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The caudate putamen (CPu) mainly contains MSNs expressing dopamine D1 receptor (dMSNs) and dopamine D2 receptor (iMSNs) exerting critical effects on motor and cognition behavior. However, the molecular mechanisms contributing to spine loss and abnormal behaviors in dMSNs and iMSNs under parkinsonian state remain unknown. In the present study, we revealed that Cell division control protein 42 (Cdc42) signaling was significantly decreased in the caudate putamen (CPu) in parkinsonian mice. In addition, overexpression of constitutively active Cdc42 in the CPu reversed spine abnormalities and improved the behavior deficits in parkinsonian mice. Utilizing conditional dopamine D1 receptor (D1R) or D2 receptor (D2R) knockout mice, we found that such a decrease under parkinsonian state was further reduced by conditional knockout of the D2R but not D1R. Moreover, the thin spine loss in iMSNs and deficits in motor coordination and cognition induced by conditional knockout of D2R were reversed by overexpression of constitutively active Cdc42 in the CPu. Additionally, conditional knockout of Cdc42 from D2R\u2010positive neurons in the CPu was sufficient to induce spine and behavior deficits similar to those observed in parkinsonian mice. Overall, our results indicate that impaired Cdc42\u00a0signaling regulated by D2R plays an important role in spine loss and behavioral deficits in PD.<\/jats:p>","DOI":"10.1111\/acel.13588","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T03:01:16Z","timestamp":1649818876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Regulation of Cdc42 signaling by the dopamine D2 receptor in a mouse model of Parkinson\u2019s disease"],"prefix":"10.1111","volume":"21","author":[{"given":"Li","family":"Ying","sequence":"first","affiliation":[{"name":"Key Laboratory of Functional Proteomics of Guangdong Province Key Laboratory of Mental Health of the Ministry of Education School of Basic Medical Sciences Pediatric Center of Zhujiang Hospital Center for Orthopaedic Surgery of the Third Affiliated Hospital Southern Medical University  Guangzhou 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