Wang Xiaona, Chen Mengyuan, Mei Daoqi, Shi Shengli, Guo Jisheng, Gao Chao, Wang Qi, Zhao Shuai, Yan Xingxue, Zhang Huichun, Wang Yanli, Guo Bin, Zhang Yaodong
Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan Children's Neurodevelopment Engineering Research Center, Zhengzhou, China.
Department of Neurology, Children's Hospital of Suzhou University, Suzhou, China.
Mol Autism. 2025 Mar 11;16(1):18. doi: 10.1186/s13229-025-00653-5.
Dysfunction in social interactions is a core symptom of autism spectrum disorder (ASD). Nevertheless, the neural mechanisms underlying social deficits in ASD are poorly understood. By integrating electrophysiological, in vivo fiber photometry, viral-mediated tracing, optogenetic and pharmacological stimulation, we show reduced intrinsic excitability and hypoactivity of SOM interneurons in medial prefrontal cortex (mPFC) in Magel2-deficient mice, an established ASD model, were required to social defects. Chemogenetic inhibition of mPFC SOM-containing interneurons resulted in reduced social interaction in wild-type Magel2 mice. These sociability deficits can be rescued by optogenetic activation by excitability of SOM in the mPFC and mPFC-LS inhibitory pathway in Magel 2 knockout mice. These results demonstrate the hypoactivity for SOM action in the mPFC in social impairments, and suggest targeting this mechanism that may prove therapeutically beneficial for mitigating social behavioral disturbances observed in ASD.
社交互动功能障碍是自闭症谱系障碍（ASD）的核心症状。然而，人们对ASD社交缺陷背后的神经机制了解甚少。通过整合电生理学、体内光纤光度法、病毒介导的追踪、光遗传学和药理学刺激，我们发现，在已确立的ASD模型Magel2缺陷小鼠中，内侧前额叶皮质（mPFC）中SOM中间神经元的内在兴奋性降低和活动不足是社交缺陷所必需的。对mPFC中含有SOM的中间神经元进行化学遗传学抑制，导致野生型Magel2小鼠的社交互动减少。通过光遗传学激活Magel 2基因敲除小鼠mPFC中SOM的兴奋性和mPFC-LS抑制通路，可以挽救这些社交能力缺陷。这些结果证明了mPFC中SOM在社交障碍中的活动不足，并表明针对这一机制可能对减轻ASD中观察到的社交行为障碍具有治疗益处。
