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Here, it is demonstrated that physical exercise can downregulate the S\u2010nitrosylation of gephyrin (SNO\u2010gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO\u2010gephyrin is significantly increased in the BLA of high\u2010anxiety rats and a downregulation of SNO\u2010gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO\u2010gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABA<jats:sub>A<\/jats:sub>R \u03b32 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic\u2010like effects of physical exercise. This study reveals a key role of downregulating SNO\u2010gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post\u2010translational modifications in the brain after exercise.<\/jats:p>","DOI":"10.1002\/advs.202400205","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T01:46:10Z","timestamp":1720143970000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Wheel\u2010Running Exercise Alleviates Anxiety\u2010Like Behavior via Down\u2010Regulating S\u2010Nitrosylation of Gephyrin in the Basolateral Amygdala of Male Rats"],"prefix":"10.1002","volume":"11","author":[{"given":"Ping\u2010Fen","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Department of Pharmacology School of Basic Medicine Tongji Medical College Huazhong University of Science and 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