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

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.
Mesh Terms:
Adaptor Proteins, Vesicular Transport, Animals, Autistic Disorder, Disease Models, Animal, Female, Homeostasis, Mice, Proteolysis, Synapses, Ubiquitin, Valproic Acid
Sci Rep
Date: Feb. 11, 2026
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