2022 Fiscal Year Final Research Report

Multiscale understanding of synaptic pathology of psychiatric disorders

Planned Research

PDF

Project Area	Constructive understanding of multi-scale dynamism of neuropsychiatric disorders
Project/Area Number	18H05433
Research Category	Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
Allocation Type	Single-year Grants
Review Section	Biological Sciences
Research Institution	Institute of Physical and Chemical Research (2019-2022) Gunma University (2018)
Principal Investigator	Hayashi-Takagi Akiko (林朗子) 国立研究開発法人理化学研究所, 脳神経科学研究センター, チームリーダー (60415271)
Co-Investigator(Kenkyū-buntansha)	田中昌司上智大学, 理工学部, 教授 (30188304) 干場義生群馬大学, 生体調節研究所, 助教 (40780200) 藤原和之群馬大学, 大学院医学系研究科, 助教 (20735154)
Project Period (FY)	2018-06-29 – 2023-03-31
Keywords	樹状突起スパイン / 統合失調症 / XLスパイン / 超線形神経演算
Outline of Final Research Achievements	In light of human genetics, there is little doubt regarding the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality;from the synapse to behaviour is lacking. To address this question, we examined the multiscale effects of synaptic inputs of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra-large (XL) synapses, which evoked supralinear synaptic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were significantly more abundant in the postmortem brains of schizophrenia patients than in those of matched controls. Our results suggest that certain domains of psychiatric symptoms are caused by hyper-connection via heavily-weighted synapses.
Free Research Field	基礎精神医学
Academic Significance and Societal Importance of the Research Achievements	一つの神経細胞には約1万個のシナプスが存在し、多くのシナプスが同時期に協調的に入力することが神経細胞の発火に重要とされている。しかし今回、少なくともある一群の統合失調症患者では、ごく少数の巨大スパインを介した非常に強いシナプス入力だけで、神経細胞の発火が決定付けられている可能性が示された。これらの結果より、少なくとも一部の統合失調症患者には、非常に強いシナプスにより神経演算の歪みが生じ、それらが病態生理の一部を担うという全く新しい仮説が提唱できた。これらの知見は統合失調症の治療戦略の少なくとも一部は再考を要することを示唆する。