| Project/Area Number |
16K07021
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurophysiology / General neuroscience
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
Hori Kei 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 代謝研究部, 室長 (70568790)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 自閉症 / シナプス / 自閉症感受性遺伝子 / 神経回路 / スパイン / AUTS2 / 精神疾患 / 音声コミュニケーション / 記憶学習 / 大脳 / 大脳皮質 / 海馬 |
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| Outline of Final Research Achievements |
AUTS2 gene has been associated with various psychiatric disorders, such as autism and schizophrenia. Its roles for brain development, however, remains unclear. In this study, we found that the excitatory synapses were specifically increased in Auts2 mutants. In mice lacking Auts2 in the forebrain, increased dendritic spines were observed in regions such as mPFC and hippocampus. In the mutant hippocampal slices, excitatory but not inhibitory synaptic inputs were increased, suggesting that an imbalance of excitatory and inhibitory inputs occurs in auts2 mutant brain. Auts2 KO mice exhibited autistic-like social behaviors including impairments in social interaction and altered vocal communication. Together, these data suggest that AUTS2 regulates excitatory synapse number to coordinate excitatory vs. inhibitory balance in the brain, whose impairments may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでにAUTS2遺伝子変異と精神疾患との関連性を示唆するような臨床例はいくつも報告されてきたものの、脳発達におけるAUTS2の生理学的役割やAUTS2変異と精神疾患を繋ぐ解剖・生理学的病因は明らかになっていなかった。本研究により、AUTS2変異によって引き起こされる精神疾患病態の一つとして、シナプス形成やその機能異常に原因があることが初めて明らかとなった。今後はさらに、シナプス形成に関わるAUTS2の分子機能の詳細を明らかにし、また、AUTS2変異マウスを利用した治療薬スクリーニングなどを行うことで、自閉症などの精神疾患に対する新たな診断・治療法の開発に大きく貢献できることが期待される。
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