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Molecular Mechanisms of Neurodevelopmental Disorders mediated by the Synapse Adhesion Molecule LRFN2

Research Project

Project/Area Number 19K06905
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 46010:Neuroscience-general-related
Research InstitutionShiga University of Medical Science

Principal Investigator

MORIMURA NAOKO  滋賀医科大学, 医学部, 特任助教 (00349044)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsシナプス接着分子 / 発達障害 / 非ヒト霊長類
Outline of Research at the Start

LRFN2(SALM1)は興奮性シナプスの構造・機能を制御するシナプス接着分子である。遺伝子欠損マウスでは記憶学習力の向上、社会的ひきこもり、プレパルス抑制障害、輪回しへの異常固執など自閉症様ヒト発達障害に酷似した行動表現型を示した。本研究ではヒト脳構造・機能に近縁のカニクイザルを用いてLRFN2を介する発達障害責任回路の特定と分子メカニズムの解明を行い、マウス知見をヒトへ外挿できる道筋を究明して、創薬・新規治療法の開発を目指す。

Outline of Final Research Achievements

LRFN2, a synaptic adhesion molecule that regulates the structure and function of excitatory synapses, has been shown to cause human autistic-like and schizophrenic-like behavioral and synaptic abnormalities in knockout mice. In this research project, we started to develop LRFN2 knockout crab-eating macaques by CRISPR/Cas9 genome editing technology in order to examine the mechanism of neurodevelopmental disorders in the primate brain. In addition, nuclear magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed to elucidate the structure and axon running in the developing brain of the normal crab-eating macaque.

Academic Significance and Societal Importance of the Research Achievements

自閉症や統合失調症などの発達障害とシナプス接着分子の関連性を示す研究報告の蓄積から、近年、シナプス異常と発達障害の因果関係が支持されている。マウス(齧歯類)を用いた研究から多くの発見が見出されている一方で、ヒト(霊長類)との脳構造や機能における進化的な差が大きいために治療法に結びかない現状がある。興奮生シナプスの制御に関わり、かつ自閉症や統合失調症の患者に変異が認められているLRFN2遺伝子欠損非ヒト霊長類サルが作出されることにより、基礎知見と臨床応用を結ぶ橋渡しができるものと期待される。

Report

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

    (5 results)

All 2022 2021 2019

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (3 results)

  • [Journal Article] Lrtm2 controls protein sorting in the striatal projection system and its deficiency causes disturbances in motor responses and monoamine dynamics2022

    • Author(s)
      Misato Ichise, Kazuto Sakoori, Kei-ichi Katayama, Naoko Morimura, Kazuyuki Yamada, Hiroki Ozawa, Hayato Matsunaga, Minoru Hatayama, Jun Aruga
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: - Pages: 856315-856315

    • DOI

      10.3389/fnmol.2022.856315

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Precise CAG repeat contraction in a Huntington’s Disease mouse model is enabled by gene editing with SpCas9-NG2021

    • Author(s)
      Oura Seiya、Noda Taichi、Morimura Naoko、Hitoshi Seiji、Nishimasu Hiroshi、Nagai Yoshitaka、Nureki Osamu、Ikawa Masahito
    • Journal Title

      Communications Biology

      Volume: 4 Issue: 1 Pages: 1-13

    • DOI

      10.1038/s42003-021-02304-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] グリオーマ幹細におけるエピゲノム因子 RNF20 の機析2022

    • Author(s)
      Kenny Daun, 守村直子(発表者), 深見忠輝, 谷垣健二, 椎野顯彦, 野崎和彦, 等誠司
    • Organizer
      第9回Neuro-Oncology West
    • Related Report
      2021 Annual Research Report
  • [Presentation] RNF20 as an epigenetic regulator for GBM stem-like cells maintenance and regulation.2022

    • Author(s)
      Daun K, Morimura N, Fukami T, Hayashi Y, Koyama N, Tanigaki T, Shiino A, Nozaki K, Hitoshi S
    • Organizer
      第18回成体脳ニューロン新生懇談会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Autism-like behaviors and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice.2019

    • Author(s)
      NAOKO MORIMURA, HIROKI YASUDA, KAZUHIKO YAMAGUCHI, KEI-ICHI KATAYAMA, NAOKO H. TOMIOKA, KAZUYUKI YAMADA, SEIJI HITOSHI, TAKEO YOSHIKAWA, JUN ARUGA.
    • Organizer
      The 10th IBRO World Congress of Neuroscience IBRO2019
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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