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Functional analysis of MDGA family proteins on regulation of synapse formation and social behavior.

Research Project

Project/Area Number 16K08237
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionKagawa University

Principal Investigator

Yamamoto Tohru  香川大学, 医学部, 教授 (10251480)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords自閉スペクトラム症 / 統合失調症 / MDGA1 / MDGA2 / Neuroligin / E/Iバランス / シナプス形成 / E/Iバランス / ニューロリギン / ニューレキシン / 記憶 / 社会性行動 / 自閉症スペクトラム障害 / MDGA
Outline of Final Research Achievements

MDGAs are GPI-anchored IgSF molecules that consist of two closely related family members: MDGA1 and MDGA2. MDGA1/2 directly associates with Neuroligins to interfere its binding to Neurexin for preventing inappropriately excess synapse formation. We found that loss of MDGA1 induces excess inhibitory synapse formation to cause sensorimotor-gating abnormalities that are early clinical symptom of schizophrenia, and loss of MDGA2 induces excess excitatory synapse formation to cause social behavioral abnormalities related to ASD. We also found that MDGA1- and MDGA2-deficient mice exhibit contrasting social behavioral abnormalities .

Academic Significance and Societal Importance of the Research Achievements

本研究により、シナプスの「でき過ぎ」を防いでいるシステムの存在とその分子的実態が明らかになるとともに、その機能に干渉することにより、種々の精神神経疾患における分子病態の背景にあると考えられているE/Iバランスを人為的に制御し得ることが示唆された。また、MDGA1・MDGA2両欠失マウスは、E/Iバランスをそれぞれ興奮側・抑制側に偏移させた疾患モデルとしても有用であることが示された。本解析により、高次脳機能統御におけるE/Iバランスの意義があらためて明らかになるとともに、精神神経疾患創薬シーズの獲得に向けた新たな探索プラットフォームを提示できたと考えている。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (36 results)

All 2020 2019 2018 2017 2016 Other

All Int'l Joint Research (8 results) Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (17 results) (of which Int'l Joint Research: 4 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] The University of British Columbia(カナダ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Cincinnati Children's Hospital(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] The University of British Columbia(カナダ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Cincinnati Children's Hospital(米国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] The University of British Columbia(Canada)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Cincinnati Children's Hospital(米国)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] The University of British Columbia(Canada)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Cincinnati Children's Hospital M.C.(米国)

    • Related Report
      2016 Research-status Report
  • [Journal Article] MDGA1-deficiency attenuates prepulse inhibition with alterations of dopamine and serotonin metabolism: An ex vivo HPLC-ECD analysis2020

    • Author(s)
      Hossain MR, Jamal M, Tanoue Y, Ojima D, Takahashi H, Kubota T, Ansary TM, Ito A, Tanaka N, Kinoshita H, Kishimoto Y, Yamamoto T.
    • Journal Title

      Neurosci. Lett.

      Volume: 716 Pages: 134677-134677

    • DOI

      10.1016/j.neulet.2019.134677

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Retinal ganglion cell loss in kinesin-1 cargo Alcadein α deficient mice.2020

    • Author(s)
      Nakano Y, Hirooka K, Chiba Y, Ueno M, Ojima D, Hossain MR, Takahashi H, Yamamoto T, Kiuchi Y.
    • Journal Title

      Cell Death Dis.

      Volume: 11 Issue: 3 Pages: 166-166

    • DOI

      10.1038/s41419-020-2363-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease2019

    • Author(s)
      Hata S、Omori C、Kimura A、Saito H、Kimura N、Gupta V、Pedrini S、Hone E、Chatterjee P、Taddei K、Kasuga K、Ikeuchi T、Waragai M、Nishimura M、Hu A、Nakaya T、Meijer L、Maeda M、Yamamoto T、Masters CL、Rowe CC、Ames D、Yamamoto K、Martins RN、Gandy S、Suzuki T
    • Journal Title

      Alzheimer's & Dementia: Translational Research & Clinical Interventions

      Volume: 5 Issue: 1 Pages: 740-750

    • DOI

      10.1016/j.trci.2019.09.015

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function2017

    • Author(s)
      Steven A. Connor, Ina Ammendrup-Johnsen, Yasushi Kishimoto, Parisa Karimi Tari, Vedrana Cvetkovska, Takashi Harada, Daiki Ojima, Tohru Yamamoto, Yu Tian Wang, Ann Marie Craig
    • Journal Title

      Cell Rep.

