1998 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	特定領域研究(A)
研究機関	東京大学
研究代表者	三品昌美東京大学, 大学院・医学系研究科, 教授 (80144351)
研究分担者	狩野方伸金沢大学, 医学部, 教授 (40185963) 真鍋俊也東京大学, 大学院・医学系研究科, 講師 (70251212) 渡辺雅彦北海道大学, 大学院・医学研究科, 教授 (70210945) 梅森久視東京大学, 医科学研究所, 助手 (20242117) 八木健岡崎国立共同研究機構, 生理学研究所, 助教授 (10241241)
キーワード	LTP / 学習 / グルタミン酸受容体 / NMDA受容体チャネル / リン酸化 / 小脳プルキンエ細胞 / シナプス形成 / 神経回路網
研究概要	99.99%以上の高い遺伝的均一性を持つNMDA受容体チャネルのε1サブユニット欠損マウスを作製し、ε1サブユニットの欠損により海馬シナプス長期増強と文脈依存学習の閾値がともに上昇することを明らかにした。また、NMDA受容体チャネルのε2サブユニットの細胞内C末端の一部を欠損したマウスでは、NMDA受容体チャネルのシナプス部位への局在が障害され、LTDの誘導も抑制されることを見い出し、ε2サブユニットのc末端とPSD95蛋白との相互作用がシナプス局在に重要であるることを示唆した。H-rasを欠損するマウスでは、海馬CA1領域のLTPが正常の2倍に増大する。このマウスではNMDA受容体チャネルεサブユニットのチロシンリン酸化が増加し、シナプスNMDA応答も増大していることを見い出した。立ち直り反射の消失時間を行動的指標としたエタノールの感受性がFyn欠失マウスでは亢進しており、NMDA受容体チャネルのε2サブユニットが関与していることを明らかにした。また、Fynとシナプスで結合する新規カドヘリンCNR分子群の単離に成功し、シナプス膜に存在していることを明らかにした。 AMPA受容体にはLynチロシンキナーゼが相互作用して下流にシグナルを伝え、BDNF誘導に関わることを明らかにした。また、グルタミン酸受容体チャネルのδ2サブユニット欠損マウスでは平行線維終末と結合しないプルキンエ細胞棘突起が出現していることが判明した。このシナプス結合率の低下はシナプス形成が活性化する生後第二週に起ることから、δ2サブユニットは形成過程にある平行線維シナプスの基盤強化に関わると結論した。また、GaqおよびPLCβ4ノックアウトマウスでは、生後3週目以降に約1/3のプルキンエ細胞が複数の登上線維による多重支配を受けていた。この発達異常はmGIuR1欠損マウスおよびPKCγ欠損マウスと同様であり、mGIuR1-Gaq一PLCβ4-PKCγを介する細胞内シグナル伝達系が発達期の過剰な登上線維排除に必須であることが明らかになった。また、これらのノックアウトマウスでは、平行線維-プルキンエ細胞シナプスのLTDが欠如しており、LTDにこれらの分子が関与することが明らかになった。

研究成果
(39件)

すべてその他

すべて文献書誌 (39件)

