Mice deficient for G‐protein‐coupled receptor 75 display altered presynaptic structural protein expression and disrupted fear conditioning recall

There are a number of G‐protein‐coupled receptors (GPCRs) that are considered “orphan receptors” because the information on their known ligands is incomplete. Yet, these receptors are important targets to characterize, as the discovery of their ligands may lead to potential new therapies. GPR75 was recently deorphanized because at least two ligands appear to bind to it, the chemokine CCL5 and the eicosanoid 20‐Hydroxyeicosatetraenoic acid. Recent reports suggest that GPR75 may play a role in regulating insulin secretion and obesity. However, little is known about the function of this receptor in the brain. To study the function of GPR75, we have generated a knockout (KO) mouse model of this receptor and we evaluated the role that this receptor plays in the adult hippocampus by an array of histological, proteomic, and behavioral endpoints. Using RNAscope® technology, we identified GPR75 puncta in several Rbfox3‐/NeuN‐positive cells in the hippocampus, suggesting that this receptor has a neuronal expression. Proteomic analysis of the hippocampus in 3‐month‐old GPR75 KO animals revealed that several markers of synapses, including synapsin I and II are downregulated compared with wild type (WT). To examine the functional consequence of this down‐regulation, WT and GPR75 KO mice were tested on a hippocampal‐dependent behavioral task. Both contextual memory and anxiety‐like behaviors were significantly altered in GPR75 KO, suggesting that GPR75 plays a role in hippocampal activity.