Inhibition of Semaphorin 3A in Hippocampus Alleviates Postpartum Depression-Like Behaviors in Mice.

Postpartum depression (PPD) is a widespread psychiatric condition affecting up to 20% of postpartum women. Although it is known to be associated with ovarian hormone withdrawal following delivery, current treatments remain limited due to a lack of underlying mechanism. Here, in mice, we identified that semaphorin 3A (sema3A) exhibited a notable increase in expression within the hippocampus of postpartum depression mice, whereas no such upregulation was observed in female mice experiencing depression induced by lipopolysaccharide or chronic restraint stress. The coexpression rate of sema3A and c-Fos was also elevated in the hippocampal CA3 of postpartum depression mice. Importantly, systemic inhibition or genetic knockdown of hippocampal sema3A significantly alleviated the depressive symptoms induced by ovarian hormone withdrawal. Further, overexpression of sema3A in CA3 induced depressive-like behaviors in naïve female mice. In conclusion, our cumulative findings suggest that sema3A in hippocampal CA3 plays a pivotal role in the pathogenesis of postpartum depression, and could serve as a promising treatment target for ameliorating this widespread disorder.