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Analysis of Neurexin mutant mice in which binding specificity of Neurexins to the ligands are manipulated to elucidate the molecular pathway responsible for autism.

Research Project

Project/Area Number 25282242
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Basic / Social brain science
Research InstitutionShinshu University

Principal Investigator

TABUCHI Katsuhiko  信州大学, 学術研究院医学系, 教授 (20546767)

Project Period (FY) 2013-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
Fiscal Year 2015: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2014: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Fiscal Year 2013: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
KeywordsNeurexin / 自閉症 / シナプス / Neuroligin / ニューレキシン / ニューロリギン / マウスモデル
Outline of Final Research Achievements

Neurexins are pre-synaptic cell adhesion molecules that bind post-synaptic Neuroligins to induce synapse formation and maturation. Both Neurexins and Neuroligins are implicated in autism. We hypothesized that the synaptic defects caused by disruption of Neurexins-Neuroligins interaction may be involved in the molecular pathophysiology of autism. To test this hypothesis, we generated mutant mice of Neurexins that have deficit of Neurexin-Neuroligin binding and analyzed the effect on synapse functions. Neurexin-3 ss4+ knockin mice of which Neurexin-3 lacks binding affinity to Neuroligins decreased the AMPA receptor-mediated synaptic transmission in the hippocampal neurons due to the hyper-internalization of AMPA receptor from the post-synapitc membrane. This phenotype is consistent with that in Neuroligin-3 R704C autism model mice, suggesting that this may be the mechanism caused by impaired Neurexin-Neuroligin interaction associated with autism pathophysiology.

Report

(5 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (20 results)

All 2017 2016 2015 2014 2013 Other

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 7 results,  Acknowledgement Compliant: 5 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 7 results) Remarks (2 results)

  • [Journal Article] Functions of synapse adhesion molecules neurexin/neuroligins and neurodevelopmental disorders.2017

    • Author(s)
      Cao X, Tabuchi K.
    • Journal Title

      Neurosci Res.

      Volume: 116 Pages: 3-9

    • DOI

      10.1016/j.neures.2016.09.005

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders.2017

    • Author(s)
      Baig DN, Yanagawa T, Tabuchi K.
    • Journal Title

      Brain Res Bull.

      Volume: 129 Pages: 82-90

    • DOI

      10.1016/j.brainresbull.2016.10.006

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Fluorescent protein tagging of endogenous protein in brain neurons using CRISPR/Cas9-mediated knock-in and in utero electroporation techniques.2016

    • Author(s)
      Uemura T, Mori T, Kurihara T, Kawase S, Koike R, Satoga M, Cao X, Li X, Yanagawa T, Sakurai T, Shindo T, Tabuchi K.
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 35861-35861

    • DOI

      10.1038/srep35861

    • NAID

      120007100133

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses.2015

    • Author(s)
      Aoto J, Foldy C, Ilcus SM, Tabuchi K, Sudhof TC.
    • Journal Title

      Nat Neurosci.

      Volume: 18(7) Issue: 7 Pages: 997-1007

    • DOI

      10.1038/nn.4037

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling.2015

    • Author(s)
      Anderson GR, Aoto J, Tabuchi K, Foldy C, Covy J, Yee AX, Wu D, Lee SJ, Chen L, Malenka RC, Sudhof TC.
    • Journal Title

      Cell

      Volume: 162(3) Issue: 3 Pages: 593-606

    • DOI

      10.1016/j.cell.2015.06.056

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission.2015

    • Author(s)
      Ko JS, Pramanik G, Um JW, Shim JS, Lee D, Kim KH, Chung GY, Condomitti G, Kim HM, Kim H, de Wit J, Park KS, Tabuchi K, Ko J.
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 112(6) Issue: 6 Pages: 1874-1879

    • DOI

      10.1073/pnas.1410138112

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhanced synapse remodeling as a common phenotype in mouse models of autism.2014

    • Author(s)
      Isshiki, M., Tanaka, S., Kuriu, T., Tabuchi, K., Takumi, T. and Okabe, S.
    • Journal Title

      Nat. Commun.

