Hippocampal GPR17 down regulation ameliorates CMS-induced depression-like behaviors in mice.

Chronic stress is a significant pathogenic factor that contributes to the onset of depression. GPR17 has anti-inflammatory and anti-oxidative effects, but its role in depression is still unknown. In this study, we examined the role of GPR17 in mice exposed to chronic mild stress (CMS) and elucidated its underlying molecular mechanisms. We down-regulated hippocampal GPR17 by injecting LV-GPR17-shRNA or the GPR17 antagonist cangrelor into the DG region of the mouse hippocampus. To explore the role of GPR17 in the pathogenesis of depression, we employed behavioral, pathological, and biochemical experiments. We found that CMS-induced depression-like behaviors were associated with increased GPR17 expression in the hippocampus. Pharmacological activation of GPR17 in the hippocampus triggered depression-like behaviors in normal mice. Conversely, knockdown and inhibition of GPR17 alleviated depression-like behaviors induced by CMS in mice. Furthermore, knockdown and inhibition of GPR17 significantly suppressed CMS-induced activation of hippocampal glial cells and reduced inflammatory cytokine levels, alleviating neuroinflammation in mice. Additionally, knockdown and inhibition of GPR17 also promoted hippocampal neurogenesis and improved synaptic plasticity in CMS-exposed mice. In vitro, the GPR17 antagonist cangrelor increased the survival rate of corticosterone (CORT)-treated HT22 cells and upregulated the expression of synapse-associated proteins. Moreover, we found that the antidepressant-like effects of GPR17 modulation were mediated through the hippocampal BDNF/CREB/TrkB pathway. Our findings suggest that GPR17 may be a promising therapeutic target for depression.