Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits

• Published in: Cell Vol. 147; no. 1; pp. 235 - 246
• Main Authors: Peñagarikano, Olga, Abrahams, Brett S., Herman, Edward I., Winden, Kellen D., Gdalyahu, Amos, Dong, Hongmei, Sonnenblick, Lisa I., Gruver, Robin, Almajano, Joel, Bragin, Anatol, Golshani, Peyman, Trachtenberg, Joshua T., Peles, Elior, Geschwind, Daniel H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-09-2011
• Subjects: Animal models; Animals; Autism; Autistic Disorder - genetics; Autistic Disorder - pathology; brain; Brain - growth & development; Brain - metabolism; Brain - pathology; Cell migration; Cell Movement; CNTNAP2 gene; Data processing; Disease Models, Animal; Drugs; Epilepsy; Epilepsy - genetics; genes; Humans; Hyperactivity; Interneurons; Interneurons - metabolism; knockout mutants; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural networks; Neurodevelopmental disorders; Neurons - pathology; Risperidone; Seizures
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.08.040

Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the
Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders.
Cntnap2
−/−
mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with
CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for
CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.
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► The
Cntnap2
−/−
mouse model of ASD shows striking parallels with the human disease ► CNTNAP2 affects the development of neuronal circuits, including GABAergic neurons ► Our results support a role for neuronal synchrony in the pathophysiology of ASD ► This model permits dissociation of the circuitries involved in ASD core behaviors
Existing mouse models of autism often fail to capture important aspects of human disease. Mice lacking expression of a neurexin exhibit striking parallels with autism spectrum disorders, recapitulating the key behaviors, neuroanatomical defects, and pharmacological responses of human patients.