2021 Fiscal Year Final Research Report

The synaptic insufficient delivery hypothesis of autism based on PET findings

Research Project

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Project/Area Number	19H03581
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 52030:Psychiatry-related
Research Institution	University of Fukui
Principal Investigator	Matsuzaki Hideo 福井大学, 子どものこころの発達研究センター, 教授 (00334970)
Co-Investigator(Kenkyū-buntansha)	岩田圭子福井大学, 子どものこころの発達研究センター, 助教 (30415088) 謝敏カク福井大学, 子どものこころの発達研究センター, 助教 (40444210) 深澤有吾福井大学, 学術研究院医学系部門, 教授 (60343745) 出雲信夫横浜薬科大学, 薬学部, 教授 (70368976) 石川保幸前橋工科大学, 工学部, 准教授 (90346320) 高橋琢哉横浜市立大学, 医学研究科, 教授 (20423824)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	自閉症 / シナプス / NSF / AMPA受容体 / セロトニントランスポーター
Outline of Final Research Achievements	We previously identified N-ethylmaleimide-sensitive factor (NSF) as a new serotonin transporter (SERT)-binding protein and described its importance in SERT membrane trafficking. In this study, we generated Nsf+/- mice and investigated their phenotypes in vivo. Nsf+/- mice exhibited abnormalities in sociability, communication, repetitiveness, and anxiety. Additionally, Nsf loss led to a decrease in membrane SERT expression in the raphe and accumulation of glutamate AMPA receptors at the synaptic membrane surface in the hippocampal CA1 region. We found that postsynaptic density and long-term depression were impaired in the hippocampal CA1 region of Nsf+/- mice. Taken together, these findings demonstrate that NSF plays a role in synaptic plasticity and glutamatergic and serotonergic systems, suggesting a possible mechanism by which the gene is linked to the pathophysiology of autistic behaviors. Intervention trials were also examined, but no significant effect was observed.
Free Research Field	分子精神医学
Academic Significance and Societal Importance of the Research Achievements	運動負荷による介入実験が成功しなかったために、本研究で「シナプス膜移行異常仮説」の妥当性を証明するには至らなかったが、これまでにない観点から自閉症のモデルマウスを確立することができた。このモデルマウスを用いた介入試験をシーズ探索に利用することで、将来の自閉症の治療手段の開発に役立つ可能性がある。