Modulation of NMDA receptors and its role in synaptic plasticity

• Project/Area Number: 17500204
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: The University of Tokyo
• Principal Investigator: WATABE Ayako The University of Tokyo, Institute of Medical Science, Assistant Professor (00334277)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,700,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
• Keywords: LTP / NMDA receptors / Amygdala / Hippocampus / mGluR / Learning and Memory / Emotion / リン酸化 / LTP / 神経科学 / 脳神経疾患

Research Abstract

Long-term potentiation (LTP) at excitatory synapses in the hippocampus and amygdala is considered to be a cellular mechanism underlying neural plasticity such as memory and learning. The N-methyl-D-aspartate type of glumatate receptor (NMDAR) plays a key role in the induction of LTP as well as learning. Phosphorylation-dependent changes in NMDAR function have a crucial role in dynamic modulation of neural circuitry. The NR2B subunit of the NMDAR is tyrosine-phosphorylated in the brain, with Tyr-1472 its major phosphorylation site. Mice with a knockin mutation of the Tyr-1472 site to phenylalanine (Y1472F) show that Tyr-1472 phosphorylation is essential for fear learning and amygdaloid synaptic plasticity. The knockin mice show impaired fear-related learning and reduced amygdaloid long-term potentiation. NMDA receptor-mediated CaMKII signaling is impaired in YF/YF mice. Electron microscopic analyses reveal that the Y1472F mutant of the NR2B subunit shows improper localization at synapses in the amygdala. Thus, Tyr-1472 phosphorylation is a key mediator of fear learning and amygdaloid synaptic plasticity. Next, functional properties of NR2B subunit-containing receptors were studied in the amygdala and the Cal region of the hippocampus. We have found that the NR2B subunit significantly contributes to synaptic transmission, and its contribution is greater in the LA than in the Cal region, and biophysical properties of NMDA receptors and the NR2B/NR2A ratio are different between the two brain regions. These results indicate that NR2B subunit-containing NMDA receptors accumulate on the synaptic site and responsible for the unique properties of synaptic function and plasticity in the amygdala.

