ACSS2 Confers Resilience to Stress-Induced Depression by Regulating mPFC Glutamatergic Activity
Energy metabolism dysfunction and altered glutamatergic synaptic function contribute to depression. ACSS2 converts acetate into acetyl-CoA and regulates histone acetylation and gene expression. Using conditional knockout mice and viral-mediated gene knockout, we found that ACSS2 expression in medial prefrontal cortex glutamatergic neurons is required for resilience to depression-like behaviors. ACSS2 deficiency altered glutamatergic synaptic function and neuronal activation in the mPFC. ACSS2 promoted the expression of neuronal plasticity-related genes through histone acetylation at their promoter regions. The rapid antidepressant effects of esketamine were preserved in the absence of ACSS2.