CNTNAP2: exploring association with autism phenotypes in mice

Individuals with autism spectrum disorders (ASDs) have language and behavioural abnormalities, and can suffer from other symptoms, including epileptic seizures. Many genes have been associated with ASDs, one of which is CNTNAP2, encoding a neuronal transmembrane protein. Mutations in CNTNAP2 are strongly associated with an ASD known as cortical dysplasia-focal epilepsy (CDFE). Peñagarikano and colleagues developed Cntnap2-knockout mice to investigate the mechanistic basis for this association in vivo. They found that these mice have normal stress responses and visual spatial memory, but exhibit abnormal social, language and repetitive behaviours, resembling those seen in individuals with ASDs. In addition, mutant mice are hyperactive and suffer epileptic seizures similar to patients with CDFE. Analysis of brain circuitry prior to the onset of seizures revealed that Cntnap2-knockout mice have neuronal migration abnormalities and reduced network activity, suggesting that CNTNAP2 is involved in early brain development. Treatment of the mice with the FDA-approved drug Risperidone – which is used to reduce behavioural problems in individuals with ASDs – ameliorated behavioural defects in Cntnap2-knockout mice. This study provides new insight into the mechanism of an ASD-associated gene and suggests that the Cntnap2-knockout mouse is a valuable model for testing candidate drugs for these disorders.