Regulation of depressive‐like behaviours by palmitoylation: Role of AKAP150 in the basolateral amygdala

Abstract Background and Purpose Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe that A‐kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive‐like behaviours in mice via a palmitoylation‐dependent mechanism. Experimental Approach Depressive‐like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl‐biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2‐mediated AKAP150 palmitoylation signalling pathway in depressive‐like behaviours. Electrophysiological recording, western blotting and co‐immunoprecipitation were performed to define the mechanistic pathway. Key Results Chronic stress successfully induced depressive‐like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150‐PKA interaction with the peptide Ht‐31 abolished the CRS‐induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS‐induced depressive‐like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS‐treated mice. Conclusion and Implications These results delineate that DHHC2 modulates chronic stress‐induced depressive‐like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.