Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China.
Department of Pathology of Sir Run Run Shaw Hospital, and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Cell Rep. 2024 Oct 22;43(10):114796. doi: 10.1016/j.celrep.2024.114796. Epub 2024 Oct 8.
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 that both constitutive and cell-/tissue-specific knockouts of Gpr158 in pyramidal neurons or the medial prefrontal cortex (mPFC) result in impaired novelty preference, while sociability remains unaffected in male mice. Notably, the loss of GPR158 leads to a significant decline in excitatory synaptic transmission, characterized by a 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 disorders.
社交沟通技能障碍是自闭症谱系障碍（ASD）的一个显著特征。G 蛋白偶联受体 158（GPR158）在 ASD 中的作用在很大程度上仍未得到探索。在这项研究中，我们观察到，在锥体神经元或内侧前额叶皮层（mPFC）中组成型和细胞/组织特异性敲除 Gpr158 都会导致新颖偏好受损，而雄性小鼠的社交能力不受影响。值得注意的是，GPR158 的缺失会导致兴奋性突触传递显著下降，其特征是 mPFC 中谷氨酸囊泡减少，以及 GluN2B 的表达和磷酸化减少。我们通过在 Gpr158 缺失小鼠的 mPFC 中重新引入 GPR158 或通过化学遗传激活特异性缺失 Gpr158 的锥体神经元，成功挽救了社交新颖性缺陷的表型。我们的研究结果表明，锥体神经元中的 GPR158 在调节社交新颖性方面发挥着特定的作用，可能是治疗社交障碍的潜在靶点。
