The multimodal antidepressant vortioxetine exerts therapeutic effects in male mice which is associated with normalization of hippocampal SIK2/CRTC1-related signaling and require hippocampal CRTC1.

Introduction: The multimodal antidepressant vortioxetine combines serotonin reuptake inhibition with activity at several serotonin receptor subtypes, yet its downstream mechanisms related to neuroplasticity remain incompletely understood. This study investigated whether vortioxetine's antidepressant efficacy involves hippocampal salt-inducible kinase 2 (SIK2) and CREB-regulated transcription coactivator 1 (CRTC1). Methods: By using chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), and chronic restraint stress (CRS) models in male C57BL/6J mice, we assessed the effects of vortioxetine (10 and 20 mg/kg) on depressive-like behaviors, hippocampal SIK2 and CRTC1 expression, CRTC1 subcellular localization, and CRTC1-CREB interaction in mice. Viral-mediated hippocampal CRTC1 knockdown was employed to establish causality. Results: Vortioxetine dose-dependently reversed chronic stress-induced behavioral deficits and concurrently normalized hippocampal SIK2 upregulation and CRTC1 downregulation at both transcriptional and translational levels. Furthermore, vortioxetine restored nuclear CRTC1 translocation and enhanced CRTC1-CREB binding. Critically, hippocampal CRTC1 knockdown completely abolished the behavioral benefits of vortioxetine. Discussion: These findings demonstrate that vortioxetine's antidepressant actions in male mice are associated with normalization of hippocampal SIK2/CRTC1-related signaling and require hippocampal CRTC1, providing a novel molecular mechanism underlying its multimodal efficacy.