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Pathophysiological impact of diverse deregulation of tonic inhibition in Angelman syndrome

Research Project

Project/Area Number 18H02777
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionHokkaido University

Principal Investigator

Egawa Kiyoshi  北海道大学, 医学研究院, 助教 (40450829)

Co-Investigator(Kenkyū-buntansha) 岡野 栄之  慶應義塾大学, 医学部(信濃町), 教授 (60160694)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Keywordsアンジェルマン症候群 / GABA / GABA持続抑制 / GABA作動性持続抑制 / GABA作動性抑制 / 遺伝性てんかん / 精神運動発達遅滞 / 発達障害 / GABA抑制 / 自閉症スペクトラム
Outline of Final Research Achievements

We investigated tonic inhibition of cortical pyramidal neuron and thalamic relay neurons in AS mice. Tonic inhibition was decreased in the hippocampus and the cortex, but not in thalamo-cortical relay neurons. AS mice showed significantly higherδ-θwave power in intracranial EEG. This epileptic feature was improved by MP-Ⅲ-22, positive allosteric modulator forα5 subunit-containing GABAa receptors. By using iPS cells-derived neurons, we also discovered that intrinsic firing property is maintained in AS interneurons but intracellular Cl- regulating protein was dysregulated in AS model mice. These results suggest that not a global but a relative decrease in tonic inhibition in the cortex/hippocampus can disturb the regular thalamo-cortical networks, resulting in epilepsy of AS. Our findings can contribute to the deeper understanding of pathophysiology of AS and developing a new therapeutic strategy.

Academic Significance and Societal Importance of the Research Achievements

今回の研究により、アンジェルマン症候群(AS)における皮質神経細胞選択的なシナプス外持続抑制の減弱がその病態生理に重要であることを明らかにした。GABA作動性抑制は薬剤により調整可能であり、α5サブユニット選択的陽性変力薬がてんかんの治療に有効である可能性が示唆された。持続抑制が全体に下がっているのではなく、領域間の不均等により症状が発生しうる、という結果はこれまで全く報告されておらず、ASのみならず中枢神経疾患全体への病態生理探索に一石を投じるものと思われる。また、クロライドトランスポーターの調整薬であるブメタニドも知的障害の改善に寄与することが示された。将来的な治療への応用が期待される。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (14 results)

All 2023 2021 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 1 results) Presentation (6 results) (of which Int'l Joint Research: 4 results)

  • [Int'l Joint Research] Univ of Wisconsin, Dept. of Chemistry(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Univ of Wisconsin, Dept. of Chemistry(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Imbalanced expression of cation-chloride cotransporters as potential therapeutic target in an Angelman syndrome model mouse.2023

    • Author(s)
      Egawa K#, Watanabe M#(#contributed equally to this work), Shiraishi H, Sato D, Takahashi Y, Nishio S , Fukuda A.
    • Journal Title

      Scientific Reports

      Volume: 13: 5685 Issue: 1 Pages: 5685-5685

    • DOI

      10.1038/s41598-023-32376-z

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Variance in the pathophysiological impact of the hemizygosity of gamma-aminobutyric acid type A receptor subunit genes between Prader-Willi syndrome and Angelman syndrome2021

    • Author(s)
      Egawa Kiyoshi、Saitoh Shinji、Asahina Naoko、Shiraishi Hideaki
    • Journal Title

      Brain and Development

      Volume: 43 Issue: 4 Pages: 521-527

    • DOI

      10.1016/j.braindev.2020.12.014

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Flurothyl-induced seizure paradigm revealed higher seizure susceptibility in middle-aged Angelman syndrome mouse model2021

    • Author(s)
      Egawa Kiyoshi、Nakakubo Sachiko、Kimura Shuhei、Goto Takeru、Manabe Atsushi、Shiraishi Hideaki
    • Journal Title

      Brain and Development

      Volume: 43 Issue: 4 Pages: 515-520

    • DOI

      10.1016/j.braindev.2020.12.011

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Efficacy of perampanel for epileptic seizures and daily behavior in a patient with Leigh syndrome: A case report2021

    • Author(s)
      Kimura Shuhei、Shiraishi Hideaki、Egawa Kiyoshi、Uchida Masaya、Ueno Michihiko
    • Journal Title

      Brain and Development

      Volume: 43 Issue: 1 Pages: 157-159

    • DOI

      10.1016/j.braindev.2020.07.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Short-latency somatosensory-evoked potentials demonstrate cortical dysfunction in patients with Angelman syndrome2021

    • Author(s)
      Egawa Kiyoshi、Saitoh Shinji、Asahina Naoko、Shiraishi Hideaki
    • Journal Title

      eNeurologicalSci

      Volume: 22 Pages: 100298-100298

    • DOI

      10.1016/j.ensci.2020.100298

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene2018

    • Author(s)
      Ito Tomoshiro、Narugami Masashi、Egawa Kiyoshi、Yamamoto Hiroyuki、Asahina Naoko、Kohsaka Shinobu、Ishii Atsushi、Hirose Shinichi、Shiraishi Hideaki
    • Journal Title

      Brain Dev.

      Volume: 40 Issue: 3 Pages: 226-228

    • DOI

      10.1016/j.braindev.2017.11.007

    • NAID

      120006559004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] Electrophysiological properties of excitatory or inhibitory neurons derived from induced pluripotent stem cells (iPSC) in Angelman syndrome.2019

    • Author(s)
      Kiyoshi Egawa, Yoshihiro Hirata, Mitsuru Ishikawa, Hideaki Siraishi, Shinji Saito, Yukitoshi Takahasi, Hironobu Okuno, Hideyuki Okano
    • Organizer
      The 20th Annual Meeting of Infantile Seizure Society
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Imbalanced Tonic Inhibition Between the Cortex and Thalamus Causes Epileptiform Activity in Mice Model of Angelman Syndrome.2019

    • Author(s)
      Egawa K, Shiraishi H, Savic M, Li G, Cook J.
    • Organizer
      American Epilepsy Society, 63th Scientific meeting,
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 遺伝性てんかん・発達障害動物モデルにおける認知機能評価の難しさ ―アンジェルマン症候群モデルマウスにおける経験―2019

    • Author(s)
      江川潔
    • Organizer
      第53回日本てんかん学会総会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Pathophysiological impact of diverse dysregulation of tonic inhibition in Angelman syndrome2019

    • Author(s)
      Kiyoshi Egawa and Atuo Fukuda
    • Organizer
      The 9th Federation of Asian and Oceanian Physiological Societies Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アンジェルマン症候群患者由来iPS細胞より誘導された興奮性/抑制性神経細胞の機能解析2018

    • Author(s)
      平田快洋、石川充、白石秀明、佐藤大介、斎藤伸治、高橋幸利、奥野博庸、岡野栄之、江川潔
    • Organizer
      第41回日本神経科学学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アンジェルマン症候群患者iPS細胞由来ニューロンの電気生理学的検討2018

    • Author(s)
      江川潔、平田快洋、白石秀明、佐藤大介、齋藤伸治、高橋幸利、奥野博庸、石川充、岡野栄之
    • Organizer
      第60回日本小児神経学会
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2024-01-30  

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