Autism Spectrum Disorders (ASDs) are highly prevalent developmental disorders that affect 1 in every 68 individuals. Due to the high phenotypic heterogeneity in ASDs, both the identification of causative factors and the development of successful therapeutic interventions has been challenging. Thus, understanding convergent pathophysiological mechanisms by which defined etiologies result in ASDs can serve as an invaluable starting point towards the development of successful therapeutic treatments. Here, I investigate how alterations in CNTNAP2, an autism-susceptibility gene, can lead to ASD-related deficits in neuronal function. Recessive truncating mutations in CNTNAP2 cause Cortical Dysplasia Focal Epilepsy (CDFE), a syndromic form of ASD in humans. Remarkably, Cntnap2 knock-out (KO) mice, which have been genetically engineered to lack Cntnap2 expression, recapitulate the core behavioral deficits of the disorder, including impairments in social interactions and communication, repetitive and restrictive behaviors, seizures, decreased neuronal synchrony, and neuronal migration deficits. Here, I take advantage of this invaluable research tool to dissect the synaptic, cellular, and neuronal microcircuit activity changes associated with loss of Cntnap2 in the KO mouse. I use electrophysiology and histological studies to assess these alterations within the medial prefrontal cortex (mPFC), an area associated with social behavior. I observe that although there are no significant alterations in the intrinsic excitability of pyramidal neurons or parvalbumin-positive interneurons in the KO, excitatory cells show a significant decrease in both excitatory and inhibitory inputs. These changes are accompanied by a decrease in dendritic spine density, and suggest a reduction in the total number of functional synapses within mPFC. These in vitro findings are concurrent with a notable reduction in local field potential (LFP) power in vivo, and likely reflect an overall decrease in excitatory drive, likely to be underlie some of the behavioral deficits observed in the mouse. Finally, I describe the collaborative development of a novel social interaction task that can be used to assess changes in neuronal activity in vivo, both at baseline, in a social behavioral context, and in response to potential pharmacological interventions. The findings delineated here serve as a roadmap for neurophysiological characterization of a rodent model of ASD, and provide initial mechanistic insights into how loss of Cntnap2 alters mPFC microcircuitry. This work therefore serves as a starting point to finding convergent molecular, biological and physiological pathways that can contribute to our understanding and treatment of the ever so complex ASDs.
