ACSS2 and major depressive disorder: To investigate the function of ACSS2 in depression pathogenesis, we first evaluated the behavioral phenotypes of Acss2+/− and Acss2−/− mice, and we observed that both displayed anxiety- and depressive-like behaviors in the open field test (OFT), elevated plus-maze test (EPM), tail suspension test (TST), forced swim test (FST) and sucrose preference test (SPT) compared to their wild type (WT) littermates, with subtle changes in body weight, and food and water intake, suggesting that reduced ACSS2 levels might cause spontaneous depression-like behavior in mice (Fig. 1A, B, S1A–E).