[文献書誌] Taniguchi,M.: "Efficient production of Cre-mediated site-directed recombinants through the utilization of the puromycin resistance gene,pac: a transient gene-integration marker for ES cells." Nucleic Acids Res.26. 679-680 (1998)
[文献書誌] Watanabe,M.: "Selective scarcity of NMDA receptor channel subunits in the stratum lucidum (mossy fiber-recipient layer) of the hippocampal CA3 subfield." Eur.J.Neurosci.10. 478-487 (1998)
[文献書誌] Kohmura,N.: "Diversity revealed by a novel family of cadherins expressed in neurons at synaptic complex." Neuron. 20. 1137-1151 (1998)
[文献書誌] Kiyama,Y.: "Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor ε1 subunit." J.Neurosci.18. 6704-6712 (1998)
[文献書誌] Mori,H.: "Role of the carboxyl-terminal region of the GluRε2 subunit in synaptic localization of the NMDA receptor channel." Neuron. 21. 571-580 (1998)
[文献書誌] Munemoto,Y.: "Auditory pathway and auditory brainstem response in mice lacking NMDA receptor ε1 and ε4 subunits." Neurosci.Lett.251. 101-104 (1998)
[文献書誌] Kitahara,T.: "Unilateral labyrinthectomy downregulates glutamate receptor δ2 expression in the rat vestibulocerebellum." Mol.Brain Res.61. 170-178 (1998)
[文献書誌] Morikawa,E.: "Attenuation of focal ischemic brain injury in mice deficient in the ε1 (NR2A) subunit of NMDA receptor." J.Neurosci.18. 9727-9732 (1998)
[文献書誌] Manabe,T.: "Two forms of hippocampal long-term depression,the counterpart of long-term potentiation" Rev.Neurosci.8. 179-193 (1998)
[文献書誌] Manabe,T.: "Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors" Nature. 394. 577-581 (1998)
[文献書誌] Ito,I.: "Distribution and development of NMDA receptor activities at hippocampal synapses examined using mice lacking the ε1 subunit gene." Neurosci.Res.30. 119-123 (1998)
[文献書誌] Kasahara,J.: "Modulation of glutamate sensitivities by inhibitors of a protein kinase and a protein phosphatase in cultured rat Purkinje cells." Neurosci.Lett.247. 139-142 (1998)
[文献書誌] Kato,A.: "Novel members of the Vesl/Homer family of PDZ proteins that bind metabotropic glutamate receptors." J.Biol.Chem.273. 23969-23975 (1998)
[文献書誌] Kitazawa,H.: "Abnormal synaptic transmission in the olfactory bulb of Fyn-kinase deficient mice." J.Neurophysiol.79. 137-142 (1998)
[文献書誌] Harada,T.: "Retinal glial cell glutamate transporter plays a crucial role in glutamate clearance." Proc.Natl.Acad.Sci.USA. 95. 4663-4666 (1998)
[文献書誌] Watase,K.: "Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice." Eur.J.Neurosci.10. 976-988 (1998)
[文献書誌] Nakagawa,S.: "Cytological compartmentalization in the staggerer cerebellum,as revealed by calbindin immunohistochemistry for Purkinje cells." J.Comp.Neurol.395. 112-120 (1998)
[文献書誌] Yamada,K.: "Glutamate transporter GLT-1 is transiently localized on growing axons of the mouse spinal cord before establishing astrocytic expression." J.Neurosci.18. 5706-5713 (1998)
[文献書誌] Watanabe,M.: "Patterns of expression for the mRNA corresponding to the four isoforms of phospholipase Cβ in mouse brain." Eur.J.Neurosci.10. 2016-2025 (1998)
[文献書誌] Manya,H.: "Switching of platelet-activating factor acetylhydrolase catalytic subunits in developing rat brain." J.Biol.Chem.273. 18567-18572 (1998)
[文献書誌] Mitani,A.: "Functional change of NMDA receptors related to enhancement of susceptibility to neurotoxicity in the developing pontine nucleus." J.Neurosci.18. 7941-7952 (1998)
[文献書誌] Mizuta,I.: "Developmental expression of NMDA receptor subunits and the emergence of glutamate neurotoxicity in primary cultures of murine cerebral cortical neurons." Cell.Mol.Life Sci.54. 721-725 (1998)
[文献書誌] Ikeda,K.: "Distribution of prepro-nociceptin/orphanin FQ mRNA and its receptor mRNA in developing and adult mouse central nervous systems." J.Comp.Neurol.399. 139-151 (1998)
[文献書誌] Hashimoto,K.: "Presynaptic origin of paired-pulse depression at climbing fibre to Purkinje cell synapses in the rat cerebellum." J.Physiol.(London). 506. 391-405 (1998)
[文献書誌] Watanabe,D.: "Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination." Cell. 95. 17-27 (1998)
[文献書誌] Kano,M.: "PLCβ4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum." Proc.Natl.Acad.Sci.USA.95. 15724-15729 (1998)
[文献書誌] Yamakura,T.: "Sensitivity of the N-methyl-D-aspartate receptor channel to butyrophenones is dependent on the ε2 subunit." Neuropharmacology. 37. 709-717 (1998)
[文献書誌] Yoshida,Y.: "ANA,a novel member of Tob/BTGl family,is expressed in the ventricular zone of the developing central nervous system." Oncogene. 16. 2687-2693 (1998)
[文献書誌] Hayashi,T.: "The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn." Nature. 397. 72-76 (1999)
[文献書誌] Furuyashiki,T.: "Citron,a Rho-target,interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus." J.Neurosci.19. 109-118 (1998)
[文献書誌] Tezuka,T.: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A." Proc.Natl.Acad.Sci.USA. 96. 435-440 (1999)
[文献書誌] Kobayashi,K.: "Platelet-activating factor receptor is not required for long-term potentitation in the hippocampal CA1 region." Eur.J.Neurosci.(in press). (1999)
[文献書誌] Kobayashi,K.: "Calcium-dependent mechanisms involved in presynaptic LTD at the hippocampal mossy fiber-CA3 synapse" Eur.J.Neurosci.(in press). (1999)
[文献書誌] Toki,S.: "Early establishment of lesion-insensitive mature barrelettes corresponding to upper lip vibrissae in developing mice." Neurusci.Res.(in press). (1999)
[文献書誌] Fukaya,M.: "Spatiotemporal expression of mRNAs for PSD-95/SAP90 protein family in the mouse brain." Neurosci.Res.(in press). (1999)
[文献書誌] Shibata,T.: "Different expressions of AMPA and NMDA receptor subunit mRNAs between visceromotor and somatomotor neurons of the rat lumbosacral spinal cord." J.Comp.Neurol.(in press). (1999)
[文献書誌] Yagi,T.: "Molecular mechanisms of Fyn-tyrosine kinase for regulating mammalian behaviors and an ethanol sensitivity." Biochemical Pharmacology. in press.(1999)
[文献書誌] Tsubokawa,H.: "Elevation of intracellular Na^+ induced by hyperpolarization at the dendrites of pyramidal neurones of mouse hippocampus." J.Physiol.(London). in press.(1999)
[文献書誌] Umemori,H.: "Stimulation of myelin basic protein gene transcription by Fyn tyrosine kinase for myelination." J.Neurosci.in press.(1999)

