GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in male mice

Impairment in social communication skills is a hallmark feature of autism spectrum disorder (ASD) associated with synaptic dysfunction. Despite its known involvement in Alzheimer's disease, depression, addiction, and glioma, the role of G-protein coupled receptor 158 (GPR158) in ASD remains largely unexplored. In this study, we aimed to investigate the impact of GPR158 deletion on social behaviors. We observed both constitutive and cell/tissue-specific knockout of Gpr158 in pyramidal neurons or medial prefrontal cortex (mPFC) result in impaired novelty preference, while sociability remains unaffected in male mice. Notably, loss of GPR158 led to a significant decline in excitatory synaptic transmission, characterized by the reduction in glutamate vesicles, as well as expression and phosphorylation of GluN2B in the mPFC. We successfully rescued the phenotype of social novelty deficit either by reintroducing GPR158 in the mPFC of Gpr158 null mice or by chemogenetic activation of pyramidal neurons where Gpr158 is specifically ablated. Our findings indicate that GPR158 in pyramidal neurons plays a specific role in modulating social novelty, and may represent a potential target for treating social disorder.