      Volume: 5 Issue: 1 Pages: 4742-4742

    • DOI

      10.1038/ncomms5742

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Calsyntenins function as synaptogenic adhesion molecules in concert with neurexins2014

    • Author(s)
      Um, J. W. Pramanik, G. Ko, J. S. Song, M. Y. Lee, D. Kim, H. Park, K. S. Sudhof, T. C. Tabuchi, K. Ko, J.
    • Journal Title

      Cell Rep

      Volume: 6(6) Pages: 1096-1109

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] モデルマウスに見るシナプス成熟障害と自閉症との関係2014

    • Author(s)
      田渕克彦 張文欣 Nur Farehan Mohamed Asgar Gopal Pramanik
    • Journal Title

      日本神経精神薬理学雑誌(Jpn. J. Neuropsychopharmacol.)

      Volume: 34 Pages: 1-4

    • Related Report
      2013 Annual Research Report
  • [Journal Article] シナプスと自閉症2014

    • Author(s)
      田渕克彦
    • Journal Title

      生体の科学

      Volume: 65(1) Pages: 3-6

    • Related Report
      2013 Annual Research Report
  • [Journal Article] Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking2013

    • Author(s)
      Aoto, J. Martinelli, D. C. Malenka, R. C. Tabuchi, K. Sudhof, T. C.
    • Journal Title

      Cell

      Volume: 154(1) Pages: 75-88

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Distortion of the synaptic functions in the microcircuit of the brain in modelmice for neurodevelopmental disorders.2016

    • Author(s)
      Katsuhiko Tabuchi
    • Organizer
      The 47th NIPS International Symposium “Decoding Synapses”
    • Place of Presentation
      岡崎コンファレンスセンター(愛知県岡崎市)
    • Year and Date
      2016-10-26
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 微小神経回路におけるシナプス機能の異常と自閉症の病態生理2016

    • Author(s)
      田渕克彦
    • Organizer
      3プロジェクト合同終了シンポジウム「次ステージ機能生命科学の展望」
    • Place of Presentation
      岡崎コンファレンスセンター(愛知県岡崎市)
    • Year and Date
      2016-03-10
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Modification of genes associated with synaptic functions in the subpopulation of neurons in mouse brains and the effects on pathophysiology of autism.2016

    • Author(s)
      Katsuhiko Tabuchi
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Neuroligin自閉症モデルのシナプス機能の解析2015

    • Author(s)
      田渕克彦
    • Organizer
      第2回生物学的自閉症研究会
    • Place of Presentation
      東京大学(東京都文京区)
    • Year and Date
      2015-07-10
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Neuroligin-3変異マウスを用いた非症候群性自閉症におけるシナプス異常の研究2015

    • Author(s)
      田渕克彦
    • Organizer
      第92回日本生理学会
    • Place of Presentation
      神戸国際会議場(兵庫県神戸市)
    • Year and Date
      2015-03-23
    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Invited
  • [Presentation] Impairment in Synapse Maturation as a Cause of Autism.2014

    • Author(s)
      Katsuhiko Tabuchi
    • Organizer
      International Conference on Emerging Trends in Life Sciences for Sustainable Development.
    • Place of Presentation
      Forman Christian College, Lahore, Pakistan
    • Year and Date
      2014-10-09
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Neuroliginモデルマウスに見るシナプス成熟障害と自閉症との関係2013

    • Author(s)
      田渕克彦
    • Organizer
      第55回脳の医学生物学研究会
    • Place of Presentation
      名古屋市立大学医学部
    • Year and Date
      2013-08-10
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Remarks] 信州大学分子細胞生理学講座研究内容

    • URL

      http://www.shinshu-u.ac.jp/faculty/medicine/chair/i-2seiri/ja/research.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 信州大学医学部分子細胞生理学教室

    • URL

      http://www.shinshu-u.ac.jp/faculty/medicine/chair/i-2seiri/ja/tabuchi.html

    • Related Report
      2013 Annual Research Report

URL: 

Published: 2013-05-21   Modified: 2018-03-22  

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