Exploration of synaptic mechanism underlying spatial cognitive defect of septin-null mice

• Project/Area Number: 18H02525
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Nagoya University
• Principal Investigator: KINOSHITA MAKOTO 名古屋大学, 理学研究科, 教授 (30273460)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: シナプス / 樹状突起棘 / 滑面小胞体 / セプチン / 長期記憶 / 長期増強 / 海馬 / スパイン / 空間文脈 / 空間文脈記憶 / シナプス伝達 / 電子顕微鏡

Outline of Final Research Achievements

We systematically examined Sept3-deficient mice at various levels and the following findings were obtained. In systematic behavioral analysis, they selectively showed underperformance in the spatial context discrimination task. We pinpointed the responsible region by stereotactic injection of AAV expression and knockdown vectors. 3D morphometry using ssTEM revealed normal synaptic distribution density and spine volume, but fewer spines containing smooth endoplasmic reticulum. This abnormality was reproduced in primary cultured granule cells. We optimized condition of late long-term potentiation under which ER extension followed spine enlargement. SEPT3 depletion did not affect actin-based spine enlargement, while selectively inhibited ER extension, suggesting that ER entry into the granule cell spine is activity-dependent and SEPT3-dependent.

Academic Significance and Societal Importance of the Research Achievements

記憶の獲得・想起を司る海馬神経回路において、嗅内皮質から歯状回顆粒細胞に投射するシナプスの低い発火特性は入力情報のゲーティングに寄与する。顆粒細胞は成体における新生や、PTSDやうつなどへの関与も知られており、神経科学的にも臨床医学的にも重要なニューロンである。ヒトのSEPT3（重合性GTPase）遺伝子はヒトの知能と強く関連する22q11.3領域に存在し、顆粒細胞で高発現するが、生理機能は未知である。本研究において、Sept3欠損マウスの記憶固定化減弱を端緒として得られた一連の知見は、他のアプローチでは得難い記憶の分子メカニズムを解明しつつある。

Research Products

• [Journal Article] Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks (2021)
  • Author(s): M. Asada-Utsugi, K. Uemura, M. Kubota, Y. Noda, Y. Tashiro, T. M. Uemura, H. Yamakado, M. Urushitani, R. Takahashi, S. Hattori, T. Miyakawa, N. Ageta-Ishihara, K. Kobayashi, M. Kinoshita, A. Kinoshita
  • Journal Title: Molecular Brain Volume: 14 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s13041-021-00738-1
  • Peer Reviewed / Open Access
• [Journal Article] Developmental and postdevelopmental roles of septins in the brain (2020)
  • Author(s): Ageta-Ishihara Natsumi、Kinoshita Makoto
  • Journal Title: Neuroscience Research Volume: S0168-0102(20) Issue: 20 Pages: 30440-30445
  • DOI: 10.1016/j.neures.2020.08.006
  • Peer Reviewed / Open Access
• [Presentation] 記憶固定化のシナプス基盤：神経活動およびセプチン依存的なスパインへの小胞体伸展 (2020)
  • Author(s): Ageta-Ishihara N, Kinoshita M et al.
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Activity- and septin-dependent extension of smooth endoplasmic reticulum into dendritic spines as a synaptic basis of memory consolidation. Outcome Presentation Meeting FY2019. (2020)
  • Author(s): Ageta-Ishihara N, Kosaka Y, Fukazawa Y, Takao K, Miyakawa T, Bito H, Inokuchi K, Kinoshita M.
  • Organizer: Platforms for Advanced Technologies and Research Resources
• [Presentation] ssTEM mapping of SEPT3 reveals its association with ER extending into active spines. (2019)
  • Author(s): Fujiwara R, Kinoshita M.
  • Organizer: The 7th Neural Circuits Joint Workshop
  • Int'l Joint Research
• [Presentation] Activity- and SEPT3-dependent ER entry into dendritic spines underlies long-term memory. (2019)
  • Author(s): Asami Y, Kinoshita M.
  • Organizer: The 7th Neural Circuits Joint Workshop
  • Int'l Joint Research