Abnormal Behavior, Epileptic Seizures and Atypical Neuronal Circuit Functioning In Cntnap2 Knockout Mice: a New Mouse Model of Autism Spectrum Disorders

Background:  The contactin associated protein-like 2 (CNTNAP2) gene encodes for a neuronal transmembrane protein, member of the neurexin superfamily (Poliak et al., 1999) which loss of function has been associated to a syndromic form of ASD called cortical dysplasia-focal epilepsy syndrome (CDFE), a rare disorder resulting in epileptic seizures, language delay, intellectual disability, hyperactivity and, in nearly two-thirds of the patients, autism (Strauss et al., 2006). In addition, common and rare genetic variations in CNTNAP2 have been associated to an increased risk of autism or autism-related endophenotypes (Alarcon et al., 2008; Arking et al., 2008; Bakkaloglu et al., 2008; Vernes et al. 2008). We have recently shown that the CNTNAP2 variant that increases risk for the autism endophenotype “specific language impairment”, also leads to increased short range and decreased long-range functional connectivity in human subjects (Scott-Van Zeeland et al., 2010), consistent with emerging theories of autism pathophysiology (Belmonte et al., 2004; Courchesne and Pierce, 2005). Together, these data suggest a role for CNTNAP2 in development of brain regions and/or circuits involved in Autism Spectrum Disorders (ASD).

Objectives:  Behavioral and neuropathological characterization of the Cntnap2 knockout mice as a potential mouse model for ASD.

Methods:  Ten Cntnap2 knockout mice and wildtype littermates were evaluated in a broad battery of behavioral tests relevant to ASD (Silverman, 2010). Immunohistochemistry and electrophysiological studies were performed in three mice per genotype using conventional methods.

Results:  Cntnap2 knockout mice recapitulate features observed in patients with idiopathic autism including abnormal vocal communication, repetitive and restrictive behaviors, and abnormal social interactions. In addition, they show hyperactivity and epileptic seizures, as has been reported in humans with CDFE syndrome. Neuropathologically, we observe defects in the migration of cortical projection neurons and a reduction in the number of GABAergic interneurons, which is accompanied by an imbalanced excitatory/inhibitory network. These data show that CNTNAP2 is involved in the development of cortical circuits, and further support alterations in excitatory-inhibitory balance in ASD pathophysiology. In addition, treating Cntnap2 knockout mice with risperidone, an antipsychotic drug approved for autism treatment by the FDA, rescues the repetitive behavior, but not the social deficits, a dissociation similar to what is seen in human patients.

Conclusions:  These data demonstrate the validity of the Cntnap2 knockout as a mouse model for ASD and provide initial insight into the underlying mechanisms by which CNTNAP2 affects brain development and function, being an excellent tool for further studies to unravel ASD pathophysiology and for therapeutic research.