2001 Fiscal Year Annual Research Report

記憶・学習の分子基盤

Research Project

Project/Area Number	12210007
Research Institution	The University of Tokyo
Principal Investigator	三品昌美東京大学, 大学院・医学系研究科, 教授 (80144351)
Co-Investigator(Kenkyū-buntansha)	竹内倫徳東京大学, 大学院・医学系研究科, 助手 (50323613) 森寿東京大学, 大学院・医学系研究科, 講師 (00239617)
Keywords	記憶 / 学習 / NMDA受容体 / 標的遺伝子組換え / 瞬目反射条件付け / GluRε1 / GluRδ2 / PDZドメイン
Research Abstract	(1)GluRε1サブユニット欠損マウスを用いて瞬目反射条件付けへの海馬可塑性の影響を解析したところ、条件刺激と無条件刺激とを同じタイミングで与えるDelayパラダイムではほぼ正常な学習を示すが、条件刺激と無条件刺激との間に時間的間隔を設けるTraceパラダイムではことにおいて著しく障害されていることを見出した。 (2)GluRδ2の局在と可塑性の機構を明らかにするために、細胞質側に位置すると考えられるC末端領域に結合する新規蛋白Delphilinを単離した。Delphilinは小脳においてはプルキニエ細胞に選択的に強く発現し、大脳では視床に弱い発現が認められた。小脳プルキニエ細胞においては、GluRδ2と同様に平行線維シナプスに局在していた。DelphilinはPDZドメイン、FHドメイン有するl024アミノ酸からなり、GluRδ2のC末端と、PDZドメインを介して相互作用することを明らかにした。DelphilinはGluRδ2とともに免疫沈降することを認めた。また、FHドメインを介してアクチン結合タンパク質であるProfilinやSH3領域を有するnSrcと相互作用することが示唆された。これらの結果より、DelphilinはGluRδ2の足場蛋白であるとともに、GluRδ2の細胞内への情報伝達を担う分子であることが示唆される。 (3)C57BL/6系統由来胚幹細胞を用いて、シナプス可塑性の中心分子であるグルタミン酸受容体ならびに栄養因子受容体、細胞接着分子の遺伝子に、Creリコンビネースの認識配列loxPを組み込んだベクターを構築し、組換えマウスを得た。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Nakamura K, Manabe T, Watanabe M, et al.: "Enhancement of hippocampal LTP, reference memory and sensorimotor gating in mutant mice lacking a telencephalon-specific cell adhesion molecule"Eur J Neurosci. 13. 179-189 (2001)
[Publications] Nakazawa T, Komai S, Tezuka T, et al.: "Characterization of Fyn-mediated tyrosine phosphorylation sites on GluRε2 (NR2B) subunit of the N-methyl-D-aspartate receptor"J Biol Chem. 276. 693-699 (2001)
[Publications] Miyamoto Y, Yamada K, Noda Y, et al.: "Hyperfunction of dopaminergic and serotonergic neural systems in mice lacking NMDA receptor ε1 subunit"J Neurosci. 21. 750-757 (2001)
[Publications] Uchino S, Nakamura T, Nakamura K, et al.: "Real-time two-dimensional visualization of ischemia-induced glutamate release from hippocampal slices"Eur J Neurosci. 13. 670-678 (2001)
[Publications] Kishimoto Y, Kawahara S, Mori H, et al.: "Long-trace interval eyeblink conditioning is impaired in mutant mice lacking the NMDA receptor subunit ε1"Eur J Neurosci. 13. 1221-1227 (2001)
[Publications] Kishimoto Y, Kawahara S, Suzuki M, et al.: "Classical eyeblink conditioning in glutamate receptor subunit δ2 mutant mice is impaired in the delay paradim but not in the trace paradigm"Eur J Neurosci. 13. 1249-1253 (2001)
[Publications] Takeuchi T, Kiyama Y, Nakamura K, et al.: "Roles of the glutamate receptor ε2 and δ2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex"Eur J Neurosci. 14. 153-160 (2001)
[Publications] Wainai T, Takeuchi T, Seo N, Mishina M.: "Regulation of acute nociceptive responses by the NMDA receptor GluRε2 subunit"Neuroreport. 12. 3165-3172 (2001)
[Publications] Kishimoto Y, Kawahara S, Fujimichi R. et al.: "Impairment of eyeblink conditioning in GluRδ2 mutant mice depends on the temporal overlap between conditioned and unconditioned stimuli"Eur J Neurosci. 14. 1515-1521 (2001)
[Publications] Hashimoto K, Ichikawa R, Takechi H, et al.: "Roles of GluRδ2 and mGluR1 in climbing fiber synapse elimination during postnatal cerebellar development"J Neurosci. 21. 9701-9712 (2001)
[Publications] Miyagi Y, Yamashita T, Fukaya M, et al.: "Delphilin : a novel PDZ-and formin homology-domain containing protein, which synaptically colocalizes and interacts with glutamate receptor δ2 subunit"J Neurosci. 22. 803-814 (2002)
[Publications] Miyamoto Y, Yamada K, Noda Y, et al.: "Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor ε4 subunit"J Neurosci. (in press). (2002)

