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<p>Prenatal valproic acid (VPA) exposure increases the risk of neurodevelopmental disorders, though its synaptic mechanisms remain unclear. Using multi-omics analyses, we identified Dlgap2 as a consistently dysregulated protein in VPA models. Mice with <i>Dlgap2</i> knockdown exhibited synaptic deficits and autism-like behaviors, including social and cognitive impairments. Proteomics of postsynaptic density following <i>Dlgap2</i> knockdown revealed disruption of synaptic organization and a specific reduction in Intersectin-1 (Itsn1), which interacts with Dlgap2 and undergoes ubiquitin-mediated degradation upon <i>Dlgap2</i> deficiency. Our study defines a Dlgap2-Itsn1 regulatory axis that underlies VPA-induced synaptic dysfunction.</p>

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Dlgap2 deficiency disrupts synaptic homeostasis by promoting ubiquitin-mediated Itsn1 degradation in a valproic acid-induced autism-like model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Xiaofeng Guo,
  • Ling Zhang,
  • Kai Zhuang

摘要

Prenatal valproic acid (VPA) exposure increases the risk of neurodevelopmental disorders, though its synaptic mechanisms remain unclear. Using multi-omics analyses, we identified Dlgap2 as a consistently dysregulated protein in VPA models. Mice with Dlgap2 knockdown exhibited synaptic deficits and autism-like behaviors, including social and cognitive impairments. Proteomics of postsynaptic density following Dlgap2 knockdown revealed disruption of synaptic organization and a specific reduction in Intersectin-1 (Itsn1), which interacts with Dlgap2 and undergoes ubiquitin-mediated degradation upon Dlgap2 deficiency. Our study defines a Dlgap2-Itsn1 regulatory axis that underlies VPA-induced synaptic dysfunction.