POSTMENOPAUSAL DEPRESSION DEPEND ON MICROGLIAL CASPASE-1–OVERACTIVATION LEADING TO 5-HT INHIBITION IN THE DORSAL RAPHE ​NUCLEI

Postmenopausal depression is a prevalent affective disorder primarily triggered by estrogen withdrawal, yet the localized neuroinflammatory drivers that impair the brain's serotonergic system remain to be fully elucidated. Here, we investigated whether the Caspase-1/ IL-1β axis within the dorsal raphe nuclei (DRN) serves as a fundamental mediator of serotonergic deficiency and subsequent depressive-like behaviors.
Ovariectomized (OVX) mice were utilized to simulate menopausal estrogen deficiency. We performed biochemical and histological screenings across multiple brain regions to identify the primary inflammatory hub. To establish causality, we employed Caspase-1 knockout (Cas-1 KO) mice and conducted DRN-localized microinjections of IL-1β neutralizing antibodies to evaluate their effects on serotonin synthesis and behavioral phenotypes.
Estrogen deficiency led to a significant downregulation of ERβ expression specifically within the DRN, which triggered the recruitment of the NLRP3 inflammasome and the subsequent activation of Caspase-1. This localized activation resulted in the overproduction of mature IL-1β, which was found to directly suppress the expression of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme for serotonin (5-HT) synthesis.
Consequently, OVX mice exhibited robust depressive-like behaviors. Notably, the genetic deletion of Caspase-1 completely abolished the OVX-induced elevation of IL-1β, restored TPH2 expression, and rescued 5-HT levels in the DRN, effectively preventing the development of depressive-like phenotypes. Furthermore, pharmacological neutralization of IL-1β specifically within the DRN mimicked the protective effects observed in Cas-1 KO mice, confirming the site-specific role of this inflammatory axis.
Our findings demonstrate that the DRN-specific Caspase-1/ IL-1β axis acts as a master regulator of serotonergic dysfunction during estrogen deficiency.