Mechanism and treatment of ASD related behavior in the Cntnap2 knockout mouse model
University of California, Los Angeles
Although many genes predisposing to ASD have been identified, the biological mechanism(s) underlying ASD remain unclear. Mouse models based on human disease-causing mutations provide a good system to understand the pathophysiology of ASD and to assess the potential of the treatments, as well as developing new effective interventions. The Cntnap2 knockout mouse model of ASD shows high construct, face and predictive validity, being ideal for both neurobiological and pharmacological research. Cntnap2 deficient mice show deficits in the three core ASD behavioral domains as well as hyperactivity and epileptic seizures, as has been reported in humans with CNTNAP2 recessive mutations (Strauss et al., 2006). Neuropathological and physiological analyses of these mice at an age before the onset of seizures reveal neuronal migration abnormalities, reduced number of GABAergic interneurons and abnormal neuronal network activity. In addition, treatment of this mouse model with the FDA approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a novel functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD. The Cntnap2 mouse model will be used as a tool to study the neurobiological basis that leads to the ASD related behaviors. Neurobiological analyses dissecting the observed deficits in neuronal circuitry will be very valuable in the development of targeted neuropharmacotherapy for ASD. In addition, the high predictive validity of this mouse model makes it ideal for in vivo drug screening, which will be performed for the core ASD related social and repetitive behaviors. This basic research will be integrated with a clinical-oriented research through observation of autistic patients currently on pre-clinical trials with risperidone. Together, this multidisciplinary training will provide with the experience necessary to understand autism neurobiology and current pharmacological approaches in patients as well as the challenges of cross-species pharmacological applications. The ultimate goal is to acquire the knowledge of how to apply basic research findings in the mouse model towards human interventions, which is essential in the development of a career in translational research.