Hippocampal GPR17 is involved in chronic restraint stress-induced depressive-like behaviors by regulating neuroinflammation and glutamatergic activity in mice.

Abstract

G protein-coupled receptor 17 (GPR17) is expressed in the brain and plays a crucial role in regulating cognitive function. However, its specific role in depression remains unclear. Herein, we investigate the role of GPR17 in depression. The role of GPR17 in depression was studied in a chronic restraint stress (CRS) mouse model by characterizing behavioral deficits and applying a suite of techniques spanning molecular biology, morphology, and chemogenetics. Our results indicated that CRS exposure significantly increased GPR17 expression in both the hippocampus and cortex, with a more pronounced upregulation observed in the hippocampus. Both genetic knockdown and pharmacological inhibition of GPR17 alleviated CRS-induced depressive-like behaviors by mitigating neuroinflammation, synaptic plasticity deficits, and TLR4/NF-κB/NLRP3 signaling in mice. Conversely, pharmacological activation of GPR17 notably induced depressive-like behaviors in normal mice. Moreover, molecular docking revealed that fluoxetine binds to GPR17. In addition, fluoxetine alleviates depressive-like behaviors induced by CRS in mice and suppresses hippocampal GPR17 upregulation. We also found that hippocampal glutamatergic neuronal activity is required for antidepressant-like effects of GPR17 antagonist cangrelor. These results suggest that GPR17 regulates chronic stress-induced depressive-like behaviors and hippocampal synaptic transmission through the TLR4/NF-κB/NLRP3 signaling pathway, establishing it as a promising novel therapeutic target for depression.