1994 Fiscal Year Annual Research Report

NMDA受容体チャネル欠損マウスの作成

Research Project

Project/Area Number	05404085
Research Institution	University of Tokyo
Principal Investigator	三品昌美東京大学, 医学部(医), 教授 (80144351)
Keywords	NMDA受容体チャネル / ε1サブユニット / シナプス可塑性 / シナプス長期増強 / 空間学習 / 標的遺伝子組換え(遺伝子ノックアウト) / 海馬 / 記憶・学習のシナプス可塑性仮説
Research Abstract	我々はcDNAの単離、発現と機能解析によって、NMDA受容体チャネルのε1サブユニットおよびε2サブユニットがシナプス可塑性に関与しているとの作業仮説に到達した。この仮説を検証し、同時にシナプス可塑性と記憶・学習との関係を明らかにすることを目的に、ε1サブユニット欠損マウスを標的遺伝子組換えにより作製し、以下の成果を挙げた。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。残存するNMDA受容体チャネル電流はε2サブユニットによるものと推察した。さらに、ε1サブユニット欠損マウスでは高頻度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、ε1サブユニット欠損マウスの学習能力をモリスの水迷路学習法を用いて検討した。ヒドンプラットフォームテストおよびトランスファーテストのいずれにおいても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。すなわち、ε1サブニットは実際に脳神経系で機能しているNMDA受容体チャネルを形成し、海馬シナプスの長期増強およびマウスの空間学習に関与していることを示した。これらの結果は、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。

Research Products

(17 results)

All Other

All Publications (17 results)

[Publications] Watanabe,M.: "Differential distributions of the NMDA receptor channel subunit mRNAs in the mouse retina." Brain Res.634. 328-332 (1994)
[Publications] Watanabe,M.: "Distinct gene expression of the N-methyl-D-aspartate receptor channel subunit in peripheral neurons of the mouse sensory ganglia and adrenal gland." Neurosci.Lett.165. 183-186 (1994)
[Publications] Ishida,N.: "Circadian expression of NMDA receptor mRNAs,ε3 and ζ1,in the suprachiasmatic nucleus of rat brain." Neurosci.Lett.166. 211-215 (1994)
[Publications] Watanabe,M.: "Distinct spatio-temporal expressions of five NMDA receptor channel subunit mRNAs in the cerebellum." J.Comp.Neurol.343. 513-519 (1994)
[Publications] Watanabe,M.: "Distinct distributions of five NMDA receptor channel subunit mRNAs in the brainstem." J.Comp.Neurol.343. 520-531 (1994)
[Publications] Watanabe,M.: "Distinct spatio-temporal distributions of the NMDA receptor channel subunit mRNAs in the mouse cervical cord." J.Comp.Neurol.345. 314-320 (1994)
[Publications] Nakano,R.: "A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis." Biochem.Biophys.Res.Commun.200. 695-703 (1994)
[Publications] Kawamoto,S.: "Ligand binding properties and N-glycosylation of the α-amino-3-hydroxy-5-methy1-4-isoxazole propionate(AMPA)-selective glutamate receptor channel expressed in a Baculovirus system." Eur.J.Biochem.223. 665-673 (1994)
[Publications] Takahasi,H.: "Familial amyotrophic lateral sclerosis with a mutation in the Cu-Zn superoxide dismutase gene." Acta Neuropathol.88. 185-188 (1994)
[Publications] Tsuzuki,K.: "Ion permeation properies of the cloned mouse ε2/ζ1 NMDA receptor channel." Mol.Brain Res.26. 37-46 (1994)
[Publications] Hattori,S.: "Expression and characterization of the α2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate(AMPA)-selective glutamate receptor channel in a Baculovirus system." Brain Res.666. 43-52 (1994)
[Publications] Mori,H.: "Different spatio-temporal expressions of three otx homeoprotein transcripts during zebrafish embryogenesis." Mol.Brain Res.27. 221-231 (1994)
[Publications] Hirano,T.: "Involvement of the glutamate receptor δ2 sbunit in the long-term depression of glutamate responsiveness in cultured Purkinje cells." Neurosci.Lett.182. 172-176 (1994)
[Publications] Sakimura,K.: "Reduced hippocampal LTP and spatial learning of mice lacking NMDA receptor ε1 subunit." Nature. 373. 151-155 (1995)
[Publications] Hirano,T.: "Suppression of LTD in cultured Purkinje cells deficient of glutamate receptor δ2 subunit." NeuroReport. (印刷中). (1995)
[Publications] 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-binding activity." J.Neurochem.(印刷中). (1995)
[Publications] 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.(印刷中). (1995)

