D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels.

The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+ -CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.