      Volume: 21 Issue: 13 Pages: 3637

    • DOI

      10.1016/j.celrep.2017.11.109

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Altered cortical dynamics and cognitive function upon haploinsufficiency of the autism-linked excitatory synaptic suppressor MDGA22016

    • Author(s)
      S. A. Connor, I. Ammendrup-Johnsen, A. W. Chan, Y. Kishimoto, C. Murayama, N. Kurihara, A. Tada, Y. Ge, H. Lu, R. Yan, J. M. LeDue, H. Matsumoto, H. Kiyonari, Y. Kirino, F. Matsuzaki, T. Suzuki, T. H. Murphy, Y. T. Wang, T. Yamamoto, A. M. Craig
    • Journal Title

      Neuron

      Volume: 91 Issue: 5 Pages: 1052-1068

    • DOI

      10.1016/j.neuron.2016.08.016

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] d-Allose Attenuates Overexpression of Inflammatory Cytokines after Cerebral Ischemia/Reperfusion Injury in Gerbil.2016

    • Author(s)
      Shinohara N, Nakamura T, Abe Y, Hifumi T, Kawakita K, Shinomiya A, Tamiya T, Tokuda M, Keep RF, Yamamoto T, Kuroda Y.
    • Journal Title

      J Stroke Cerebrovasc Dis.

      Volume: 25 Issue: 9 Pages: 2184-2188

    • DOI

      10.1016/j.jstrokecerebrovasdis.2016.01.030

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ryanodine receptors contribute to the induction of ischemic tolerance.2016

    • Author(s)
      Nakamura-Maruyama E, Miyamoto O, Okabe N, Himi N, Feng L, Narita K, Keep RF, Yamamoto T, Nakamura T
    • Journal Title

      Brain Research Bulletin

      Volume: 122 Pages: 45-53

    • DOI

      10.1016/j.brainresbull.2016.02.018

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] シナプス形成抑制因子MDGA1の欠失による精神神経疾患様行動異常と、これを抑止する薬剤の探索2020

    • Author(s)
      多田 篤史, 田之上 優,黒川 直弘,窪田 剛志,津島 希海,尾嶋 大喜,Razib Hossain,高橋 弘雄, 岸本 泰司, 山本 融
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Enhanced β- and β’-cleavages of APP in Alcadein α knockout mouse brain.2019

    • Author(s)
      Toshiharu Suzuki, Naoya Goto, Haruka Saito, Saori Hata, Tohru Yamamoto
    • Organizer
      Alzheimer's Association International Conference 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] シナプス形成抑制因子MDGAファミリー分子群の欠失が引き起こすE/Iバランス偏移がもたらす認知・行動異常2019

    • Author(s)
      山本 融,尾嶋 大喜,Razib Hossain,多田 篤史, 黒川 直弘, 長澤 研, 琢磨 和晃, 中井 雄規,高橋 弘雄, 冨永 貴志,岸本 泰司
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 神経活動依存的な転写因子Npas4は脳梗塞に伴う細胞死を抑制する2019

    • Author(s)
      高橋 弘雄,朝比奈 諒,山本 融,坪井 昭夫
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] キネシン-1によるFrizzledの軸索輸送が神経終末のWntシグナルを制御する2019

    • Author(s)
      満間 百音、白木 柚葉、齊藤 遥、高田 律子、山本 融、高田 慎治、羽田 沙緒里、鈴木 利治
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Alcadein α欠損マウスにおけるAPPのアミロイド生成的代謝の促進機構2019

    • Author(s)
      鈴木 利治、後藤 直也、林 理沙、羽田 沙緒里、山本 融
    • Organizer
      第38回日本認知症学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] MDGAファミリー分子群の欠失が引き起こすE/I バランス偏移に伴う認知・行動異常の解析2019

    • Author(s)
      Razib Hossain, 多田 篤史, 黒川 直弘, 長澤 研, 琢磨 和晃, 尾嶋 大喜, 高橋 弘雄, 岸本泰司, 山本 融
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] マウスモデルを用いたプラセボおよびノセボ反応条件づけの開発と評価2019

    • Author(s)
      青野 仁美, 藤原 友佳, 尾嶋 大喜, 山本 融, 岸本泰司
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Alcadein αノックアウトマウスは加齢で網膜神経節細胞が脱落する2018

    • Author(s)
      中野裕貴 小野葵 小林守 高砂縁 村山千明 尾嶋大喜 山本融 廣岡一行
    • Organizer
      第122回 日本眼科学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Retinal Ganglion Cell Loss in Alcadeinα Knockout Mice.2018