1994 Fiscal Year Annual Research Report

NMDA受容体チャネル欠損マウスの作成

Principal Investigator

三品 昌美 東京大学, 医学部(医), 教授 (80144351)

Research Products

[Publications] Watanabe,M.: "Differential distributions of the NMDA receptor channel subunit mRNAs in the mouse retina." Brain Res.634. 328-332 (1994)

[Publications] Watanabe,M.: "Distinct gene expression of the N-methyl-D-aspartate receptor channel subunit in peripheral neurons of the mouse sensory ganglia and adrenal gland." Neurosci.Lett.165. 183-186 (1994)

[Publications] Ishida,N.: "Circadian expression of NMDA receptor mRNAs,ε3 and ζ1,in the suprachiasmatic nucleus of rat brain." Neurosci.Lett.166. 211-215 (1994)

[Publications] Watanabe,M.: "Distinct spatio-temporal expressions of five NMDA receptor channel subunit mRNAs in the cerebellum." J.Comp.Neurol.343. 513-519 (1994)

[Publications] Watanabe,M.: "Distinct distributions of five NMDA receptor channel subunit mRNAs in the brainstem." J.Comp.Neurol.343. 520-531 (1994)

[Publications] Watanabe,M.: "Distinct spatio-temporal distributions of the NMDA receptor channel subunit mRNAs in the mouse cervical cord." J.Comp.Neurol.345. 314-320 (1994)

[Publications] Nakano,R.: "A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis." Biochem.Biophys.Res.Commun.200. 695-703 (1994)

[Publications] Kawamoto,S.: "Ligand binding properties and N-glycosylation of the α-amino-3-hydroxy-5-methy1-4-isoxazole propionate(AMPA)-selective glutamate receptor channel expressed in a Baculovirus system." Eur.J.Biochem.223. 665-673 (1994)

[Publications] Takahasi,H.: "Familial amyotrophic lateral sclerosis with a mutation in the Cu-Zn superoxide dismutase gene." Acta Neuropathol.88. 185-188 (1994)

[Publications] Tsuzuki,K.: "Ion permeation properies of the cloned mouse ε2/ζ1 NMDA receptor channel." Mol.Brain Res.26. 37-46 (1994)

[Publications] Hattori,S.: "Expression and characterization of the α2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate(AMPA)-selective glutamate receptor channel in a Baculovirus system." Brain Res.666. 43-52 (1994)

[Publications] Mori,H.: "Different spatio-temporal expressions of three otx homeoprotein transcripts during zebrafish embryogenesis." Mol.Brain Res.27. 221-231 (1994)

[Publications] Hirano,T.: "Involvement of the glutamate receptor δ2 sbunit in the long-term depression of glutamate responsiveness in cultured Purkinje cells." Neurosci.Lett.182. 172-176 (1994)

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

[Publications] Hirano,T.: "Suppression of LTD in cultured Purkinje cells deficient of glutamate receptor δ2 subunit." NeuroReport. (印刷中). (1995)

[Publications] 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-binding activity." J.Neurochem.(印刷中). (1995)

[Publications] 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.(印刷中). (1995)

三品昌美東京大学, 医学部(医), 教授 (80144351)