Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two major diagnostic criteria – persistent deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior (RRBs). Evidence from both human and animal model studies of ASD suggest that alteration of striatal circuits, which mediate motor learning, action selection, and habit formation, may contribute to the manifestation of RRBs. CNTNAP2 is a syndromic ASD risk gene, and loss of function of Cntnap2 in mice is associated with RRBs. How loss of Cntnap2 impacts striatal neuron function is largely unknown. In this study, we utilized Cntnap2−/− mice to test whether altered striatal neuron activity contributes to aberrant motor behaviors relevant to ASD. We find that Cntnap2−/− mice exhibit increased cortical drive of direct pathway striatal projection neurons (dSPNs). This enhanced drive is likely due to increased intrinsic excitability of dSPNs, which make them more responsive to cortical inputs. We find that Cntnap2−/− mice exhibit spontaneous repetitive behaviors, increased motor routine learning, perseveration, and cognitive inflexibility. Increased corticostriatal drive of the direct pathway may therefore contribute to the acquisition of repetitive, inflexible behaviors in Cntnap2 mice. Competing Interest Statement The authors have declared no competing interest. Footnotes New data and analyses were performed and three new figures were added to address the mechanism by which loss of Cntnap2 affects striatal neuron excitability.