Research Products

• [Journal Article] Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS (2008)
  • Author(s): Miwa, H., Fukaya, M., Watabe, A. M., Watanabe, M., Manabe T.
  • Journal Title: Journal of Physiology 586 Pages: 2539-2550
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 扁桃体シナプス長期増強と情動記憶の分子制御 (2008)
  • Author(s): 渡部文子、真鍋俊也
  • Journal Title: Clinical Neuroscience 26 Pages: 402-405
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS. (2008)
  • Author(s): Miwa H., Fukaya M., Watabe A. M., Watanabe M., Manabe T.
  • Journal Title: J. Physiol. in press(掲載確定)
  • Peer Reviewed
• [Journal Article] 扁桃体シナプス長期増強と情動記憶の分子機序 (2008)
  • Author(s): 渡部 文子、真鍋 俊也
  • Journal Title: Clinical Neuroscience 26 Pages: 402-405
• [Journal Article] NR2B tyrosine phosphorylation modulates fear learing as well as amygdaloid naptic plasticity (2006)
  • Author(s): Nakazawa T*, Komai S*, Watabe AM*, Kiyama Y, Fukaya M, Arima-Yoshida F, Horai R, Sudo K, Ebine K, Delawary M, Goto J, Umemori H, Tezuka T, Iwakura Y, Watanabe M, Yamamoto T & Manabe T. (*These authors contributed equally to this work)
  • Journal Title: EMBO Journal 25 Pages: 2867-2877
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 神経可塑性(長期増強、長期抑圧、講造変化) (2006)
  • Author(s): 渡部文子、真鍋俊也
  • Journal Title: 脳神経科学イラストレイテッド Pages: 181-187
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] (These authors contributed equally to this work) NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity (2006)
  • Author(s): Nakazawa T, Komai S, Watabe AM, Kiyama Y, Fukaya M, Arima-Yoshida F, Horai R, Sudo K, Ebine K, Delawary M, Goto J, Umemori H, Tezuka T, Iwakura Y, Watanabe M, Yamamoto T & Manabe T.
  • Journal Title: EMBO Journal 25 Pages: 2867-2877
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity. (2006)
  • Author(s): Nakazawa T, Komai S, Watabe AM, Kiyama Y, Fukaya M, Arima-yoshida F, Horai R, Sudo K, Ebine K, Delawary M, Goto J, Umemori H, Tezuka T, Iwakura Y, Watanabe M, Yamamoto T, Manabe T
  • Journal Title: The EMBO Journal 25 Pages: 2867-2877
• [Journal Article] Neuronal leucine-rich repeat protein 4 functions in hippocampus-dependent long-lasting memory. (2005)
  • Author(s): Bando T, Sekine K, Kobayashi S, Watabe AM, Rump A, Tanaka M, Suda Y, Kato S, Morikawa Y, Manabe T, Miyajimsa A.
  • Journal Title: Molecular and Cellular Biology 25 Pages: 4166-4175
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Neuronal leucine-rich repeat protein 4 functions in hippocampus-dependent long-lasting memory (2005)
  • Author(s): Bando T, Sekine K, Kobayashi S, Watabe AM, Rump A, Tanaka M, Suda Y, Kato S, Morikawa Y, Manabe T, Miyajima A.
  • Journal Title: Molecular and Cellular Biology 25 Pages: 4166-4175
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuronal leucine-rich repeat protein 4 functions in hippocampus-dependent long-lasting memory. (2005)
  • Author(s): Bando T, Sekine K, Kobayashi S, Watabe AM, Rump A, Tanaka M, Suda Y, Kato S, Morikawa Y, Manabe T, Miyajima A
  • Journal Title: Mol.Cell.Biol 25(10) Pages: 4166-4175
• [Presentation] 扁桃体外側核のNMDA 受容体特性:海馬CA1領域との比較 (2007)
  • Author(s): 三輪秀樹、深谷昌弘、渡部文子、渡辺雅彦、真鍋俊也
  • Organizer: 日本生理学会
  • Place of Presentation: 大阪
  • Year and Date: 2007-03-20
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Inhibitory modulation of synaptic plasticity is stronger in the dentate gyrus than in the CAl region of the hippocampus. (2006)
  • Author(s): Arima, F., Watabe, A. M., Manabe, T.
  • Organizer: 北米神経科学会
  • Place of Presentation: アトランタ
  • Year and Date: 2006-10-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The presynaptic TrkB receptor modulates an N-type Ca2+ channel-dependent component of post-tetanic potetiation. (2006)
  • Author(s): Kumazawa, N., Kato, E., Takeuchi, T., Watebe, A. M., Mishina, M., Manabe, T.
  • Organizer: 北米神経科学会
  • Place of Presentation: アトランタ
  • Year and Date: 2006-10-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Roles of NMDA Receptor Phosphorylation in the Amygdala (2006)
  • Author(s): 渡部文子、真鍋俊也
  • Organizer: 日本生理学会
  • Place of Presentation: 群馬
  • Year and Date: 2006-03-28
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Inhibitory modulation of synaptic plasticity is stronger in the dentate gyrus than in the CAl region of the hippocampus (2006)
  • Author(s): Arima, F., Watabe, A. M., Manabe, T.
  • Organizer: 36th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Atlanta. U. S. A
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The presynaptic TrkB receptor modulates an N-type Ca2+ channel-dependent component of post-tetanic potetiation (2006)
  • Author(s): Kumazawa, N., Kato, E., Takeuchi, T., Watebe, A. M., Mishina, M., Manabe, T.
  • Organizer: 36th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Atlanta. U. S. A
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] NR2B tyrosine-phosphorylation modulates fear learning and NMDAR localization at synapses (2006)
  • Author(s): Watabe A. M., Nakazawa T., Komai S., Kiyama Y., Fukaya M., Arima F., Watanabe M., Yamamoto T., and Manabe T.
  • Organizer: Gordon Research Conference, Neural Circuits and Plasticity
  • Place of Presentation: Salve Regina University Newport, RI, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] NR2B tyrosine-phosphorylation modulates fear learning and NMDAR localization at synapses (2005)
  • Author(s): Watabe A. M., Nakazawa T., Komai S., Kiyama Y., Fukaya M., Arima F., Watanabe M., Yamamoto T., and Manabe T.
  • Organizer: Gordon Research Conference Neural Circuits and Plasticity
  • Place of Presentation: Newport, RI
  • Year and Date: 2005-06-28
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 脳神経科学イラストレイテッド(うち「シナプス可塑性」の章を担当) (2006)
  • Author(s): 渡部 文子, 真鍋 俊也
  • Total Pages: 372
  • Publisher: 羊土社