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Molecular basis of brain neural circuitry formation and function

Research Project

Project/Area Number 19H03334
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 46020:Anatomy and histopathology of nervous system-related
Research InstitutionShinshu University

Principal Investigator

Takeshi Uemura  信州大学, 学術研究院総合人間科学系, 准教授 (00372368)

Co-Investigator(Kenkyū-buntansha) 惣谷 和広  佐賀大学, 医学部, 准教授 (80415207)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Keywords脳神経回路形成 / シナプス間接着分子 / シナプス / 形成と再編 / 阻害分子 / 細胞接着分子 / 神経回路形成 / 再編 / 脳神経回路網形成
Outline of Research at the Start

脳神経回路網は発達期におけるシナプスの形成と再編を経て構築される。シナプスはシナプスオーガナイザーと呼ばれる細胞接着分子同士の物理的会合が引き金となり構築されるが、物理的会合がなぜシナプス形成を誘導することになるのか、構築されたシナプスがどのように消失するのか、そのメカニズムには不明な点が多い。本研究では、シナプスオーガナイザーに働きかけてシナプス形成と再編を制御しうる分子に注目し、その働きを明らかにしシナプス形成、再編の分子基盤を解明することを目的とする。シナプスの制御機構の基礎的知見は、シナプス形成・機能異常の破綻に起因する神経発達障害の病態の解明や治療戦略の進展に寄与すると期待される。

Outline of Final Research Achievements

In this study, we obtained the following research results on the molecular basis of brain neural circuits' formation and functional regulation. (1) We identified a secreted protein that binds to the synaptic organizer Nrxn and inhibits the binding of Nrxn to its ligand Nlgn. In neurons overexpressing this molecule, Nrxn-induced synaptogenesis was severely inhibited. In addition, mice lacking this molecule showed enhanced learning and memory, suggesting the physiological importance of this inhibitory molecule. (2) Nrxn plays an important role in cerebellar granule cell survival by regulating neurotrophic factor secretion in the cerebellum. (3) We found that one of the lysophospholipids can act as a regulatory molecule of neural circuit formation.

Academic Significance and Societal Importance of the Research Achievements

脳機能を支える神経回路網は発達期におけるシナプスの形成と再編を経て構築される。 発達期におけるこれらの調節機構の破綻は自閉症などの神経発達障害の発症と深く関わることが知られている。シナプス形成はシナプスオーガナイザーと呼ばれる特殊な細胞接着分子によって担われている。シナプス形成を担うシナプスオーガナイザーの脳形成過程における新たな機能についての知見とシナプスオーガナイザー自身の機能を修飾する分子を同定しその働きの一旦を明らかにした本研究は、脳神経回路形成のメカニズムの解明や自閉症などの神経発達障害に関わる今後の研究に役立つ知見になると期待される。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (12 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (5 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results)

  • [Int'l Joint Research] Univ of Massachusetts Chan Med Sch(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Univ of Massachusetts Med Sch(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Univ of Massachusetts Med School(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins2022

    • Author(s)
      Uemura T, Suzuki-Kouyama E, Kawase S, Kurihara T, Yasumura M, Yoshida T, Fukai S, Yamazaki M, Fei P, Abe M, Watanabe M, Sakimura K, Mishina M, Tabuchi K
    • Journal Title

      Cell Reports

      Volume: 39 Issue: 1 Pages: 110624-110624

    • DOI

      10.1016/j.celrep.2022.110624

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structurally different lysophosphatidylethanolamine species stimulate neurite outgrowth in cultured cortical neurons via distinct G-protein-coupled receptors and signaling cascades2021

    • Author(s)
      Hisano Kazutoshi、Kawase Shiori、Mimura Tetsuhiko、Yoshida Hironori、Yamada Hiroki、Haniu Hisao、Tsukahara Tamotsu、Kurihara Taiga、Matsuda Yoshikazu、Saito Naoto、Uemura Takeshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 534 Pages: 179-185

    • DOI

      10.1016/j.bbrc.2020.11.119

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Abundant oleoyl-lysophosphatidylethanolamine in brain stimulates neurite outgrowth and protects against glutamate toxicity in cultured cortical neurons2021

    • Author(s)
      Kazutoshi Hisano, Hironori Yoshida, Shiori Kawase, Tetsuhiko Mimura, Hisao Haniu, Tamotsu Tsukahara, Taiga Kurihara, Yoshikazu Matsuda, Naoto Saito, Takeshi Uemura
    • Journal Title

      The Journal of Biochemistry

      Volume: 170 Issue: 3 Pages: 327-336

    • DOI

      10.1093/jb/mvab046

    • NAID

      40022722431

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Specific Neuroligin3?αNeurexin1 signaling regulates GABAergic synaptic function in mouse hippocampus2020

    • Author(s)
      Uchigashima Motokazu、Konno Kohtarou、Demchak Emily、Cheung Amy、Watanabe Takuya、Keener David G、Abe Manabu、Le Timmy、Sakimura Kenji、Sasaoka Toshikuni、Uemura Takeshi、Imamura Kawasawa Yuka、Watanabe Masahiko、Futai Kensuke
    • Journal Title

      eLife

      Volume: 9

    • DOI

      10.7554/elife.59545

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Specific Neuroligin3-αNeurexin1 Trans-synaptic Interaction Regulates GABAergic Synaptic Function in an Input Cell Type-Dependent Manner2021

    • Author(s)
      Uchigashima Motokazu、Konno Kohtarou、Demchak Emily、Cheung Amy、Watanabe Takuya、Keener David G、Abe Manabu、Le Timmy、Sakimura Kenji、Sasaoka Toshikuni、Uemura Takeshi、Imamura Kawasawa Yuka、Watanabe Masahiko、Futai Kensuke
    • Organizer
      第126回 日本解剖学会総会・全国学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Effect of phospholipids on neurite outgrowth of cortical neurons in culture2020

    • Author(s)
      Kazutoshi Hisano, Shiori Kawase, Hisao Haniu, Tamotsu Tsukahara, Yoshikazu Matsuda, Naoto Saito, Takeshi Uemura.
    • Organizer
      Neuro2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Lysophosphatidylethanolamines with different fatty acid lengths stimulate neurite outgrowth in cultured cortical neurons through distinct signaling cascades2020

    • Author(s)
      Hironori Yoshida, Kazutoshi Hisano, Shiori Kawase, Tetsuhiko Mimura, Hisao Haniu, Tamotsu Tsukahara, Taiga Kurihara, Yoshikazu Matsuda, Naoto Saito, Takeshi Uemura
    • Organizer
      The 94th Annual Meeting of the Japanese Pharmacological Society
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] tructural basis of transsynaptic interactions between type IIa receptor protein tyrosine phosphatases and their synaptic organizer partners2019

    • Author(s)
      Atsushi Yamagata, Sakurako Goto-Ito, Yusuke Sato, Tomoko Shiroshima, Asami Maeda, Tomoyuki Yoshida, Takeshi Uemura, Shuya Fukai
    • Organizer
      Neuro2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional roles of synapse organizers in the cerebellum2019

    • Author(s)
      Takeshi Uemura
    • Organizer
      Neuro2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2019-04-18   Modified: 2024-01-30  

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