miR-124 alleviates behavioral deficits via inhibiting hippocampal microglial pyroptosis by targeting P2X7R in PTSD...

Post-traumatic stress disorder (PTSD) is a refractory psychiatric disorder with limited effective treatments. Emerging evidence indicates that abnormal microglial activation and pyroptosis in the hippocampus trigger persistent neuroinflammation, neuronal synaptic damage and progressive behavioral disorders. MicroRNA-124 (miR-124) is a brain-enriched miRNA with anti-inflammatory and neuroprotective functions. In the present study, we identified P2X7R as a direct target of miR-124 via bioinformatics prediction and dual-luciferase reporter assay. Using an mSPS-established rat PTSD model, we found that hippocampal miR-124 was markedly decreased in model animals, accompanied by upregulated P2X7R, enhanced NLRP3 inflammasome activation and excessive microglial pyroptosis. Lentivirus-mediated miR-124 overexpression downregulated P2X7R, reduced the levels of pyroptosis-related proteins and pro-inflammatory cytokines, and effectively rescued multiple PTSD-like behavioral phenotypes. Pharmacological blockade of P2X7R with A438079 recapitulated the protective effects of miR-124. Further in vitro co-culture experiments demonstrated that P2X7R-mediated microglial pyroptosis impaired neuronal synaptic function, while suppressing P2X7R restored the expression of synaptic proteins. This study demonstrates that miR-124 modulates microglial pyroptosis and hippocampal neuroinflammation through directly targeting P2X7R, thereby improving neuronal synaptic function and alleviating PTSD symptoms. Our findings provide novel mechanistic insights into PTSD pathogenesis and offer potential molecular targets for clinical intervention.