Mechanisms and therapeutic strategy for cognitive dysfunction in Angelman syndrome

• Project/Area Number: 15K09611
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hokkaido University
• Principal Investigator: EGAWA Kiyoshi 北海道大学, 医学研究院, 助教 (40450829)
• Research Collaborator: KAWANO Osamu 北海道大学, 医学院, 大学院生
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: アンジェルマン症候群 / 自閉症スペクトラム / GABA / 自閉症 / GABA持続抑制 / GABAシナプス伝達 / 自閉症モデル

Outline of Final Research Achievements

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the UBE3A gene. We have recently shown that tonic form of GABAergic inhibition is significantly decreased in the cerebellar granule cells of Ube3a knockout mice (AS mice). Because tonic inhibition is ubiquitously present within CNS, deregulation of tonic inhibition may be involved in pathophysiology of various in AS. To clarify this, we investigated GABAergic function in the hippocampus and thalamus of AS mice.Tonic inhibition of CA1 hippocampal pyramidal neurons was significantly decreased in AS mice, while thalamic relay neurons not.Thus, deregulation of tonic inhibition in AS mice differs by brain region. THIP, a enhancer of tonic inhibition in the entire brain, did not improve cortical dysfunctions such as epilepsy or memory deficit, suggesting that the discrepancy of intensity of tonic inhibition among brain regions itself may contribute to the pathophysiology of AS.

Research Products

• [Int'l Joint Research] Department of Neurology/Massachusetts General Hospital(米国)
• [Int'l Joint Research] University of Wisconsin Milwaukee(米国)
• [Journal Article] Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential (2017)
  • Author(s): Joseph Glykys, Volodymyr Dzhala, Kiyoshi Egawa, Kristopher T. Kahle, Eric Delpire, Kevin Staley
  • Journal Title: Trends in Neuroscience Volume: 40 Issue: 5 Pages: 276-294
  • DOI: 10.1016/j.tins.2017.03.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Deregulated tonic inhibition in the hippocampus of mice model of Angelman syndrome (2017)
  • Author(s): 江川潔 河野修
  • Organizer: １４ｔｈAsian and Oceanian Congress of Child Neurology
  • Place of Presentation: ヒルトン福岡シーホーク（福岡県福岡市）
  • Year and Date: 2017-05-11
  • Int'l Joint Research
• [Presentation] Diverse deregulation of tonic inhibition in thalamo‐cortical networks of mice model of Angelman syndrome. (2017)
  • Author(s): 江川潔
  • Organizer: 第51回日本てんかん学会 京都府京都市
• [Presentation] Aberrant oscillation property of Perkinje cells is caused by decreased tonic inhibition in granule cells in mice model of Angelman syndrome. (2016)
  • Author(s): 江川潔 福田敦夫
  • Organizer: 日本生理学会総会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-03-22