SCTR-Expressing Astrocyte-Serotonergic Neuron Signaling Drives Sexual Dimorphism in Depression Through KAT7/H4ac-Foxc2 Epigenetic Axis in an AMPK-Dependent Manner.

Peripheral hormonal dysfunction is associated with multiple neurological disorders, yet how astrocytes sense circulating stress-related hormones to influence depression pathogenesis remains incompletely understood. Here, we showed that disruption of secretin receptor (SCTR) signaling in dorsal raphe nucleus (DRN) astrocytes promotes depression-like behaviors. We identified AMPKα1 as a key downstream effector of astrocytic SCTR signaling and demonstrate its role in regulating astrocytic secretion of metallothionein-1 (Mt1) and downstream megalin-mediated AMPKα2 signaling in serotonergic neurons. We further identified the transcription factor Foxc2 as a downstream target of neuronal AMPKα2 that modulates depressive-like behaviors through suppression of serotonergic activity and reduced neuronal excitability. Mechanistically, AMPKα2 regulates phosphorylation of the acetyltransferase KAT7, thereby modulating histone H4 acetylation and Foxc2 transcription. Together, these findings delineate an astrocyte-neuron signaling axis linking SCTR-AMPKα1 signaling in astrocytes to epigenetic regulation of Foxc2 by AMPKα2-KAT7/H4ac signaling in serotonergic neurons, providing fundamental insight into circuit-level mechanisms underlying depression.