Serotonin-1A Receptors Mediate Sex-Dependent Regulation of Neural Stem Cell Expansion and Stress Vulnerability in Adult Hippocampus

Abstract

The serotonin (5HT) system mediates pathophysiology of stress responses and influences adult hippocampal neurogenesis from radial neural stem cells (rNSCs) in a sex-dependent manner. However, the mechanisms underlying sex differences in serotonergic regulation and stress vulnerability of rNSCs remain elusive. Here we report sex-dependent expression of 5HT1ARs in rNSCs of adult mouse hippocampus, with higher levels of 5HT1AR expression in rNSCs of females. Functionally, selective deletion of 5HT1ARs decreases rNSC production through decreased symmetric self-renewal in females. Mechanistically, 5HT1AR deletion in females results in 5HT-induced depolarization in rNSCs mediated by 5HT7R upregulation. Interestingly, stress exerts sex-dependent effects on 5HT release in the neurogenic niche and interacts with 5HT1ARs to regulate rNSC production in females through 5HT7R-mediated calcium signaling. These findings reveal a sex-dependent role of 5HT1ARs in regulating expansion and stress vulnerability of adult hippocampal rNSCs.

Keywords: neural stem cells, adult hippocampus, 5HT1ARs, serotonin, stress vulnerability, sex difference