1998 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, 大学院・医学系研究科, 教授 (80144351)

研究成果

[文献書誌] Taniguchi,M.: "Efficient production of Cre-mediated site-directed recombinants through the utilization of the puromycin resistance gene,pac: a transient gene-integration marker for ES cells." Nucleic Acids Res.26. 679-680 (1998)

[文献書誌] Watanabe,M.: "Selective scarcity of NMDA receptor channel subunits in the stratum lucidum (mossy fiber-recipient layer) of the hippocampal CA3 subfield." Eur.J.Neurosci.10. 478-487 (1998)

[文献書誌] Kohmura,N.: "Diversity revealed by a novel family of cadherins expressed in neurons at synaptic complex." Neuron. 20. 1137-1151 (1998)

[文献書誌] Kiyama,Y.: "Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor ε1 subunit." J.Neurosci.18. 6704-6712 (1998)

[文献書誌] Mori,H.: "Role of the carboxyl-terminal region of the GluRε2 subunit in synaptic localization of the NMDA receptor channel." Neuron. 21. 571-580 (1998)

[文献書誌] Munemoto,Y.: "Auditory pathway and auditory brainstem response in mice lacking NMDA receptor ε1 and ε4 subunits." Neurosci.Lett.251. 101-104 (1998)

[文献書誌] Kitahara,T.: "Unilateral labyrinthectomy downregulates glutamate receptor δ2 expression in the rat vestibulocerebellum." Mol.Brain Res.61. 170-178 (1998)

[文献書誌] Morikawa,E.: "Attenuation of focal ischemic brain injury in mice deficient in the ε1 (NR2A) subunit of NMDA receptor." J.Neurosci.18. 9727-9732 (1998)

[文献書誌] Manabe,T.: "Two forms of hippocampal long-term depression,the counterpart of long-term potentiation" Rev.Neurosci.8. 179-193 (1998)

[文献書誌] Manabe,T.: "Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors" Nature. 394. 577-581 (1998)

[文献書誌] Ito,I.: "Distribution and development of NMDA receptor activities at hippocampal synapses examined using mice lacking the ε1 subunit gene." Neurosci.Res.30. 119-123 (1998)

[文献書誌] Kasahara,J.: "Modulation of glutamate sensitivities by inhibitors of a protein kinase and a protein phosphatase in cultured rat Purkinje cells." Neurosci.Lett.247. 139-142 (1998)

[文献書誌] Kato,A.: "Novel members of the Vesl/Homer family of PDZ proteins that bind metabotropic glutamate receptors." J.Biol.Chem.273. 23969-23975 (1998)

[文献書誌] Kitazawa,H.: "Abnormal synaptic transmission in the olfactory bulb of Fyn-kinase deficient mice." J.Neurophysiol.79. 137-142 (1998)

[文献書誌] Harada,T.: "Retinal glial cell glutamate transporter plays a crucial role in glutamate clearance." Proc.Natl.Acad.Sci.USA. 95. 4663-4666 (1998)

[文献書誌] Watase,K.: "Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice." Eur.J.Neurosci.10. 976-988 (1998)