2001 Fiscal Year Annual Research Report

記憶・学習の分子基盤

Principal Investigator

三品 昌美 東京大学, 大学院・医学系研究科, 教授 (80144351)

Research Products

[Publications] Nakamura K, Manabe T, Watanabe M, et al.: "Enhancement of hippocampal LTP, reference memory and sensorimotor gating in mutant mice lacking a telencephalon-specific cell adhesion molecule"Eur J Neurosci. 13. 179-189 (2001)

[Publications] Nakazawa T, Komai S, Tezuka T, et al.: "Characterization of Fyn-mediated tyrosine phosphorylation sites on GluRε2 (NR2B) subunit of the N-methyl-D-aspartate receptor"J Biol Chem. 276. 693-699 (2001)

[Publications] Miyamoto Y, Yamada K, Noda Y, et al.: "Hyperfunction of dopaminergic and serotonergic neural systems in mice lacking NMDA receptor ε1 subunit"J Neurosci. 21. 750-757 (2001)

[Publications] Uchino S, Nakamura T, Nakamura K, et al.: "Real-time two-dimensional visualization of ischemia-induced glutamate release from hippocampal slices"Eur J Neurosci. 13. 670-678 (2001)

[Publications] Kishimoto Y, Kawahara S, Mori H, et al.: "Long-trace interval eyeblink conditioning is impaired in mutant mice lacking the NMDA receptor subunit ε1"Eur J Neurosci. 13. 1221-1227 (2001)

[Publications] Kishimoto Y, Kawahara S, Suzuki M, et al.: "Classical eyeblink conditioning in glutamate receptor subunit δ2 mutant mice is impaired in the delay paradim but not in the trace paradigm"Eur J Neurosci. 13. 1249-1253 (2001)

[Publications] Takeuchi T, Kiyama Y, Nakamura K, et al.: "Roles of the glutamate receptor ε2 and δ2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex"Eur J Neurosci. 14. 153-160 (2001)

[Publications] Wainai T, Takeuchi T, Seo N, Mishina M.: "Regulation of acute nociceptive responses by the NMDA receptor GluRε2 subunit"Neuroreport. 12. 3165-3172 (2001)

[Publications] Kishimoto Y, Kawahara S, Fujimichi R. et al.: "Impairment of eyeblink conditioning in GluRδ2 mutant mice depends on the temporal overlap between conditioned and unconditioned stimuli"Eur J Neurosci. 14. 1515-1521 (2001)

[Publications] Hashimoto K, Ichikawa R, Takechi H, et al.: "Roles of GluRδ2 and mGluR1 in climbing fiber synapse elimination during postnatal cerebellar development"J Neurosci. 21. 9701-9712 (2001)

[Publications] Miyagi Y, Yamashita T, Fukaya M, et al.: "Delphilin : a novel PDZ-and formin homology-domain containing protein, which synaptically colocalizes and interacts with glutamate receptor δ2 subunit"J Neurosci. 22. 803-814 (2002)

[Publications] Miyamoto Y, Yamada K, Noda Y, et al.: "Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor ε4 subunit"J Neurosci. (in press). (2002)

三品昌美東京大学, 大学院・医学系研究科, 教授 (80144351)