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Here, we report a novel role of palmitoylation in regulating amygdalar synaptic plasticity and fear memory, involving the regulation of palmitate cycling on PSD\u201095. Using a series of multi\u2010methodological experiments, we demonstrated that conditioned fear learning impairs amygdalar metaplasticity\u2014an effect not observed in the hippocampus. Furthermore, PSD\u201095 recruits LTP\u2010like mechanisms at lateral amygdala (LA) synapses, and its palmitoylation is critically involved in fear memory expression. Notably, PSD\u201095 palmitoylation contributes to the occlusion of LA\u2010LTP following fear conditioning. Mechanistically, DHHC2 drives PSD\u201095 palmitoylation and modulates LA synaptic plasticity following fear conditioning, whereas PICK1 facilitates the activity\u2010dependent trafficking of DHHC2 to PSD\u201095 at synapses. Collectively, these findings highlight the PICK1\u2010DHHC2\u2010PSD\u201095 pathway as a critical regulator of learning\u2010dependent metaplasticity in the LA, which occludes further HFS\u2010induced LTP while promoting fear memory expression.<\/jats:p>","DOI":"10.1002\/advs.76302","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:12:15Z","timestamp":1783347135000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Palmitoylation of PSD\u201095 Orchestrates Learning\u2010Dependent Metaplasticity in the Amygdala and Fear Memory"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4206-0928","authenticated-orcid":false,"given":"Zu\u2010Cheng","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmacy Fujian Medical University  Fuzhou 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