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嗅内皮質-海馬歯状回シナプス機能不全による空間弁別障害と適応的代償機構の解析

Publicly Offered Research

Project AreaMechanisms underlying the functional shift of brain neural circuitry for behavioral adaptation
Project/Area Number 17H05564
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNagoya University

Principal Investigator

木下 専  名古屋大学, 理学研究科, 教授 (30273460)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywordsシナプス / スパイン / 長期増強 / 空間文脈 / 長期記憶 / 滑面小胞体 / 電子顕微鏡 / 空間弁別障害 / 海馬歯状回 / グルタミン酸作動性シナプス / 遺伝子改変マウス / セプチン / 細胞骨格 / 海馬 / 認知 / 空間弁別 / 嗅内皮質
Outline of Annual Research Achievements

セプチン細胞骨格系を構成するサブユニットSEPT1-14のうち、SEPT3は脳特異的かつニューロン選択的に発現するが、生理機能は不明である。Sept3欠損マウスは空間文脈課題で長期記憶障害を呈する。責任領域(海馬歯状回;DG)の主要ニューロン(顆粒細胞)の樹状突起棘(スパイン)の体積は正常であるが滑面小胞体(ER)含有率が少なく、この異常は初代培養顆粒細胞のSEPT3枯渇によって再現された。スパイン内ERの役割として、Ca2+シグナル伝達や膜輸送を介してシナプス伝達ないし長期増強への寄与が推測されている。Sept3欠損マウスでER含有スパインが減少するメカニズムとして、①顆粒細胞のER生合成の減少、②スパインへの侵入率の減少・退出率の増加、が考えられる。本研究では、①の検証を目的として、透過型電子顕微鏡連続切片像3次元再構築法(serial section Transmission Electron Microscopy; ssTEM法)により、野生型およびSept3欠損マウスの樹状突起内ER体積を比較した。その結果、Sept3欠損マウスの長期記憶障害の責任領域であるDG領域において、ER含有スパインの割合が有意に低いことを再確認した。一方、樹状突起基幹部内のER体積、基部にER集積部を持つスパインの割合には野生型との間に有意差を認めなかったことから、上記①(ER生合成ないし樹状突起基幹部内のERネットワーク減少に起因する可能性)は否定された。樹状突起基幹部内で局所的に形成されるER集積部の生理機能は不明である。本研究で、スパイン基部におけるER集積とスパイン内ERに強い関連を認めたことから「ER集積部は、スパイン内へのER侵入を効率化する足場としてシナプス入力依存的に形成される」いう新たな仮説を立てた。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (10 results)

All 2019 2018 2017

All Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (6 results) (of which Int'l Joint Research: 6 results,  Invited: 3 results) Book (1 results)

  • [Journal Article] CDC42EP4, a perisynaptic scaffold protein in Bergmann glia, is required for glutamatergic tripartite synapse configuration.2018

    • Author(s)
      Ageta-Ishihara N, Konno K, Yamazaki M, Abe M, Sakimura K, Watanabe M, Kinoshita M.
    • Journal Title

      Neurochem Int

      Volume: S0197-0186 Issue: 17 Pages: 30442-4

    • DOI

      10.1016/j.neuint.2018.01.003

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Septin-dependent remodeling of cortical microtubule drives cell reshaping during epithelial wound healing2018

    • Author(s)
      Asako Shindo, Anastasia Audrey, Maki Takagishi, Masahide Takahashi, John Wallingford, and Makoto Kinoshita
    • Journal Title

      Journal of Cell Science

      Volume: 131 Issue: 12 Pages: 1-13

    • DOI

      10.1242/jcs.212647

    • NAID

      120006545911

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] UBL3 modification influences protein sorting to small extracellular vesicles.2018

    • Author(s)
      Ageta H, Ageta-Ishihara N, Hitachi K, Karayel O, Onouchi T, Yamaguchi H, Kahyo T, Hatanaka K, Ikegami K, Yoshioka Y, Nakamura K, Kosaka N, Nakatani M, Uezumi A, Ide T, Tsutsumi Y, Sugimura H, Kinoshita M, Ochiya T, Mann M, Setou M, Tsuchida K.
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 3936-3936

    • DOI

      10.1038/s41467-018-06197-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Septin-dependent entry of smooth endoplasmic reticulum into dendritic spines as a synaptic basis of persistent memory.2019

    • Author(s)
      Kinoshita M
    • Organizer
      The 16th International Membrane Research Forum. Okinawa (Japan).
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] An activity-regulated septin subunit SEPT3 is required for the entry of sER into dendritic spines and spatial discrimination.2018

    • Author(s)
      Ageta-Ishihara N, Fukazawa Y, Takao K, Miyakawa T, Bito H, Inokuchi K, Kinoshita M.
    • Organizer
      Gordon Research Conference “Cell Biology of the Neuron”. Waterville Valley, NH (USA).
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] “Dynamics and significance of subcellular distribution and turnover of crucial molecules in the spine.”2018

    • Author(s)
      A postsynaptic dysregulation in hippocampal granule cells that underlies spatial discrimination defect. Ageta-Ishihara N, Fukazawa Y, Takao K, Miyakawa T, Bito H, Inokuchi K, Kinoshita M.
    • Organizer
      The Joint Congress of the 40th Annual Meeting of Japanese Society of Biological Psychiatry and the 61st Annual Meeting of the Japanese Society for Neurochemistry.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Unexpected motor and histopathological phenotype found in cerebellum-selective Sept7 knockout mice.2018

    • Author(s)
      Kinoshita M
    • Organizer
      The 8th Brain Research Institute International Symposium“Innovative progress of neuroscientific research through the use of advanced animal models”
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A septin-mediated synaptic regulation required for spatial discrimination.2017

    • Author(s)
      Kinoshita M
    • Organizer
      Gordon Research Conference “Excitatory Synapses & Brain Function”
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Entorhinal cortex-hippocampal dentate gyrus synapse anomaly underlying spatial discrimination defects in Sept3-null mice.2017

    • Author(s)
      Kinoshita M
    • Organizer
      International Symposium on Adaptive Circuit Shift 2017 “Integrative Neural Network Linking Multiple Brain Areas for Behavioral Adaptation”
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Book] DOJIN BIOSCIENCE SERIES 28脳神経化学 脳はいま化学の言葉でどこまで語れるか2018

    • Author(s)
      木下 専(森泰生、尾藤晴彦編)
    • Total Pages
      368
    • Publisher
      化学同人
    • ISBN
      4759817263
    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2019-12-27  

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