated calcium release in rat cerebellar Purkinje neurones" Journal of Physiology(London). 487. 1-16 (1995)
[文献書誌] Kano, M.: "Impaired synapse elimination during cerebellar development in PKCγ mutant mice" Cell. 83. 1223-1231 (1995)
[文献書誌] Chen, C.: "Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKCγ mutant mice" Cell. 83. 1233-1242 (1995)
[文献書誌] Kano, M.: "Depolarization-induced calcium signals in the somata of cerebellar Purkinje neurons" Neuroscience Research. 24. 87-95 (1995)
[文献書誌] Kano, M.: "Plasticity of inhibitory synapses in the brain:a possible memory mechanism that has been overlooked" Neuroscience Research. 21. 177-182 (1995)
[文献書誌] Tempia, F.: "The fractional calcium current through neuronal AMPA receptor channels with a ‘low' calcium permeability" Journal of Neuroscience. (in press).
[文献書誌] Kano, M.: "Long-lasting potentiation of GABAergic inhibitory synaptic transmission in cerebellar Purkinje cells:its properties and possible mechanisms" Behavioral Brain Science. (in press).
[文献書誌] Takeshi Yagi: "Genes for development,cell growth and infectious diseases(Gene targeting of fyn tyrosine kinase in murine nervous Syatem)" 262 (1995)

1995 年度 実績報告書

シナプス伝達受容分子と可塑性

研究代表者

三品 昌美 東京大学, 医学部(医), 教授 (80144351)

研究成果

[文献書誌] Mori, H.: "Structure and function of the NMDA receptor channel." Neuropharmacology. 34. 1219-1237 (1995)

[文献書誌] Morita, T.: "Differential expression of two zebrafish emx homeoprotein mRNAs in the developing brain." Neurosci. Lett.198. 131-134 (1995)

[文献書誌] Kawamoto, S.: "N-linked glycosylation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate(AMPA)-selective glutamate receptor channel α2 subunit is essential for the acquisition of ligand-bindingactivity." J. Neurochem.64. 1258-1266 (1995)

[文献書誌] Hirano, T.: "Suppression of LTD in cultured Purkinje cells deficient in the glutamate receptor δ2 subunit." NeuroReport. 6. 524-526 (1995)

[文献書誌] Kawamoto, S.: "Expression and characterization of the ζ1 subunit of the N-methyl-D-aspartate(NMDA)receptor channel in a Baculovirus system." Mol. Brain Res.30. 137-148 (1995)

[文献書誌] Ibaraki, K.: "Identification of four different forma of syntaxin3." Biochem. Biophys. Res. Commun.211. 997-1005 (1995)

[文献書誌] Sakimura, K.: "Upstream and intron regulatory regions for expression of the rat neuron-specific enolase gene" Molecular Brain Research. 28. 19-28 (1995)

[文献書誌] Yamakura, T.: "Effects of propofol on various AMPA-,kainate- and NMDA-selective glutamate receptor channels expressed in Xenopus oocytes" Neuroscience Letters.188. 187-190 (1995)

[文献書誌] Yamakura, T.: "The sensitivity of AMPA-selective glutamate receptor channels to pentobarbital is determined by a single amino residue of the α2 subunit" FEBS Letters.374. 412-414 (1995)

[文献書誌] Nagasawa, M.: "Gene structure and chromosomal localization of the mouse NMDA receptor channel subunits" Molecular Brain Research. (in press).

[文献書誌] Kutsuwada, T.: "Impairment of suckling response,trigeminal neuronal pattern formation and hippocampal LTD in NMDA receptor ε2 subunit mutant mice" Neuron. (in press).

[文献書誌] T. Tezuka: "Physical and functional association of the cbl proto-oncogene product with a Src-family protein tyrosine kinase, p53/56lyn" Journal of Experimental Medicine. (in press).

[文献書誌] Tsuyoshi Miyakawa: "Enhanced susceptibility of audiogenic seizures in Fyn-kinase deficient mice." Molecular Brain Research. 28. 349-352 (1995)

[文献書誌] Tsuyoshi Miyakawa: "Radial maze performance,open-field. and elevated plus maze behaviors in Fyn-kinase deficient mice." Molecular Brain Research. (in press).

