Gpr17, a G-protein-coupled receptor (GPCR), responds to nucleotide sugars and cysteinyl leukotrienes. It is mainly expressed in the CNS, especially in neurons and oligodendrocyte precursor cells (OPCs), and also in organs prone to ischemic damage. Gpr17 is involved in multiple biological processes, such as myelination, energy homeostasis, and gut hormone secretion, and is associated with pathways like NF-κB/CREB/BDNF signaling [2,3,5,7,8]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In LPS-induced cognitive impairment mouse models, knockdown and inhibition of hippocampal Gpr17 improved cognitive function, inhibited Aβ production, regulated inflammatory cytokines, and modulated NF-κB/CREB/BDNF signaling, suggesting its potential as a target for AD prevention and treatment [1]. In the context of myelination, co-manipulation of Gpr17 and microglia in injured optic nerves led to extensive myelination of regenerated axons, as OPC-intrinsic Gpr17 signaling inhibits OPC differentiation [4]. Intestinal Gpr17 deficiency in mice improved glucose metabolism by promoting GLP-1 secretion, indicating its potential as a target for diabetes and obesity intervention [5]. In a chronic restraint stress mouse model, inhibition of Gpr17 in basolateral amygdala glutamatergic neurons improved anxiety-like behaviors [6].

In conclusion, Gpr17 plays essential roles in cognition, myelination, glucose metabolism, and anxiety-like behaviors. Studies using KO/CKO mouse models have revealed its significance in diseases such as AD, multiple sclerosis, diabetes, and anxiety disorders, providing insights into potential therapeutic strategies targeting Gpr17 for these conditions.