The selective SIK2/3 inhibitor GLPG3970 exhibits antidepressant-like effects via the hippocampal SIK2-CRTC1-CREB-BDNF pathway in chronic stress models.

Introduction: Depression is a common mental disorder driven by biopsychosocial factors. Although traditional antidepressants serve as first-line therapies, they face clinical challenges, underscoring the need for novel therapeutic agents with improved efficacy. Our previous studies have identified hippocampal SIK2 as a key regulator in the pathogenesis of depression, acting through the cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1)-CREB-brain derived neurotrophic factor (BDNF) signaling pathway. In this study, we investigated the antidepressant-like effects of GLPG3970, a novel selective inhibitor of SIK2/3, in male C57BL/6J mice. Methods: Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression were employed, combined with behavioral tests, virus-mediated gene transfer, Western blotting, co-immunoprecipitation, and immunofluorescence. Results: It was found that repeated administration of GLPG3970 significantly suppressed depressive-like behaviors in both CSDS and CUMS model mice, blocked stress-induced increases in hippocampal SIK2 expression and CRTC1 cytoplasmic translocation, and consequently restored the hippocampal BDNF signaling cascade and neurogenesis. More importantly, by using adeno-associated virus (AAV)-mediated overexpression of SIK2 or silencing of CRTC1/CREB/BDNF in the hippocampus, the antidepressant-like effects of GLPG3970 in mice were notably eliminated. Discussion: Collectively, these findings together demonstrate that the antidepressant-like actions of GLPG3970 in mice depend on the hippocampal SIK2-CRTC1-CREB-BDNF signaling pathway, highlighting its potential as a novel candidate for antidepressant therapy.