ASIC2 Deletion in Medial Prefrontal Cortex Enhances Social Dominance in Mice

Social dominance is essential for maintaining a stable social society and has well-established positive and negative impacts on sociable animals, including humans. However, the regulatory mechanisms governing social dominance, as well as the crucial regulators and biomarkers involved, remain poorly understood. We discover that mice lacking acid-sensing ion channel 2 (ASIC2) exhibit a persistent higher social dominance ranking compared to their wild-type cagemates. Conversely, the overexpression of ASIC2 in the medial prefrontal cortex (mPFC) reverses the dominance hierarchy observed in ASIC2 knockout mice. ASIC2 deletion prolongs the inactivation time of ASICs, resulting in enhanced ASIC-dependent synaptic transmission and plasticity in the mPFC through the protein kinase A signaling pathway. Furthermore, ASIC2 exhibits distinct functional roles in excitatory and inhibitory neurons, thereby modulating the balance of neuronal activities underlying social dominance behaviors—a phenomenon suggestive of a cell-subtype-specific mechanism. Finally, this research establishes a foundational understanding of the mechanisms governing social dominance formation, offering potential insights for the management or prevention of social disorders, such as depression and anxiety.