Cognitive Deficits in Female GPR158 Knockout Mice Revealed by Automated Home-Cage Testing

GPR158 is a G protein coupled receptor (GPCR) that is abundantly expressed in the brain and has been shown to organize synaptic architecture and regulate synaptic function. Previous studies have demonstrated a role for GPR158 in hippocampal-dependent learning and stress-related affective behaviors yet its contribution to cognitive function under naturalistic, low-stress conditions remains unclear. Here, we investigated the role of GPR158 in spatial learning, cognitive flexibility, and working memory using both traditional and automated home-cage paradigms. The use of automated, socially enriched testing paradigms minimizes stress-related confounds and allows us to discover the naturalistic roles of GPR158 in cognition and behavior. Using the IntelliCage to test spatial learning and working memory in a social enriched environment, we found that female GPR158 knockout mice exhibited deficits in spatial learning but showed intact working memory. Consistent with these findings, spatial impairments were also observed in the Barnes Maze, where female GPR158 KO mice showed pronounced deficits in spatial strategy acquisition, increased latency, reduced time spent in the reward area, and impaired performance during the probe trial. Male GPR158 knockout mice showed no significant difference in either spatial learning or working memory compared to their wild-type littermates in the IntelliCage, whereas in the Barnes Maze knockout mice showed mild impairment in spatial strategy acquisition. These findings reveal a profound impairment with female GPR158 knockout mice in hippocampal-dependent cognition and highlight the importance of low-stress, ethologically testing environments.