Investigation on a novel synaptic mechanism underlying memory consolidation

• Project/Area Number: 21K19427
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 51:Brain sciences and related fields
• Research Institution: Nagoya University
• Principal Investigator: Kinoshita Makoto 名古屋大学, 理学研究科, 教授 (30273460)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: シナプス / スパイン / 長期増強 / 記憶 / ミオシン / セプチン / 滑面小胞体 / リン酸化 / 空間文脈

Outline of Research at the Start

学習・記憶の素過程であるシナプス伝達の長期増強(LTP)は、強い興奮性入力によってシナプス伝達効率が高くリセットされる、ポジティブ・フィードバック現象である。そのメカニズムは、1)シナプス後膜上のイオンチャネル型グルタミン酸受容体の増加、2)アクチン重合による樹状突起棘(スパイン)の拡大の結果としてのシナプス面積の拡大である。さらに強い入力は、新規蛋白質合成に依存する持続性の LTPをもたらし、短期記憶を長期記憶に固定化するが、メカニズムには不明な点が多い。応募者らは先行研究と予備実験データに基づき、「スパインへの滑面小胞体の伸展が持続性のLTPに寄与する」という作業仮説を立て、検証を行う。

Outline of Final Research Achievements

As a part of the synaptic mechanism of memory consolidation, we set and tested the working hypothesis that "SEPT3 is phosphorylated at synaptic input, released from the spine base, and migrates onto the ER membrane to contribute to ER extension as an adaptor between MYO5A and ER". A mutant SEPT3 that mimics the synaptic activity-dependent phosphorylation, and an active mutant MYO5A additively promoted ER extension into spines of DG neurons. Given that artificial association of either ERj1-SEPT3 or MYO5A-ERj1 by the CID method promotes ER inclusion, we assume a molecular mechanism in which "the phosphorylated SEPT3-MYO5A complex directly or indirectly contacts the ER membrane at the spine base and extends the ER along actin into active spines.

Academic Significance and Societal Importance of the Research Achievements

シナプス伝達効率が強い入力で亢進する長期増強現象(LTP)は、一過性の前期相(E-LTP)と蛋白質合成に依存する持続性の後期相(L-LTP)に区分される。E-LTPからL-LTPへの移行は短期記憶から長期記憶への転換(固定化)のシナプス基盤とされているが、不明な点が多い。ヒトの知能とSEPT3の関連はGWASで示唆されているが、脳特異的かつニューロン選択的に発現するSEPT3の存在意義は不明であった。本研究では、SEPT3欠損マウスの記憶固定化障害を見出したことを端緒に、シナプス活動とMYO5A/SEPT3に依存したスパイン内へのERの伸展が記憶固定化のシナプス機構であることを見出した。

Research Products

• [Journal Article] Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and late onset Alzheimer disease. (2022)
  • Author(s): Viard J, Loe-Mie Y, Daudin R, Khelfaoui M, Plancon C, Boland A, Tejedor F, Huganir R, Kim E, Kinoshita M, Liu G, Haucke V, Moncion T, Yu Y, Hindie V, Blehaut H, Mircher C, Herault Y, Deleuze J-F, Rain J, Simonneau M, Lepagnol-Bestel A-M.
  • Journal Title: Life Science Alliance Volume: 5(12) Issue: 12 Pages: e202101205-e202101205
  • DOI: 10.26508/lsa.202101205
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Activity- and septin-dependent extension of smooth endoplasmic reticulum into dendritic spines as a synaptic mechanism of memory consolidation (2023)
  • Author(s): Natsumi Ageta-Ishihara, Yugo Fukazawa, Keizo Takao, Mineko Kengaku, Tsuyoshi Miyakawa, Kaoru Inokuchi, Haruhiko Bito, Makoto Kinoshita.
  • Organizer: 生理研研究会「ナノ・メゾスケールから捉えるシナプス制御機構の新展開」
  • Int'l Joint Research / Invited
• [Presentation] The pivotal septin subunit SEPT7 localizes to pre-/post-/peri-synaptic membrane domains and interacts with MYH10/nonmuscle myosin IIB (2022)
  • Author(s): Mitsui R, Ageta-Ishihara N, Kurita H, Suzuki A, Fukazawa Y, Hosokawa T, Kinoshita M.
  • Organizer: NEURO2022 (The 45th Annual Meeting of the Japan Neuroscience Society, The 65th Annual Meeting of the Japanese Society for Neurochemistry)
  • Int'l Joint Research
• [Presentation] Activity-triggered extension of endoplasmic reticulum into dendritic spines as a synaptic basis of memory consolidation. (2022)
  • Author(s): Ageta-Ishihara N, Fukazawa Y, Kosaka Y, Mizukami M, Takao K, Kengaku M, Miyakawa T, Inokuchi K, Bito H, Kinoshita M.
  • Organizer: NEURO2022 (The 45th Annual Meeting of the Japan Neuroscience Society, The 65th Annual Meeting of the Japanese Society for Neurochemistry)
  • Int'l Joint Research / Invited
• [Presentation] Activity- and septin-dependent extension of smooth endoplasmic reticulum into dendritic spines as a synaptic mechanism of memory consolidation (2022)
  • Author(s): Natsumi Ageta-Ishihara, Yugo Fukazawa, Keizo Takao, Mineko Kengaku, Tsuyoshi Miyakawa, Kaoru Inokuchi, Haruhiko Bito, Makoto Kinoshita.
  • Organizer: 記憶学習研究会「記憶・学習の包括的理解に向けたアプローチ」
  • Int'l Joint Research / Invited
• [Presentation] A myosin/septin-dependent postsynaptic regulation required for memory consolidation (2021)
  • Author(s): Natsumi Ageta-Ishihara, Yugo Fukazawa, Keizo Takao, Mineko Kengaku, Tsuyoshi Miyakawa, Kaoru Inokuchi, Haruhiko Bito, Makoto Kinoshita
  • Organizer: 第44回日本神経科学会年会/第1回CJK国際会議
  • Int'l Joint Research
• [Presentation] 記憶の長期化に寄与するスパイン内小胞体の役割 (2021)
  • Author(s): 上田(石原)奈津実, 木下 専
  • Organizer: 第19回神経科学研究会
  • Invited
• [Presentation] Activity-triggered extension of endoplasmic reticulum into dendritic spines as a synaptic basis of memory consolidation (2021)
  • Author(s): Makoto Kinoshita
  • Organizer: EMBO Workshop Molecular and cell biology of septins
  • Int'l Joint Research / Invited
• [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（MBSJ2021）
  • Int'l Joint Research / Invited