Duloxetine ameliorates chronic stress-induced depressive behaviors by normalizing hippocampal SIK2-CRTC1 signaling.

Introduction: Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is clinically effective for major depressive disorder, yet the intracellular mechanisms underlying its therapeutic actions remain incompletely understood. The hippocampal salt-inducible kinase 2 (SIK2)-CREB-regulated transcription coactivator 1 (CRTC1) signaling cascade has been implicated in chronic stress-induced neuroplasticity deficits, but whether duloxetine engages this pathway to produce antidepressant effects is unknown. Methods: Male C57BL/6J mice were subjected to chronic social defeat stress, chronic unpredictable mild stress, or chronic restraint stress, followed by duloxetine treatment. Behavioral assessments included the forced swim test, tail suspension test, sucrose preference test, and social interaction test. Hippocampal tissues were analyzed for SIK2 and CRTC1 expression (protein and mRNA), CRTC1 subcellular distribution, and CRTC1-CREB interaction using western blotting, qRT-PCR, and co-immunoprecipitation. Adeno-associated virus-mediated hippocampal CRTC1 knockdown was employed to assess pathway requirement. Results: Duloxetine treatment effectively reversed chronic stress-induced behavioral abnormalities across all three models. At the molecular level, duloxetine normalized stress-induced upregulation of hippocampal SIK2 and downregulation of CRTC1, restored nuclear CRTC1 translocation, and enhanced CRTC1-CREB binding. Notably, hippocampal CRTC1 knockdown completely abrogated duloxetine's behavioral effects. Discussion: These findings identify the hippocampal SIK2-CRTC1-CREB axis as a key downstream mediator of duloxetine's antidepressant efficacy, expanding our understanding of how serotonin-norepinephrine reuptake inhibitors modulate neuroplasticity and providing a potential molecular target for antidepressant action.