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). The role of G-protein coupled receptor 158 (GPR158) in ASD remains largely unexplored. In this study, we observed both constitutive and cell/tissue-specific knockouts 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 leads to a significant decline in excitatory synaptic transmission, characterized by the reduction in glutamate vesicles, as well as the expression and phosphorylation of GluN2B in the mPFC. We successfully rescue the phenotype of social novelty deficits either by reintroducing GPR158 in the mPFC of Gpr158 deficient 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. To elucidate the molecular basis underlying glutamate vesicle shortage induced by loss of glutamatergic GPR158, we conducted RNA-sequencing analysis in the mPFC tissues from CamK2A-Cre;Gpr158fl/fl (CaKO) and Gpr158fl/fl control mice (4 mice each group). Total RNA was extracted from the mPFC of adult male CaKO mice and the littermate Gpr158fl/fl controls with Tripure Isolation Reagent (Roche, Germany). RNA-sequencing analysis was carried out using the Illumina NovaSeq 6000 platform (Novogene, China). Paired-end clean reads were aligned to the mouse reference genome (Ensemble_GRCm38.90) with TopHat (version 2.0.12), and HTSeq-count (version 0.6.1) was used to quantify the mRNA levels.