Astrocytic connexin43 in the medial prefrontal cortex regulates depressive- and anxiety-like behaviors via ATP release

Major depressive disorder (MDD) affects 17% of the global population and is highly comorbid with anxiety disorders. Emerging evidence indicates that dysregulation of astrocytic ATP contributes to the pathophysiology of depression. However, the molecular substrates underlying the stress-induced reduction in ATP release remain poorly understood, and the basis for the comorbidity of depression and anxiety disorders is still unknown. Here, we showed that Cx43 expression and extracellular ATP levels were significantly reduced in the medial prefrontal cortex (mPFC) of chronic social defeat stress (CSDS)-susceptible mice. Astrocyte-specific knockout or knockdown of Cx43 in the mPFC induced depressive-like behaviors--including anhedonia and despair-like behavio--and anxiety-like behaviors, alongside a reduction in ATP release, whereas neuronal knockout of Cx43 showed no effects on these behaviors. Notably, exogenous ATPγS administration reversed these behavioral deficits. Furthermore, overexpression of astrocytic Cx43 in the mPFC rescued both ATP levels and emotion-related behaviors in CSDS-susceptible mice. Taken together, our study provided the first evidence that astrocytic Cx43 reduction was sufficient to induce depressive- and anxiety-like behaviors and identified a novel ATP-mediated mechanism linking astrocytic Cx43 to both depression and anxiety pathogenesis. These findings open up promising therapeutic targets for treating these comorbid disorders.