<b>GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in </b><b>male mice</b>

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<i> </i>deletion on social behaviors. We observed both constitutive and cell/tissue-specific knockout of <i>Gpr158</i> 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<i>,</i> 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 <i>Gpr158</i> null mice or by chemogenetic activation of pyramidal neurons where <i>Gpr158 </i>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.社交沟通技能受损是自闭症谱系障碍（autism spectrum disorder, ASD）的标志性特征，且与突触功能障碍相关。尽管G蛋白偶联受体158（G-protein coupled receptor 158, GPR158）已被证实参与阿尔茨海默病、抑郁症、成瘾及神经胶质瘤的病理进程，但其在ASD中的作用仍未得到充分探索。本研究旨在探究GPR158缺失对社交行为的影响。我们发现，锥体神经元（pyramidal neurons）或内侧前额叶皮层（medial prefrontal cortex, mPFC）中Gpr158的全身性敲除及细胞/组织特异性敲除，均会导致雄性小鼠出现社交新异偏好受损，但社交能力未受影响。值得注意的是，GPR158缺失会显著降低兴奋性突触传递功能，具体表现为内侧前额叶皮层内谷氨酸囊泡数量减少，同时GluN2B的表达及磷酸化水平下降。我们通过在Gpr158敲除小鼠的内侧前额叶皮层中重新表达GPR158，或对特异性敲除Gpr158的锥体神经元进行化学遗传学激活，成功逆转了社交新异缺陷表型。本研究结果表明，锥体神经元中的GPR158可特异性调控社交新异行为，或可成为治疗社交障碍的潜在靶点。