Autism spectrum disorder (ASD) risk is imparted by both common and rare genetic variation, making it, in part, a collection of rare diseases. One of these rare forms is caused by recessive mutations in the gene CNTNAP2, which causes a syndrome with high penetrance for ASD and is now the most common neurodevelopmental disorder observed in the Amish.

Previously, the laboratory of Daniel Geschwind modeled this condition in mice, demonstrating deficits in social behavior and the presence of repetitive behavior and hyperactivity in CNTNAP2 knockout (KO) mice¹. More recently, Geschwind’s team found, somewhat unexpectedly, a deficit in the oxytocin system of these mice². CNTNAP2 KO mice exhibit reduced levels of oxytocin in the brain and reduced oxytocin immunoreactivity in the paraventricular nucleus (PVN) of the hypothalamus. Pharmacologically increasing oxytocin or triggering the activity-dependent release of PVN oxytocin-containing neurons via DREADD (Designer Receptors Exclusively Activated by Designer Drugs) successfully alleviates the social deficits exhibited by these mice. Geschwind proposes to capitalize on these findings to understand how oxytocin might be regulating circuit activity, leading to behavioral recovery.

Recent neuroimaging evidence suggests that abnormalities in neural circuit connectivity are commonly found in ASD, in a manner positively correlated with social symptom severity. Preliminary resting functional magnetic resonance imaging (fMRI) results from the Geschwind lab suggests that CNTNAP2 KO mice also exhibit increased local frontal connectivity. Based on these data, Geschwind hypothesizes that oxytocin may influence social behavior through modifying connectivity strengths, with the hyperconnectivity phenotype playing a causal role in social behavior impairments. Geschwind’s team will investigate i) whether this abnormal connectivity pattern is observed in a larger, more statistically powered cohort in the CNTNAP2 KO mouse model, ii) if experimentally increasing brain oxytocin in vivo can alleviate the connectivity phenotype in parallel with the social behavior rescue and iii) the existence of structural and functional abnormalities involving the oxytocin system, which could contribute to the connectivity phenotype.

The team will combine cutting-edge approaches, including selective stimulation of oxytocin neurons by DREADD, small animal fMRI to measure brain-wide functional connectivity, and CLARITY to visualize oxytocin projections. These approaches will enable whole-brain profiling of structural and functional connectivity elements and investigate how they interact at rest and after triggering selective increases in brain oxytocin. Results obtained from these experiments will yield key insights on how disruptions of an ASD gene can lead to functional and structural abnormalities in brain circuits related to oxytocin to potentially underlie social impairment.