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. Display omitted Display omitted ► 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.