[文献書誌] Nakagawa,S.: "Cytological compartmentalization in the staggerer cerebellum,as revealed by calbindin immunohistochemistry for Purkinje cells." J.Comp.Neurol.395. 112-120 (1998)

[文献書誌] Yamada,K.: "Glutamate transporter GLT-1 is transiently localized on growing axons of the mouse spinal cord before establishing astrocytic expression." J.Neurosci.18. 5706-5713 (1998)

[文献書誌] Watanabe,M.: "Patterns of expression for the mRNA corresponding to the four isoforms of phospholipase Cβ in mouse brain." Eur.J.Neurosci.10. 2016-2025 (1998)

[文献書誌] Manya,H.: "Switching of platelet-activating factor acetylhydrolase catalytic subunits in developing rat brain." J.Biol.Chem.273. 18567-18572 (1998)

[文献書誌] Mitani,A.: "Functional change of NMDA receptors related to enhancement of susceptibility to neurotoxicity in the developing pontine nucleus." J.Neurosci.18. 7941-7952 (1998)

[文献書誌] Mizuta,I.: "Developmental expression of NMDA receptor subunits and the emergence of glutamate neurotoxicity in primary cultures of murine cerebral cortical neurons." Cell.Mol.Life Sci.54. 721-725 (1998)

[文献書誌] Ikeda,K.: "Distribution of prepro-nociceptin/orphanin FQ mRNA and its receptor mRNA in developing and adult mouse central nervous systems." J.Comp.Neurol.399. 139-151 (1998)

[文献書誌] Hashimoto,K.: "Presynaptic origin of paired-pulse depression at climbing fibre to Purkinje cell synapses in the rat cerebellum." J.Physiol.(London). 506. 391-405 (1998)

[文献書誌] Watanabe,D.: "Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination." Cell. 95. 17-27 (1998)

[文献書誌] Kano,M.: "PLCβ4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum." Proc.Natl.Acad.Sci.USA.95. 15724-15729 (1998)

[文献書誌] Yamakura,T.: "Sensitivity of the N-methyl-D-aspartate receptor channel to butyrophenones is dependent on the ε2 subunit." Neuropharmacology. 37. 709-717 (1998)

[文献書誌] Yoshida,Y.: "ANA,a novel member of Tob/BTGl family,is expressed in the ventricular zone of the developing central nervous system." Oncogene. 16. 2687-2693 (1998)

[文献書誌] Hayashi,T.: "The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn." Nature. 397. 72-76 (1999)

[文献書誌] Furuyashiki,T.: "Citron,a Rho-target,interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus." J.Neurosci.19. 109-118 (1998)

[文献書誌] Tezuka,T.: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A." Proc.Natl.Acad.Sci.USA. 96. 435-440 (1999)

[文献書誌] Kobayashi,K.: "Platelet-activating factor receptor is not required for long-term potentitation in the hippocampal CA1 region." Eur.J.Neurosci.(in press). (1999)

[文献書誌] Kobayashi,K.: "Calcium-dependent mechanisms involved in presynaptic LTD at the hippocampal mossy fiber-CA3 synapse" Eur.J.Neurosci.(in press). (1999)

[文献書誌] Toki,S.: "Early establishment of lesion-insensitive mature barrelettes corresponding to upper lip vibrissae in developing mice." Neurusci.Res.(in press). (1999)

[文献書誌] Fukaya,M.: "Spatiotemporal expression of mRNAs for PSD-95/SAP90 protein family in the mouse brain." Neurosci.Res.(in press). (1999)

[文献書誌] Shibata,T.: "Different expressions of AMPA and NMDA receptor subunit mRNAs between visceromotor and somatomotor neurons of the rat lumbosacral spinal cord." J.Comp.Neurol.(in press). (1999)

[文献書誌] Yagi,T.: "Molecular mechanisms of Fyn-tyrosine kinase for regulating mammalian behaviors and an ethanol sensitivity." Biochemical Pharmacology. in press.(1999)

[文献書誌] Tsubokawa,H.: "Elevation of intracellular Na^+ induced by hyperpolarization at the dendrites of pyramidal neurones of mouse hippocampus." J.Physiol.(London). in press.(1999)

[文献書誌] Umemori,H.: "Stimulation of myelin basic protein gene transcription by Fyn tyrosine kinase for myelination." J.Neurosci.in press.(1999)

1998 年度実績報告書

三品昌美東京大学, 大学院・医学系研究科, 教授 (80144351)