[文献書誌] Nobuko Kashiwabuchi: "Impairment of motor coordination,Purkinje cell synaps formation, and cerebellar long-term depression in GluR d2 mutant" Cell. 81. 245-252 (1995)

[文献書誌] Kazuaki Ikeda: "Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel." Molecular Brain Research. 33. 61-71 (1995)

[文献書誌] Michio Yoshida: "A new strategy of gene trapping in ES cells using 3′RACE." Transgenic Research. 4. 277-287 (1995)

[文献書誌] Satoshi Watanabe: "Stable production of mutant mice from double gene converted ES cells with puromycin and neomycin." Biochemical and Biophysical Research Communications. 213. 130-137 (1995)

[文献書誌] Watanabe, M.: "Cerebellum of the adult reeler mutant mouse contains two Purkinje cell populations with respect to gene expression for the N-methyl-D-aspartate receptor channel." Neurosci. Res.22. 335-345 (1995)

[文献書誌] Watanabe, M.: "Mice deficient in cystathionine β-synthase:Aminal models for mild and severe homocyst(e)inemia." Proc. Natl. Acad. Sci. USA. 92. 1585-1589 (1995)

[文献書誌] Takayama, C.: "Light-and electron-microscopic localization of the glutamate receptor channel δ2 subunit in the mouse Purkinje cell." Neurosci. Lett.188. 89-92 (1995)

[文献書誌] Ono, Y.: "Developmental expression of APEX nuclease, a multifunctional DNA repair enzyme, in mouse brain." Dev. Brain Res.86. 1-6 (1995)

[文献書誌] Shibata, T.: "Dynamic changes in expression of glutamate transporter mRNAs in developing brain." Neuroreport. (in press).

[文献書誌] Takayama, C.: "Developmental changes in expression and distribution of the glutamate receptor channel δ2 subunit according to the Purkinje cell maturation." Dev. Brain Res.(in press).

[文献書誌] Tatanabe, M.: "Developmental regulation of ionotropic glutamate receptor gene expression and functional correlations." Receptor Dynamics in Neural Development. (ed. Shaw. C. ). CRC Press.(in press).

[文献書誌] 渡辺雅彦: "脳の発達とグルタミン酸受容体" 化学と生物. 34. 7-9 (1996)

[文献書誌] 渡辺雅彦: "NMDA型グルタミン酸受容体サブユニット" 細胞. 28. 7-12 (1996)

[文献書誌] Silver RA: "Non-NMDA receptor occupancy during transmission at rat cerebellar mossy fibre-granule cell synapses with only one functional release site." Journal of Physiology(London). 489. 16P (1995)

[文献書誌] Larkman PM: "Adenosine3′: 5′-cyclic monophosphate mediates a 5-HT-induced response in neonatal rat motoneurons." Pflugers Arch. 430. 763-769 (1995)

[文献書誌] Takei Y: "Synapsin I deficiency results in the structural change in the presynaptic terminals in the murine nervous system." Journal of Cell Biology. 131. 1789-1800 (1995)

[文献書誌] Minakami, R.: "The expression of two splice variants of metabotropic glutamate receptor subtype 5 in the rat brain and neuronal cells during development" J. Neurochem.65. 1536-1542 (1995)

[文献書誌] Sakimura, K.: "Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit" Nature. 373. 151-155 (1995)

[文献書誌] Ito, I.: "Age-dependent reductuion of hippocampal LTP in mice lacking NMDA receptor ε1 subuint" Neurosci. Lett.203. 69-71 (1996)

[文献書誌] 杉山博之: "メタボトロピック・グルタミン酸受容体の特性と海馬シナプスにおける役割" 日本生理学雑誌(J. Physiol. Soc. Jpn.). 57. 253-260 (1995)

[文献書誌] Hori Y: "Long-lasting synaptic facilitation induced by serotonin in superficial dorsal horn neurones of rat spinal cord." Journal of Physiology(London). (in press).

[文献書誌] Silver RA: "Non-NMDA glutamate receptor occupancy and open probability at a rat cerebellar synapse with single and multiple release sites." Journal of Physiology(London). (in press).

[文献書誌] Kano, M.: "Ryanodine receptor-mediated calcium release in rat cerebellar Purkinje neurones" Journal of Physiology(London). 487. 1-16 (1995)

[文献書誌] Kano, M.: "Impaired synapse elimination during cerebellar development in PKCγ mutant mice" Cell. 83. 1223-1231 (1995)

[文献書誌] Chen, C.: "Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKCγ mutant mice" Cell. 83. 1233-1242 (1995)

[文献書誌] Kano, M.: "Depolarization-induced calcium signals in the somata of cerebellar Purkinje neurons" Neuroscience Research. 24. 87-95 (1995)

[文献書誌] Kano, M.: "Plasticity of inhibitory synapses in the brain:a possible memory mechanism that has been overlooked" Neuroscience Research. 21. 177-182 (1995)

[文献書誌] Tempia, F.: "The fractional calcium current through neuronal AMPA receptor channels with a ‘low' calcium permeability" Journal of Neuroscience. (in press).

[文献書誌] Kano, M.: "Long-lasting potentiation of GABAergic inhibitory synaptic transmission in cerebellar Purkinje cells:its properties and possible mechanisms" Behavioral Brain Science. (in press).

[文献書誌] Takeshi Yagi: "Genes for development,cell growth and infectious diseases(Gene targeting of fyn tyrosine kinase in murine nervous Syatem)" 262 (1995)

1995 年度実績報告書

三品昌美東京大学, 医学部(医), 教授 (80144351)