    • Author(s)
      Yuki Nakano, Aoi Ono, Mamoru Kobayashi, Yukari Takasago, Chiaki Murakami, Daiki Ozima, Tohru Yamamoto, Kazuyuki Hirooka
    • Organizer
      ARVO 2018: The Association for Research in Vision and Ophthalmology Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] シナプス形成抑制因子MDGA1の欠損は興奮/抑制バランスの抑制側へのシフトによる学習・記憶障害をもたらす2018

    • Author(s)
      山本 融 Steven A. Connor  Ina Ammendrup-Johnsen 岸本 泰司 原田 岳 尾嶋 大喜 Razib Hossain Ann Marie Craig
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Synaptopathies associated with loss of MDGAs.2018

    • Author(s)
      Steven Connor, Ina Ammendrup-Johnsen, Yasushi Kishimoto, Parisa Karimi Tari, Vedrana Cvetkovska, Takashi Harada, Daiki Ojima, Tohru Yamamoto, Yu Tian Wang, Ann Marie Craig
    • Organizer
      17th Annual Molecular and Cellular Cognition Society Meeting.
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] MDGA1は抑制性シナプス形成抑制因子であり、その欠損は興奮性の抑制と学習・記憶能力の障害をもたらす2018

    • Author(s)
      山本 融 Steven A. Connor 岸本 泰司 Ina Ammendrup-Johnsen 原田 岳 尾嶋 大喜 Razib Hossain  Ann Marie Craig
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] MDGA2は興奮性シナプス形成抑制因子であり、そのヘミ欠損は興奮性の亢進とASD様の行動異常をもたらす2017

    • Author(s)
      山本 融 Steven A. Connor 岸本 泰司 Ina Ammendrup-Johnsen 栗原 直和 村山 千明 尾嶋 大喜 Razib Hossain 鈴木 利治 Ann Marie Craig
    • Organizer
      日本薬学会第137年
    • Place of Presentation
      仙台国際センター・東北大学
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] シナプス形成抑制因子MDGA2のヘミ欠損は興奮/抑制バランスの興奮側へのシフトによるASD様の社会性行動異常をもたらす2017

    • Author(s)
      山本 融 Steven A. Connor 岸本 泰司 Ina Ammendrup-Johnsen 栗原 直和 村山 千明 尾嶋 大喜 Razib Hossain 鈴木 利治 Ann Marie Craig
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Research-status Report
  • [Presentation] シナプス形成抑制因子MDGA2のヘミ欠失マウスは興奮性入力の亢進によりもたらされる自閉症スペクトラム障害のモデルとなる2016

    • Author(s)
      山本 融 Steven A. Connor 岸本 泰司 Ina Ammendrup-Johnsen 栗原 直和 村山 千明 鈴木 利治 Ann Marie Craig
    • Organizer
      第39回分子生物学会年会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] Haploinsufficiency of the neuronal surface protein MDGA2 enhances excitatory synapse development, alters cortical circuit dynamics and yields behavioral phenotypes consistent with autism in mice.2016

    • Author(s)
      Connor SA, Ammendrup-Johnsen I, Chan AW, Kishimoto Y, Murayama C, Ojima D, Kurihara N, Tada A, Ge Y, Lu H, Yan R, LeDue JM, Matsumoto H, Kiyonari H, Kirino Y, Matsuzaki F, Suzuki T, Murphy TH, Wang YT, Yamamoto T, Craig AM.
    • Organizer
      Society for Neuroscience annual meeting
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2016-11-12
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Remarks] シナプスの形成抑制タンパク質MDGA2のヘミ欠損は自閉症スペクトラム様の異常をもたらす

    • URL

      http://first.lifesciencedb.jp/archives/14652

    • Related Report
      2016 Research-status Report
  • [Remarks] 香川大学教員の研究成果について

    • URL

      http://www.kagawa-u.ac.jp/files/4714/7330/1707/0908_kenkyuseika.pdf

    • Related Report
      2016 Research-status Report
  • [Remarks] 香川大学医学部教員の研究成果について

    • URL

      http://www.med.kagawa-u.ac.jp/topics/other/yamamoto/

    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] パーキンソン病の診断指標2019

    • Inventor(s)
      山本 融 他
    • Industrial Property Rights Holder
      香川大学 他
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-033661
    • Filing Date
      2019
    • Related Report
      2018 Research-status Report

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Published: 2016-04-21   Modified: 2022-02-21  

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