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<p>The molecular etiology of numerous risk genes for autism spectrum disorder (ASD), including <i>Cadherin 11</i> (<i>CDH11</i>), 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 <i>Cdh11</i> 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 <i>Cdh11</i>-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 <i>Cdh11</i>-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.</p><p></p>

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Cadherin 11 regulates presynaptic vesicle trafficking and neuronal activity in autism-related brain circuit

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Xiaoxiao Cao,
  • Jingyan Jia,
  • Ze Li,
  • Simeng Guo,
  • Jiale Duan,
  • Ji Ma,
  • Xiao-Bing Yuan,
  • Yi-Hsuan Pan

摘要

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.