Deficiency of Serotonin Receptor 6 (5-HT6R) or/and its constitutive activity leads to the reduced neurogenesis and the depression-like behavior

Here, we reported that the genetic knock-out of 5-HT6R or specific knock-down of the receptor constitutive activity led to the depression-like behavior in mice. This was likely due to the impaired hippocampal neurogenesis and progressive loss of the neural stem cell (NSC) pool. Furthermore, the critical role of receptor and constitutive activity was confirmed in human NSC function with genetic and chemical modulation, and were well reproduced in human cerebral organoids. The following mechanistic study revealed that cAMP-CREB signaling was involved in the 5-HT6R regulation and its constitutive activity keeps the basal cAMP level.