RAPID ANTIDEPRESSANT EFFECTS OF GPER1 DEPEND ON SEX-SPECIFIC INTRACELLULAR SIGNALING

Mood and anxiety disorders carry a substantial societal burden and show higher prevalence in women yet remain inadequately treated. Increasing evidence implicates rapid, non-genomic estrogen signaling in affective regulation, positioning the G protein-coupled estrogen receptor 1 (GPER1) as a promising antidepressant target. Targeted viral overexpression of GPER1 in dorsal hippocampal CA1 pyramidal neurons did not robustly modify affective behavior, indicating that receptor abundance alone is insufficient to drive antidepressant responses. Pharmacological stimulation of hippocampal GPER1 produced rapid anxiolytic- and antidepressant-like effects selectively in females, which were abolished by PI3K/Akt but not MEK/ERK pathway inhibition, revealing sex-dependent intracellular signaling requirements. Acute systemic GPER1 activation confirmed a sex bias in hippocampal GPER1 coupling to distinct Gα subunits, accompanied by differential engagement of key intracellular signaling proteins, including Akt, mTOR, ERK, and PKA Cα, and promoted dopaminergic activity in the prefrontal cortex of females. Under chronic stress, GPER1 activation exerted robust antidepressant effects in both sexes, accompanied by marked restoration of hippocampal dendritic complexity and synaptic structure. Together, these findings establish GPER1 as a sex-dependent modulator of mood, emphasizing the importance of sex-informed experimental frameworks and paving the way for the development of antidepressant interventions tailored to biological sex.