Pi4KIIα Regulates Unconditioned Stimulus Retrieval-Induced Fear Memory Reconsolidation through Endosomal Trafficking of AMPA Receptors

Summary Targeting memory reconsolidation is an effective intervention for treating posttraumatic stress disorder (PTSD). Disrupting unconditioned stimulus (US) retrieval-induced fear memory reconsolidation has become an effective therapeutic approach to attenuate fear memory, but the underlying molecular mechanisms remain unknown. Here, we report that US retrieval-dependent increase in phosphatidylinositol 4-kinase IIα (Pi4KIIα) promotes early endosomal trafficking of AMPA receptors, leading to the enhancement of synaptic efficacy in basolateral amygdala (BLA) neurons. The inhibition of Pi4KIIα by an inhibitor or short-hairpin RNA impaired contextual fear memory reconsolidation. This disruptive effect persisted for at least 2 weeks, which was restored by Pi4KIIα overexpression with TAT-Pi4KIIα. Furthermore, the blockade of early endosomal trafficking following US retrieval reduced synaptosomal membrane GluA1 levels and decreased subsequent fear expression. These data demonstrate that Pi4KIIα in the BLA is crucial for US retrieval-induced fear memory reconsolidation, the inhibition of which might be an effective therapeutic strategy for treating PTSD.