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

Patients with psychiatric disorders show higher serum phospholipase A2 (PLA2) activity, however the relationship between PLA2 and psychiatric disorders has been poorly understood. It has been known that 129S1/SvImJ (S1) mice exhibit impaired fear extinction, one of the major symptoms of post-traumatic stress disorder (PTSD). In fear conditioning, sensory and somatic inputs arrive in the basolateral amygdala (BLA) and relay to the medial division of the central amygdala (CEm), the final output in the amygdala projecting to fear response-generating areas. Here we found that S1 mice showed increased expression of PLA2 mRNA in the BLA and CEm compared to control C57BL/6 (B6) mice. Basal inhibitory transmission of CEm neurons was decreased in S1 mice and acute inhibition of PLA2 successfully elevated the basal inhibitory transmission levels in the CEm both in naïve B6 and S1 mice. PLA2 inhibition also weakened BLA to CEm synapses in S1 mice after fear extinction, thereby leading the synaptic responses from CEm while stimulating BLA back to the levels comparable to B6. Ultimately, the selective infusion of PLA2 inhibitors into the CEm enhanced fear extinction in S1 mice. Our data suggest that PLA2 activity modulates inhibitory transmission of the CEm and fear extinction, thus possibly serves as a key molecular mediator of impaired fear extinction in PTSD. Overall design: To identify differentially expressed genes that are related to impaired fear extinction in S1 mice, we conducted RNA Sequencing (RNA-Seq) using BLA and CEm tissues collected from B6 and S1 mice before and after fear conditioning and extinction