Wheel‐Running Exercise Alleviates Anxiety‐Like Behavior via Down‐Regulating S‐Nitrosylation of Gephyrin in the Basolateral Amygdala of Male Rats

Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S‐nitrosylation of gephyrin (SNO‐gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO‐gephyrin is significantly increased in the BLA of high‐anxiety rats and a downregulation of SNO‐gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO‐gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABAAR γ2 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‐like effects of physical exercise. This study reveals a key role of downregulating SNO‐gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post‐translational modifications in the brain after exercise. This study explored the molecular mechanism underlay the therapeutic effect of physical exercise on anxiety disorders. Physical exercise can downregulate the S‐nitrosylation of gephyrin (SNO‐gephyrin) in the basolateral amygdala (BLA) and increase the surface expression of GABAAR γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect.