CELL-SPECIFIC EFFECT OF ATP P2X4 RECEPTORS IN HIPPOCAMPAL SYNAPTIC PLASTICITY AND STRESS/ANXIETY

The purinergic P2X4 receptor is an ATP-gated ion channel widely expressed in the brain and involved in modulating synaptic plasticity. Under basal conditions, P2X4 is largely internalized, whereas different pathological conditions promote its surface expression and functional activity. Although previous studies suggested a cell type–dependent role for P2X4 in anxiety-like behavior and plasticity, this has not been further investigated. Here, we aimed to determine whether P2X4 differentially modulates excitatory and inhibitory neurons to regulate hippocampal plasticity and anxiety-like behavior. We used conditional P2X4 knock-in or knock-out mouse models to increase surface expression or delete P2X4 either in all neurons or selectively in forebrain excitatory or inhibitory neurons, and performed behavioral testing and hippocampal electrophysiology. Increased surface expression of P2X4 in excitatory neurons reduced anxiety-like behavior selectively in male mice, an effect not observed in females or following global P2X4 manipulation. Consistently, field EPSP recordings in the CA1 region revealed a decrease in long-term potentiation exclusively in male mice with elevated P2X4 expression in excitatory neurons. Furthermore, acute stress induced a marked upregulation of P2X4 expression in both dorsal and ventral hippocampus in males, whereas in females this increase was restricted to the ventral hippocampus. Together, these findings suggest P2X4 as a cell type- and sex-specific regulator of hippocampal plasticity and anxiety-like behavior, highlighting its potential relevance as a therapeutic target for stress-related disorders.