Mirtazapine alleviates depressive-like behaviors through the paraventricular SIK1-CRTC1 signaling pathway

The paraventricular nucleus (PVN) plays a pivotal role in integrating neuroendocrine responses to stress, with the salt-inducible kinase 1 (SIK1)-CREB-regulated transcription co-activator 1 (CRTC1) pathway critically regulating corticotropin-releasing hormone expression and hypothalamic-pituitary-adrenal (HPA) axis activity. Mirtazapine is a clinically effective antidepressant with a unique noradrenergic and specific serotonergic mechanism, yet whether its therapeutic actions involve modulation of this PVN pathway remains unexplored.

Adult male C57BL/6J mice were subjected to chronic social defeat stress (CSDS) or chronic unpredictable mild stress (CUMS), with mirtazapine (5 or 10 mg/kg, i.p.) administered for two weeks. Behavioral assessments included the forced swim test, tail suspension test, sucrose preference test, and social interaction test. HPA axis function was evaluated through plasma corticosterone and adrenocorticotropic hormone (ACTH) measurements. Molecular analyses of PVN tissue included western blotting, quantitative real-time PCR, co-immunoprecipitation, and immunofluorescence. AAV-mediated SIK1 knockdown in the PVN was employed to establish pathway necessity.

Mirtazapine treatment effectively reversed chronic stress-induced behavioral deficits and normalized HPA axis hyperactivity. Chronic stress reduced SIK1 expression, increased total and nuclear CRTC1 levels, decreased cytoplasmic phosphorylated CRTC1, and enhanced CRTC1-CREB binding in PVN neurons-all of which were normalized by mirtazapine administration. Notably, SIK1 knockdown significantly attenuated mirtazapine's antidepressant-like effects and its ability to normalize HPA axis function.

These findings identify the SIK1-CRTC1 system in the PVN as a critical mediator of mirtazapine's antidepressant-like actions, expanding our understanding of its therapeutic mechanism and reinforcing the relevance of this pathway as a target for depression treatment.