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Elucidation of regulatory mechanism of liquid-liquid phase separation underlying synaptic plasticity

Research Project

Project/Area Number 22KF0163
Project/Area Number (Other) 21F21384 (2021-2022)
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeMulti-year Fund (2023)
Single-year Grants (2021-2022)
Section外国
Review Section Basic Section 46010:Neuroscience-general-related
Research InstitutionKyoto University (2023)
Nagoya University (2021-2022)

Principal Investigator

劉 品吾 (2023)  京都大学, 医学研究科, 研究員 (60886563)

木下 専 (2021-2022)  名古屋大学, 理学研究科, 教授 (30273460)

Co-Investigator(Kenkyū-buntansha) LIU PIN-WU  名古屋大学, 理学(系)研究科(研究院), 外国人特別研究員
Project Period (FY) 2023-03-08 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2023: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 2022: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2021: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordssynaptic plasticity / memory / phase separation / シナプス / シナプス伝達 / シナプス可塑性 / 液-液相分離 / シナプス後膜肥厚 / 樹状突起棘 / スパイン / 記憶
Outline of Research at the Start

学習・記憶の素過程であるシナプスの情報伝達は、PSDと呼ばれる蛋白質の集合体により調節されており、PSDの大きさがシナプス強度に比例する。学習後や睡眠時などでは細胞全体のシナプスの恒常性と可塑性を維持するためにPSDが縮小し、シナプス強度が抑圧されるが、その分子機構は不明である。本研究ではCaMKNsによるPSDの離散がシナプス強度の抑圧を介して恒常性維持に寄与するという仮説を検証する。

Outline of Annual Research Achievements

Our study aims to understand memory formation by investigating synaptic plasticity and liquid-liquid phase separation (LLPS). We previously identified a “CaMKII-mediated LLPS condensate” responsive to calcium stimulation, indicative of learning-like events. In this project, we found that dissociation of this LLPS condensate revealed a gradual loss of resistance to its disruptor, suggesting a role in synaptic transmission down-regulation. Additionally, we found an unfamiliar phosphorylation of NMDA-type glutamate receptors within this condensate, linking LLPS dynamics to synaptic protein modifications.
This discovery not only enhances our understanding of synaptic plasticity but also opens possibilities for exploring LLPS in other neurobiological processes. For example, follow-up studies can involve validating LLPS-mediated synaptic modulation using gene-editing tools, like CRISPR-Cas9 knock-in, with living cell and/or tissue cultures. Also, we can develop photoresponsible sensors based on these finding, that would enable us to directly manipulate the formation and dissociation of LLPS condensate. By doing so, we can advance our knowledge of memory formation and potentially identify therapeutic targets for memory-related disorders, like dementia.

Report

(3 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (8 results)

All 2024 2023 2022 2021

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (4 results) (of which Int'l Joint Research: 4 results,  Invited: 3 results)

  • [Journal Article] Molecular diversity and functional dynamics in the central amygdala2024

    • Author(s)
      Yeh Li-Feng、Zuo Shuzhen、Liu Pin-Wu
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 17

    • DOI

      10.3389/fnmol.2024.1364268

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation2021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Regulation of synaptic nanodomain by liquid?liquid phase separation: A novel mechanism of synaptic plasticity2021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of the Stability and Localization of Post-synaptic Membrane Proteins by Liquid-Liquid Phase Separation2021

    • Author(s)
      Hosokawa Tomohisa、Liu Pin-Wu
    • Journal Title

      Frontiers in Physiology

      Volume: 12 Pages: 795757-795757

    • DOI

      10.3389/fphys.2021.795757

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Dissociation factors for the nanodomain of glutamate receptors on postsynaptic membrane2023

    • Author(s)
      Liu P-W, Hosokawa T, Hayashi Y.
    • Organizer
      Retreat for Multidimensional Analysis of Memory Mechanisms
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 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のデュアルカラーSTORMイメージング2022

    • Author(s)
      劉 品吾、細川 智永、林 康紀
    • Organizer
      Neuro2022 (第45回日本神経科学会大会)
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Calcium-induced persistent formation of protein condensate on Post-Synaptic Density by liquid-liquid phase separation2021

    • Author(s)
      Tomohisa Hosokawa, Pin-Wu Liu, Makoto Kinoshita, Yasunori Hayashi
    • Organizer
      第44回日本神経科学会年会/第1回CJK国際会議
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Modification of physical properties and reconstruction of postsynaptic density by liquid-liquid phase separation2021

    • Author(s)
      Tomohisa Hosokawa, Pin-Wu Liu, Makoto Kinoshita
    • Organizer
      第 44 回日本分子生物学会年会(MBSJ2021)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2022-02-08   Modified: 2024-12-25  

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