| Project/Area Number |
17K07058
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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 | Tokyo Women's Medical University (2018-2019)
Hiroshima University (2017) |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 小脳 / プルキンエ細胞 / シナプス刈り込み / ミクログリア / 登上線維 / パッチクランプ / シナプス / 神経回路発達 / 神経回路形成 / 発達 / シナプス再編成 |
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| Outline of Final Research Achievements |
Synapse elimination during postnatal development is mainly regulated by neuronal interactions. Recent studies suggest participation of microglia in this process, but it is unclear how microglia cooperatively act with neuronal mechanisms. To examine roles of microglia, we ablate microglia by microglia-selective deletion of Csf1r by crossing floxed-Csf1r and Iba1-Cre mice (Csf1r-cKO). In Csf1r-cKO mice, refinement of climbing fiber (CF) to Purkinje cell (PC) innervation after P10–P12 is severely impaired. However, there is no clear morphological evidence suggesting massive engulfment of CFs by microglia. In Csf1r-cKO mice, inhibitory transmission is impaired and CF elimination and is restored by diazepam, suggesting that impairment of CF elimination is caused by a defect of inhibition on PCs, a prerequisite for CF elimination. These results indicate that microglia primarily promote inhibitory transmission and secondarily facilitate the mechanism for CF elimination inherent in PCs.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、ミクログリア由来因子によってニューロン間のシナプス機能が調節され、シナプス刈り込みに関わるという、神経回路発達におけるミクログリアの新たな役割を提唱した点で学術的意義がある。これにより、グリアとニューロンネットワークの相互作用による脳機能成熟の統合的理解が深まると期待できる。また、自閉症や統合失調症などでは脳の興奮と抑制のバランスの乱れに加えて、ミクログリア機能の破綻も指摘されているので、健常脳の発達過程において、ミクログリアが抑制性シナプス伝達を修飾するという本研究成果は、それらの精神・神経疾患の病態の理解と治療方法の解明に貢献するものと期待される。
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