| Project/Area Number |
18K14849
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 46030:Function of nervous system-related
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| Research Institution | Fujita Health University (2020)
Nagoya University (2018-2019) |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | Rho ファミリー / CaMKⅡ / Rho-Kinase / リン酸化 / プロテオミクス解析 / グルタミン酸 / 学習・記憶 / シナプス可塑性 / プロテオミクス / Rhoファミリー / SHANK3 / カルシウム / Shank3 |
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| Outline of Final Research Achievements |
We performed phosphoproteomics to identify CaMKII substrates and found that CaMKII phosphorylated ARHGEF2 (RhoGEF) and stimulated its RhoGEF activity downstream of NMDAR. Glutamate induced CaMKII-mediated ARHGEF2 phosphorylation and Rho-kinase/ROCK activation in the striatum/nucleus accumbens (NAc). Inhibition of Rho-kinase in dopamine D2 receptor (D2R)-expressing medium spiny neurons (MSNs) in the NAc attenuated aversive learning. We also found that Rho-kinase phosphorylated SHANK3 and increased its interaction with NMDAR and AMPA receptors via DLGAP3. Manipulation of SHANK3 in D2R-MSNs regulated aversive learning in a phosphorylation-dependent manner. These results demonstrated that NMDA-induced phosphorylation of SHANK3 via the CaMKII-Rho-kinase pathway regulates aversive learning.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、脳内の主要な神経伝達物質であるグルタミン酸の下流で働くCaMKⅡやRho-Kinaseの基質とそれらのリン酸化部位が明らかになった。さらに、CaMKⅡやRho-Kinaseとそれらの基質による情動行動と学習・記憶の制御機構の一端が明らかになった。これらの成果は基礎神経科学において重要というだけでなく、認知症などの神経疾患の病因・病態解明や診断・治療法の確立等の医学分野に貢献する可能性が高い。
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