Phospholipase A2 downregulates inhibitory transmission in the amygdala and impairs fear extinction.

Dysregulated phospholipase A2 (PLA2) activity has been reported in multiple psychiatric disorders, yet its mechanistic contribution to pathological fear remains unclear. The 129S1/SvImJ (S1) mouse strain, which shows intact fear conditioning but profound deficits in fear extinction, provides a useful model for examining molecular pathways relevant to post-traumatic stress disorder. Using RNA sequencing, electrophysiology, and targeted pharmacological manipulation, we investigated whether altered PLA2 expression in amygdala circuits contributes to impaired extinction in S1 mice. S1 mice displayed markedly elevated Pla2g4e mRNA expression in both the basolateral amygdala (BLA) and the medial division of the central amygdala (CEm) compared with C57BL/6 controls. Electrophysiological analyses revealed reduced basal inhibitory transmission onto CEm neurons in S1, a deficit reversed by acute PLA2 inhibition in both naïve and behaviorally tested mice. PLA2 inhibition also normalized the diminished inhibitory/excitatory balance in the BLA→CEm pathway following extinction training. Behaviorally, selective infusion of a PLA2 inhibitor into the CEm robustly enhanced extinction learning and retrieval in S1mice. These findings identify PLA2 as a key regulator of inhibitory signaling within central amygdala circuits and suggest that heightened PLA2 activity contributes to extinction failure, highlighting a potential molecular target for therapeutic intervention in trauma-related disorders.