| Project/Area Number |
15K06789
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Shiga University of Medical Science (2016-2018)
Ritsumeikan University (2015) |
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Principal Investigator |
Morimura Naoko 滋賀医科大学, 医学部, 特任助教 (00349044)
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| Research Collaborator |
Aruga Jun
Mishina Masami
Hitoshi Seiji
Yasuda Hiroki
Yoshikawa Takeo
Yanaga Aki
|
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | シナプス接着分子 / 興奮性シナプス / 可塑性 / 自閉症 / 統合失調症 / シナプスオーガナイザー / 神経発達障害 / 非ヒト霊長類 / シナプス可塑性 |
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| Outline of Final Research Achievements |
Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. We demonstrated that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 were decreased. And the synapses were structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments revealed that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. We also detected functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, our research indicate that Lrfn2 serves as a core synaptic components of excitatory neurons, associating with psychiatric disorders,
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| Academic Significance and Societal Importance of the Research Achievements |
神経細胞と神経細胞との繋ぎ目であるシナプスは、記憶・学習、認知、感情、実行機能といった高次脳機能の要所であり、シナプス形成や維持機構を分子レベルで理解することは、高次脳機能を反映する『こころ』の解明につながると考えられる。近年シナプス異常と脳発達障害との関連性にも注目されており、更なる高次脳機能における分子機序解明が求められている。本研究で明らかとなったLrfn2の興奮性シナプスの分子メカニズムは、シナプス接着分子の脳機能における生理的役割を明らかにしただけでなく、『シナプス異常と発達障害』とを結びつける知見の一つとなり脳発達障害発症のメカニズム解明および新規治療法につながる成果となった。
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