Cao Xiaoxiao, Jia Jingyan, Li Ze, Guo Simeng, Duan Jiale, Ma Ji, Yuan Xiao-Bing, Pan Yi-Hsuan
Key Laboratory of Brain Functional Genomics of Shanghai and Ministry of Education, Institute of Brain Functional Genomics, School of Life Science and the Collaborative Innovation Center for Brain Science, East China Normal University, Shanghai, 200062, China.
Mol Psychiatry. 2025 Aug 12. doi: 10.1038/s41380-025-03141-7.
The molecular etiology of numerous risk genes for autism spectrum disorder (ASD), including Cadherin 11 (CDH11), remains elusive. We investigated the role of CDH11 in the development of ASD-related behaviors using gene-deficient mice. CDH11 is enriched at synapses in glutamatergic neurons of the anterior cingulate cortex (ACC), which project to the dorsal striatum, nucleus accumbens, and the basolateral amygdala. Developmental ablation of Cdh11 in these neurons led to increased self-grooming, reduced sociability, and decreased neuronal activity in the ACC. Chemogenetic inhibition of ACC glutamatergic neurons recapitulates the over-grooming phenotype, while activation of these neurons mitigates self-grooming in Cdh11-deficient mice. Moreover, targeted expression of CDH11 in the ACC of these mice significantly attenuated their over-grooming behaviors. Proteomics of ACC synaptosomes and CDH11 interactomes revealed that CDH11 participates in synaptic vesicle trafficking, as evidenced by a reduction in presynaptic vesicle density at excitatory synapses in Cdh11-deficient mice. These findings highlight an important role of CDH11 in the development of ASD-related brain circuits and provide insights into the molecular basis of repetitive behaviors in ASD.
包括钙黏蛋白11（CDH11）在内的众多自闭症谱系障碍（ASD）风险基因的分子病因仍不清楚。我们使用基因缺陷小鼠研究了CDH11在ASD相关行为发展中的作用。CDH11在前扣带回皮质（ACC）的谷氨酸能神经元突触中富集，这些神经元投射到背侧纹状体、伏隔核和基底外侧杏仁核。这些神经元中Cdh11的发育性缺失导致自我梳理增加、社交性降低以及ACC中神经元活动减少。对ACC谷氨酸能神经元进行化学遗传学抑制可重现过度梳理表型，而激活这些神经元可减轻Cdh11缺陷小鼠的自我梳理行为。此外，在这些小鼠的ACC中靶向表达CDH11可显著减弱它们的过度梳理行为。ACC突触体和CDH11相互作用组的蛋白质组学表明，CDH11参与突触小泡运输，Cdh11缺陷小鼠兴奋性突触处突触前小泡密度降低证明了这一点。这些发现突出了CDH11在ASD相关脑回路发育中的重要作用，并为ASD重复行为的分子基础提供了见解。
