Structural role of CaMKII in PSD and the induction of LTP by optpgenetics.

• Project/Area Number: 18KK0421
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Nagoya University (2020-2021); Kyoto University (2018-2019)
• Principal Investigator: HOSOKAWA TOMOHISA 名古屋大学, 理学研究科, 講師 (30602883)
• Project Period (FY): 2019 – 2021
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
• Keywords: シナプス可塑性 / シナプス / 液－液相分離 / 受容体 / 記憶 / 長期増強 / 液-液相分離 / 液液相分離

Outline of Research at the Start

シナプスの長期増強現象（LTP）は記憶と学習の細胞レベルのメカニズムとして広く知られている。これまでの申請者らの研究により、LTPのシナプス内の分子メカニズムとして、細胞内Ca2+流入によりグルタミン酸受容体をはじめとする蛋白質群がシナプスへ移行することでシナプス伝達が増強することがわかってきた。では蛋白質を移行させる分子機構はなにか。本研究では少種類の精製蛋白質のみを用いてin vitroでシナプス可塑性現象を再構成する最小主義アプローチにより、シナプス可塑性の最も本質的な分子機構を明らかにし、それを操作することでシナプスの構造と可塑性の新たなモデルを提唱する。

Outline of Final Research Achievements

In this study, through the collaboration with Hong Kong University of Science and technology and Bordeaux University Interdisciplinary Institute for Neuroscience, we established a novel theory to explain the behavior of neurotransmitter receptor on the postsynaptic membrane. This theory based on “liquid-liquid phase separation” phenomenon, which recently becomes a hot topic in biochemistry, is totally consistent with the recent report regarding nano-scale distribution of neurotransmitter receptors on synaptic membrane using super-resolution microscopy and molecular feature of representative postsynaptic protein CaMKII. This theory is expected as the novel mechanism to explain synaptic plasticity and memory formation. We reported this achievement on Nature neuroscience 2021 and several review paper.

Academic Significance and Societal Importance of the Research Achievements

記憶形成は一時的な情報がシナプス強度の増強として固定されるプロセスであるが、その詳細なメカニズムはわかっていなかった。本課題により、興奮性刺激によるカルシウム流入がシナプス蛋白質のコンデンセートの可塑的な形成を引き起こし、シナプス強度を増強していることが明らかになった。このことは認知症患者の記憶を強化するような治療戦略に利用できるほか、逆にコンデンセートの離散を誘導することでPTSDの治療に役立てることができる。また、タンパク質のコンデンセート形成は神経変性疾患に見られるタンパク質アグリゲートと密接に関わっていることが報告されており、本課題によりそれら疾患の原因の理解を促進できる。

Research Products

• [Int'l Joint Research] 香港科学技術大学(中国) (2019)
• [Journal Article] Novel mechanism of synaptic plasticity mediated by CaMKII (2021)
  • Author(s): 林 康紀、細川 智永、劉 品吾、實吉 岳郎
  • Journal Title: 生化学 Volume: 93 Issue: 2 Pages: 191-202
  • DOI: 10.14952/SEIKAGAKU.2021.930191
  • ISSN: 0037-1017
  • Year and Date: 2021-04-25
  • Peer Reviewed
• [Journal Article] CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation (2021)
  • Author(s): Hosokawa Tomohisa、Liu Pin-Wu、Cai Qixu、Ferreira Joana S.、Levet Florian、Butler Corey、Sibarita Jean-Baptiste、Choquet Daniel、Groc Laurent、Hosy Eric、Zhang Mingjie、Hayashi Yasunori
  • Journal Title: Nature Neuroscience Volume: not yet Issue: 6 Pages: 777-785
  • DOI: 10.1038/s41593-021-00843-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of the Stability and Localization of Post-synaptic Membrane Proteins by Liquid-Liquid Phase Separation (2021)
  • Author(s): Hosokawa Tomohisa、Liu Pin-Wu
  • Journal Title: Frontiers in Physiology Volume: 12 Pages: 795757-795757
  • DOI: 10.3389/fphys.2021.795757
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of synaptic nanodomain by liquid?liquid phase separation: A novel mechanism of synaptic plasticity (2021)
  • Author(s): Liu Pin-Wu、Hosokawa Tomohisa、Hayashi Yasunori
  • Journal Title: Current Opinion in Neurobiology Volume: 69 Pages: 84-92
  • DOI: 10.1016/j.conb.2021.02.004
  • Peer Reviewed / Open Access
• [Journal Article] Shank3 Binds to and Stabilizes the Active Form of Rap1 and HRas GTPases via Its NTD-ANK Tandem with Distinct Mechanisms (2020)
  • Author(s): Cai Qixu、Hosokawa Tomohisa、Zeng Menglong、Hayashi Yasunori、Zhang Mingjie
  • Journal Title: Structure Volume: 28 Issue: 3 Pages: 290-300.e4
  • DOI: 10.1016/j.str.2019.11.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Arc self‐association and formation of virus‐like capsids are mediated by an N‐terminal helical coil motif (2020)
  • Author(s): Eriksen MS, Nikolaienko O, Hallin EI, Grodem S, Bustad HJ, Flydal MI, Merski I, Hosokawa T, Lascu D, Akerkar S, Cuellar J, Chambers JJ, O'Connell R, Muruganandam G, Loris R, Touma C, Kanhema T, Hayashi Y, Stratton MM, Valpuesta JM, Kursula P, Martinez A, Bramham CR.
  • Journal Title: The FEBS Journal Volume: 288 Issue: 9 Pages: 2930-2955
  • DOI: 10.1111/febs.15618
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Modification of physical properties and reconstruction of postsynaptic density by liquid-liquid phase separation (2021)
  • Author(s): Tomohisa Hosokawa, Pin-Wu Liu, Makoto Kinoshita
  • Organizer: 第44回日本分子生物学会年会
  • Int'l Joint Research / Invited
• [Presentation] Calcium-induced persistent formation of protein condensate on Post-Synaptic Density by liquid-liquid phase separation (2021)
  • Author(s): Tomohisa Hosokawa, Pin-Wu Liu, Makoto Kinoshita, Yasunori Hayashi
  • Organizer: 第44回日本神経科学大会
  • Int'l Joint Research / Invited
• [Presentation] CaMKIIの液-液相分離によるグルタミン酸受容体のシナプス内分離 (2020)
  • Author(s): 細川 智永、劉 品吾、林 康紀
  • Organizer: Neuroscience2020
• [Presentation] CaMKIIの液液相分離によるグルタミン酸受容体のシナプス内区画化 (2020)
  • Author(s): 細川 智永、劉 品吾、林 康紀
  • Organizer: 第６３回日本神経化学会大会
• [Presentation] Subsynaptic segregation of glutamate receptors by CaMKII-mediated liquid-liquid phase separation (2020)
  • Author(s): Tomohisa Hosokawa
  • Organizer: Neuroscience2020
  • Int'l Joint Research