Dual regulatory roles of CPT1C in chronic stress-induced depression-related outcomes

Regulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) function has emerged as a novel strategy for major depressive disorder (MDD); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that enhanced GluA1 depalmitoylation in the nucleus accumbens mediates depressive-like behaviors following chronic stress, and identify that the dysfunction of carnitine palmitoyltransferase 1 C (CPT1C), a depalmitoylating enzyme that specifically depalmitoylates GluA1, mediated depression-like behaviors in mice. Furthermore, dopamine D2 receptor-expressing medium spiny neurons (D2-MSN)-specific knockdown of CPT1C prevented stress-induced depression-like behaviors, and CPT1C deficiency in D1-MSN abolished the behavioral and synaptic plasticity alterations caused by fluoxetine treatment. More importantly, CPT1C is directly involved in regulating GluA1 synthesis through disinhibiting mTORC1 signaling by targeting tuberous sclerosis complex 2. Collectively, these results newly identify CPT1C as a dual regulator of GluA1 function from protein synthesis, post-translational modification to subcellular localization, and show that CPT1C may serve as a promising novel therapeutic target for MDD.