Abnormal Oxytocin Pathway in the Cntnap2 Mouse Model of ASD

Background:  

Genetic, neurobiological and imaging data provide convergent evidence for the contactin associated protein-like 2 (CNTNAP2) gene as a risk factor for Autism Spectrum Disorder (ASD) and other neurodevelopmental disorders. The 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). Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. We have previously demonstrated the construct, face and predictive validity of a mouse knockout for the Cntnap2gene (Penagarikano et al., 2011), providing an excellent tool for further studies to unravel ASD pathophysiology and for therapeutic research.

Objectives:

To perform an in vivo drug screening in Cntnap2mutant mice targeting affected social behaviors.

Methods:  

Ten Cntnap2knockout mice and wildtype littermates were pharmacologically treated and tested for improvements in social interactions as in Silverman et al. (2010). Immunohistochemistry and receptor binding analysis were performed in four mice per genotype using conventional methods.

Results:  

We found that intranasal administration of the neuropeptide oxytocin (OXT) dramatically improves social deficits in this mouse model. Interestingly, the same treatment in wild-type (WT) littermates did not show any behavioral response, suggesting a hyper-reactivity to OXT in Cntnap2 mice. OXT is synthesized in magnocellular neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. It is released both peripherally, where it is involved in diverse physiological functions, and centrally, where it acts as a neuromodulator. Analysis of the expression of Cntnap2 by in situ hybridization shows that it is enriched in the PVN, supporting a role for this gene in the development and/or functioning of these neurons. Interestingly, quantitative PCR from dissected hypothalamus showed that Oxt RNA levels are reduced in Cntnap2 mutant mice compared to WT and decreased OXT immunoreactivity was found in the PVN of mutant mice. Furthermore, analysis of the distribution of OXT receptors by receptor binding auutoradiography shows an abnormal distribution of these receptors in mutant mice comparing to WT littermates.

Conclusions:  Several lines of evidence suggest an association of the OXT pathway and ASD, and clinical trials with OXT agonists are underway. Here, we report that the Cntnap2 mouse model of autism responds to OXT and provide initial evidence that the OXT-OXT receptor pathway is dysregulated in the knockout. Additional work is needed to clarify the neurobiological basis for this deficit and to study the mechanism whereby OXT exerts its behavioral effects.