Palmitoylation of PSD-95 Orchestrates Learning-Dependent Metaplasticity in the Amygdala and Fear Memory

Palmitoylation has been implicated in learning and memory processes, yet its precise role and underlying mechanisms remain poorly understood. Here, we report a novel role of palmitoylation in regulating amygdalar synaptic plasticity and fear memory, involving the regulation of palmitate cycling on PSD-95. Using a series of multi-methodological experiments, we demonstrated that conditioned fear learning impairs amygdalar metaplasticity-an effect not observed in the hippocampus. Furthermore, PSD-95 recruits LTP-like mechanisms at lateral amygdala (LA) synapses, and its palmitoylation is critically involved in fear memory expression. Notably, PSD-95 palmitoylation contributes to the occlusion of LA-LTP following fear conditioning. Mechanistically, DHHC2 drives PSD-95 palmitoylation and modulates LA synaptic plasticity following fear conditioning, whereas PICK1 facilitates the activity-dependent trafficking of DHHC2 to PSD-95 at synapses. Collectively, these findings highlight the PICK1-DHHC2-PSD-95 pathway as a critical regulator of learning-dependent metaplasticity in the LA, which occludes further HFS-induced LTP while promoting fear memory expression.