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.