A P2X7 receptor antagonist alleviates PTSD-like behaviors in adolescent rats through gut microbiota modulation and hippocampal transcriptomic remodeling.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder that frequently manifests during adolescence, a critical neurodevelopmental period. Although the P2X7 receptor is implicated in the pathophysiology of PTSD, its role in adolescent-onset PTSD, particularly concerning gut microbiota dysbiosis and hippocampal transcriptomic alterations, remains unclear. This study investigated the effects of the P2X7 receptor antagonist Brilliant Blue G (BBG) on PTSD-like behaviors, gut microbiota, and hippocampal transcriptomic profiles in adolescent rats subjected to single prolonged stress and electric foot shock (SPS&S). BBG treatment significantly ameliorated SPS&S-induced fear- and anxiety-like behaviors and spatial working memory deficits. Metagenomic analysis revealed that BBG partially reversed SPS&S-induced gut microbiota dysbiosis, significantly enriching key bacterial taxa (e.g., Bacteroidota) and modulating functional pathways related to immunity and metabolism. Hippocampal transcriptomic analysis demonstrated that BBG normalized a majority of SPS&S-induced differentially expressed genes; these corrected genes were significantly enriched in pathways for extracellular matrix organization, neural differentiation, and PI3K-Akt signaling pathway. Integrated multi-omics correlation analyses revealed significant correlations among key microbial abundances, hippocampal gene expression, and behavioral outcomes, supporting a gut-brain axis mechanism underlying the therapeutic effects of BBG. These findings position the P2X7 receptor as a promising therapeutic target for adolescent PTSD and highlight the crucial role of gut microbiota in modulating stress-related neuropathology via the gut-brain axis.