Lactic acid is a novel antidepressant that mediates its effects by modulating the levels and activity of histone deacetylases (HDAC). (c2018)

Abstract

Depression is one of the most common psychiatric disorders and a leading cause of disability worldwide. Environmental factors, such as chronic stress, can promote depression in some individuals, but have no effect in others. Indeed, susceptible individuals exhibit anxious and anti-social behavior and ultimately develop depression; whereas resilient individuals live normally. These differences in susceptibility versus resilience to stress are thought to be due to distinctive changes in gene expression in the nucleus accumbens and the hippocampal regions of the brain. Here, we use chronic social defeat stress, an ethologically validated model of depression to show that the protein levels of class I histone deacetylases, epigenetic modulators that regulate gene expression, are reduced in susceptible mice and that lactate, an endogenous molecule released after exercise, promotes resilience to stress by restoring their levels. We also assess the anti-depressive effect of lactate. We find that lactate rescues the anti-social and anxiety defects observed in susceptible mice and that this therapeutic effect is mediated by an alternate mechanism. Interestingly, we find that lactate mediates its anti-depressive effect by inhibiting the activity of class II HDACs. Our work reveals that the molecular pathways involved in promoting susceptibility to stress are mediated by a loss of class I HDACs; whereas the molecular mechanisms involved in sustaining the depressive phenotype once susceptibility is established are mediated by induction of HDAC activity. This suggests that HDACs play opposing roles in mediating different aspects of psychiatric diseases and highlights the need to focus on assessing the roles of the specific HDAC isoforms in mediating this disorder.