Inhibition of ERα in the mPFC ameliorates depression-like behaviors by suppressing GALR1-mediated synaptic dysfunction in an estrogen withdrawal-induced rat model.

Postpartum depression (PPD) is a major perinatal mood disorder closely associated with the abrupt decline in estrogen levels after childbirth. Galanin receptor1 (GALR1) is one of the receptors of galanin (GAL), which activates Gi-coupled inhibitory signaling and may play a pro-depression role. Our previous study showed that suppression of GALR1 in the medial prefrontal cortex (mPFC) alleviated depression-like behaviors in an estrogen withdrawal-induced rat model of PPD, whereas the upstream regulatory mechanisms remained unclear. Here, we identified putative estrogen response elements within the GALR1 promoter and found that ERα and GALR1 expression were significantly increased and positively correlated in the mPFC of PPD rats. Luciferase reporter and ChIP analysis, supported ERα binding to the GALR1 promoter and transcriptional regulation of GALR1. Cellular analyses further showed that ERα and GALR1 were predominantly co-expressed in CaMKII-positive glutamatergic neurons. Functionally, ERα knockdown in the mPFC alleviated depression-like behaviors, reduced GALR1 expression, and restored synaptic protein levels and ultrastructure. Notably, GALR1 overexpression markedly reversed these behavioral and synaptic improvements induced by ERα knockdown, providing functional evidence that GALR1 acts downstream of ERα. Collectively, these findings support an ERα-GALR1 regulatory pathway in glutamatergic neurons that contributes to synaptic dysfunction and depression-like behaviors following estrogen withdrawal, highlighting this pathway as a potential therapeutic target for PPD.