Novel regulatory mechanisms of the synaptic plasticity by BRAG2-Arf6 signaling pathway

• Project/Area Number: 17K07082
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Kitasato University
• Principal Investigator: Fukaya Masahiro 北里大学, 医学部, 准教授 (10360900)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: シナプス可塑性 / AMPA受容体 / エンドサイトーシス / BRAG2 / Arf6 / 興奮性シナプス / マウス / 海馬 / PSD / シナプス / 神経科学 / 小胞輸送

Outline of Final Research Achievements

In this study, I focused on novel BRAG2-binding molecules, PSD-95 and endophilin 3, for the purpose of elucidating the regulatory mechanisms of AMPA receptor surface expression by BRAG2-Arf6 signaling pathway during synaptic plasticity. As a result, the interaction between BRAG2 and PSD-95 was involved in the postsynaptic localization mechanism of BRAG2. The interaction between BRAG2 and endophilin 3 played an indispensable role in synaptic surface expression of AMPA receptors with an increase in Arf6 activity during mGluR-stimulated synaptic plasticity. This study has elucidated novel regulatory mechanisms of the synaptic plasticity at excitatory synapses by BRAG2-Arf6 signaling pathway.

Academic Significance and Societal Importance of the Research Achievements

本研究は、興奮性シナプス後部に局在するBRAG2の機能的役割を、エンドサイトーシス関連分子のendophilin 3 との相互作用機能とともに、シナプス可塑性発現の実態であるAMPA受容体の細胞表面発現量を指標にして、新たなAMPA受容体輸送機構の分子機序となるシナプス可塑性の一端を解明できた点において学術的意義があると考える。また、記憶や学習などの高次脳機能の新たな機序の解明の一助となり、精神・神経疾患病因解明の基礎となると考えられる。

Research Products

• [Journal Article] BRAG2a mediates mGluR-dependent AMPA receptor internalization at excitatory postsynapses through the interaction with PSD-95 and endophilin 3 (2020)
  • Author(s): Fukaya M, Sugawara T, Hara Y, Itakura M, Watanabe M, Sakagami H
  • Journal Title: The Journal of Neuroscience Volume: - Issue: 22 Pages: 4277-4296
  • DOI: 10.1523/jneurosci.1645-19.2020
  • Peer Reviewed
• [Journal Article] Mice lacking EFA6C/Psd2, a guanine nucleotide exchange factor for Arf6, exhibit lower Purkinje cell synaptic density but normal cerebellar motor functions. (2019)
  • Author(s): Saegusa S, Fukaya M, Kakegawa W, Tanaka M, Katsumata O, Sugawara T, Hara Y, Itakura M, Okubo T, Sato T, Yuzaki M, Sakagami H
  • Journal Title: PLoS One Volume: 14 Issue: 5 Pages: e0216960-e0216960
  • DOI: 10.1371/journal.pone.0216960
  • Peer Reviewed / Open Access
• [Journal Article] Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells. (2019)
  • Author(s): Sakai Y, Kassai H, Nakayama H, Fukaya M, Maeda T, Nakao K, Hashimoto K, Sakagami H, Kano M, Aiba A.
  • Journal Title: Scientific Reports Volume: Feb 26;9(1) Issue: 1 Pages: 2799-2799
  • DOI: 10.1038/s41598-019-38730-4
  • Peer Reviewed / Open Access
• [Presentation] 海馬神経細胞におけるBRAG2-Arf6シグナル経路を介したAMPA受容体のシナプス発現調節機構 (2020)
  • Author(s): 深谷昌弘, 阪上洋行
  • Organizer: 第125回 日本解剖学会全国学術集会