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Microglia permit climbing fiber elimination by promoting inhibitory synaptic transmission in the developing cerebellum

Research Project

Project/Area Number 17K07058
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurophysiology / General neuroscience
Research InstitutionTokyo Women's Medical University (2018-2019)
Hiroshima University (2017)

Principal Investigator

Kawamura-Nakayama Hisako  東京女子医科大学, 医学部, 助教 (70397181)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords小脳 / プルキンエ細胞 / シナプス刈り込み / ミクログリア / 登上線維 / パッチクランプ / シナプス / 神経回路発達 / 神経回路形成 / 発達 / シナプス再編成
Outline of Final Research Achievements

Synapse elimination during postnatal development is mainly regulated by neuronal interactions. Recent studies suggest participation of microglia in this process, but it is unclear how microglia cooperatively act with neuronal mechanisms. To examine roles of microglia, we ablate microglia by microglia-selective deletion of Csf1r by crossing floxed-Csf1r and Iba1-Cre mice (Csf1r-cKO). In Csf1r-cKO mice, refinement of climbing fiber (CF) to Purkinje cell (PC) innervation after P10–P12 is severely impaired. However, there is no clear morphological evidence suggesting massive engulfment of CFs by microglia. In Csf1r-cKO mice, inhibitory transmission is impaired and CF elimination and is restored by diazepam, suggesting that impairment of CF elimination is caused by a defect of inhibition on PCs, a prerequisite for CF elimination. These results indicate that microglia primarily promote inhibitory transmission and secondarily facilitate the mechanism for CF elimination inherent in PCs.

Academic Significance and Societal Importance of the Research Achievements

本研究は、ミクログリア由来因子によってニューロン間のシナプス機能が調節され、シナプス刈り込みに関わるという、神経回路発達におけるミクログリアの新たな役割を提唱した点で学術的意義がある。これにより、グリアとニューロンネットワークの相互作用による脳機能成熟の統合的理解が深まると期待できる。また、自閉症や統合失調症などでは脳の興奮と抑制のバランスの乱れに加えて、ミクログリア機能の破綻も指摘されているので、健常脳の発達過程において、ミクログリアが抑制性シナプス伝達を修飾するという本研究成果は、それらの精神・神経疾患の病態の理解と治療方法の解明に貢献するものと期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (11 results)

All 2020 2019 2018 2017 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (8 results) (of which Int'l Joint Research: 3 results) Remarks (1 results)

  • [Journal Article] Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells2019

    • Author(s)
      Sakai Y, Kassai H, Nakayama H, Fukaya M, Maeda T, Nakao K, Hashimoto K, Sakagami H, Kano M, Aiba A.
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 2799-2799

    • DOI

      10.1038/s41598-019-38730-4

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microglia permit climbing fiber elimination by promoting GABAergic inhibition in the developing cerebellum2018

    • Author(s)
      Nakayama Hisako、Abe Manabu、Morimoto Chie、Iida Tadatsune、Okabe Shigeo、Sakimura Kenji、Hashimoto Kouichi
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 2830-2830

    • DOI

      10.1038/s41467-018-05100-z

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 発達期視床のヒゲ経験依存的シナプス再編における神経活動の役割2020

    • Author(s)
      中山寿子,宮田麻理子
    • Organizer
      第97回 日本生理学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] mTORC1シグナル亢進による小脳プルキンエ細胞の細胞内ホメオスタシスの撹乱2019

    • Author(s)
      坂井 祐介,葛西 秀俊,中山 寿子,深谷 昌弘,前田 達也,中尾 和貴,橋本 浩一,阪上 洋行,狩野 方伸,饗場 篤
    • Organizer
      第42回 日本分子生物学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Microglia permit climbing fiber pruning by promoting synaptic inhibition in the developing cerebellm.2019

    • Author(s)
      Hisako Nakayama
    • Organizer
      9th FAOPS, 第96回 日本生理学会大会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Microglia permit climbing fiber refinement by promoting inhibitory synaptic transmission in the developing cerebellum.2018

    • Author(s)
      Hisako Nakayama, Manabu Abe, Chie Morimoto, Kenji Sakimura, Kouichi Hashimoto
    • Organizer
      Latest Advances in Development & Function of Neuronal Circuits meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Microglia-dependent refinement of the cerebellar circuit during postnatal development.2018

    • Author(s)
      Hisako Nakayama, Manabu Abe, Chie Morimoto, Tadatune Iida, Shigeo Okabe, Kenji Sakimura and Kouichi Hashimoto
    • Organizer
      新学術領域研究「グリアアセンブリによる脳機能発現の制御と病態」第5回成果報告会
    • Related Report
      2017 Research-status Report
  • [Presentation] Microglia-dependent GABAergic synaptogenesis promotes refinement of climbing fibers to Purkinje cell synapses2018

    • Author(s)
      Hisako Nakayama, Manabu Abe, Chie Morimoto, Tadatune Iida, Shigeo Okabe, Kenji Sakimura and Kouichi Hashimoto
    • Organizer
      第8回新潟大学脳研究所共同研究拠点国際シンポジウム “The innovative progress of neuroscientific research through the use of advanced animal models”
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 小脳におけるミクログリア依存的神経回路発達2017

    • Author(s)
      中山 寿子, 阿部 学, 森本 千恵, 﨑村 建司, 橋本 浩一
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Contribution of microglia to postnatal development of neuronal circuits in the cerebellum.2017

    • Author(s)
      Hisako Nakayama, Shin Suzuki, Manabu Abe, Kenji Sakimura and Kouichi Hashimoto
    • Organizer
      新学術領域研究「グリアアセンブリによる脳機能発現の制御と病態」第4回夏のワークショップ
    • Related Report
      2017 Research-status Report
  • [Remarks] ミクログリアは抑制性シナプス伝達の促進を介して発達期小脳における興奮性シナプス結合の精緻化に関わる

    • URL

      https://www.neurochemistry.jp/mue7rd9hl-15/#_15

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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