Animal models guided drug discovery in autism: The case for oxytocin

抄録

Autism spectrum disorder (ASD) is a heterogeneous condition characterized by deficits in social interactions and repetitive behaviors/restricted interests. Mouse models based on human disease-causing mutations provide the potential for understanding associated neuropathology and developing targeted treatments. Genetic, neurobiological and imaging data provide convergent evidence for the CNTNAP2 gene as a risk factor for ASD and other neurodevelopmental disorders. Accordingly, we demonstrated that a mouse knockout for the Cntnap2 gene shows construct, face and predictive validity, providing a tool for mechanistic and therapeutic research in autism. In fact, through an in vivo drug screen in this model we found that administration of the neuropeptide oxytocin, widely implicated in social behavior in mammals, dramatically improves social deficits. Similar behavioral effects were observed when chemogenetically evoking endogenous oxytocin release using DREADDs. Strikingly, reduced neuropeptide levels in this model seemed to account for the behavioral response. Last, I will present ongoing work in my lab evaluating the oxytocin system and interacting neurotransmitter systems, such as dopaminergic, in this model. Alterations in the oxytocin system and/or dysfunction in its related biological processes could potentially be more common in autism than previously anticipated.