Study on the regulatory mecanism of synaptic plasticity by calcium / Rho signal

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K14849
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46030:Function of nervous system-related
• Research Institution: Fujita Health University (2020); Nagoya University (2018-2019)
• Principal Investigator: Funahashi Yasuhiro 藤田医科大学, 総合医科学研究所, 講師 (00749913)
• Project Period (FY): 2018-04-01 – 2021-03-31
• 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

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.

Free Research Field

神経化学・神経薬理学

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。