{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:34:36Z","timestamp":1785429276480,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2021-I2M-1-034"],"award-info":[{"award-number":["2021-I2M-1-034"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences","award":["2023-PT180-01"],"award-info":[{"award-number":["2023-PT180-01"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970510"],"award-info":[{"award-number":["31970510"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["31970510"],"award-info":[{"award-number":["31970510"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013314","name":"111 Project","doi-asserted-by":"crossref","award":["B20095"],"award-info":[{"award-number":["B20095"]}],"id":[{"id":"10.13039\/501100013314","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical and Health Science and Technology Project of Shandong Province","award":["202302011596"],"award-info":[{"award-number":["202302011596"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>To investigate the neural circuit mechanisms linking the physiological loss of \u03b1-synuclein (\u03b1-syn) function to depressive-like states, we explored whether constitutive \u03b1-syn depletion disrupts the excitation and inhibition balance within the medial prefrontal cortex. We integrated comprehensive behavioral paradigms, whole-cell patch-clamp electrophysiology, and targeted chemogenetics within an \u03b1-syn knockout mouse model. Behavioral profiling revealed that \u03b1-syn deficiency was accompanied by basal psychomotor hyperactivity and profound stress-coping deficits. Cellular electrophysiology in the medial prefrontal cortex demonstrated a significantly enhanced intrinsic excitability across both GABAergic and glutamatergic populations. Furthermore, targeted chemogenetic suppression of GAD67-positive interneurons partially alleviated the depressive-like phenotype without confounding baseline locomotion. In summary, the physiological depletion of endogenous \u03b1-syn is associated with altered stress-coping behaviors and increased mPFC neuronal excitability. Chemogenetic suppression of mPFC GAD67-positive interneurons partially reduces immobility in SYN-KO mice, implicating prefrontal inhibitory circuit dysregulation in these behavioral alterations. These findings underscore the importance of \u03b1-syn homeostasis in modulating cortical microcircuits and provide novel insights into the early non-motor manifestations of synucleinopathies.<\/jats:p>","DOI":"10.3390\/ijms27125235","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:33:44Z","timestamp":1781073224000},"page":"5235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Knockout of \u03b1-Synuclein Is Associated with Depression-like Behaviors by Altered Excitability of Medial Prefrontal Cortex Neurons in Mice"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4059-0554","authenticated-orcid":false,"given":"Tong","family":"Shang","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model 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Diseases Animal Model Resource Center, Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Yang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Comparative Medicine, National Center of Technology Innovation for Animal 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