Both Genetic Manipulation and Acupuncture Alleviate Depressive-Like Behavior Mediated by Astrocytic P2X7 Receptors

Major depressive disorder (MDD) has been associated with P2X7 receptors (P2X7Rs), yet the contribution of astrocytic P2X7Rs to neuronal dysfunction remains unclear. We investigated the role of astrocytic P2X7Rs in depression-like behaviors using a chronic unpredictable mild stress (CUMS) mouse model and further examined whether electroacupuncture (EA) exerts antidepressant effects by modulating astrocytic P2X7Rs. Astrocytic P2X7Rs in the medial prefrontal cortex (mPFC) were selectively knocked down or overexpressed via gene manipulation. Depression-like behaviors were assessed after CUMS exposure and EA intervention, and in vivo fiber photometry was used to monitor calcium dynamics in excitatory and inhibitory neurons within the mPFC. CUMS markedly increased P2X7R expression in the mPFC and induced depression-like behaviors. Genetic deletion or knockdown of astrocytic P2X7Rs alleviated these abnormalities, whereas overexpression of astrocytic P2X7Rs exacerbated them and diminished the antidepressant efficacy of EA. Fiber photometry revealed that astrocytic P2X7Rs contributed to stress-induced dysregulation of neuronal calcium activity. EA restored the balance between excitatory and inhibitory neuronal activity in the mPFC, and this effect depended on appropriate regulation of astrocytic P2X7Rs. These findings suggest that astrocytic P2X7Rs are key mediators of stress-induced depressive phenotypes and may represent a promising therapeutic target for MDD.