Autism spectrum disorders (ASDs) are prevalent neurodevelopmental disorders whose etiology includes a substantial and heterogeneous genetic contribution. Thus, finding effective treatment options that are broadly applicable necessitates mechanistic identification of possible converging biological processes. The central oxytocin (OXT) system may be a potential point of convergence connecting genetic disruptions with abnormal social behaviors in ASD. OXT is a peptide neurohormone critical for social bonding and trust, and has emerged as a promising treatment option for the debilitating social symptoms of ASD. Interestingly, several mouse lines with loss-of-function mutations in ASD genes (Cntnap2, Fmr1, Shank3) display impaired central OXT system and/or reversal of social impairment by OXT treatment, enabling investigation of the presently unknown neural mechanisms that underlie the pro-social effects of OXT. These mice also display many other common phenotypes, such as abnormalities in synaptic structure and function, as well as circuit connectivity in the mesoscale range. These observations raise a hypothesis that A) disruptions in these ASD genes impact cellular and synaptic processes in hypothalamic OXT neurons and the downstream brain regions to which they project; and that B) the resulting impairment in the central OXT system leads to aberrant functional connectivity in the brain and disrupts social behavior, both of which can be normalized by administration of exogenous OXT. Indeed, my pilot data from Cntnap2 knockout (KO) mice indicate a unique pattern of gene expression associated with aberrant neural excitability and long-range communication, and reduced connectivity in several brain circuits that is rescued by OXT treatment. These functional connectivity phenotypes and the mechanisms of OXT effect will be further characterized in Cntnap2, Fmr1, and Shank3 KO mice (Aim 1). Next, molecular and cellular abnormalities potentially underlying the lowered connectivity in the KO mouse will be identified by performing RNA-seq in each mouse line (Aim 2). Cellular and synaptic properties of OXT neurons will be investigated, and impacted ion channels will be molecularly rescued to test whether both aberrant connectivity and impaired social behavior are rescued (Aim 3). During the K99 phase, a number of current fMRI and RNA- seq analysis techniques will be obtained and applied with help from the Geschwind and Dapretto labs at the UCLA School of Medicine, providing an outstanding training environment with all necessary equipment and facilities. Additional guidance on electrophysiological and mouse fMRI experiments and analysis will be provided by Drs. Golshani, Harris, and Eberhardt, respectively. These five faculty members make up the strong advisory committee that will oversee progress on the research project and career development. This proposed training plan will allow the candidate to acquire the necessary skillset and research background for the independent R00 phase, and potentially contribute to increased OXT treatment success in ASD patients as well as advance our fundamental understanding of the neurobiology the disorder.
Oxytocin is an emerging drug candidate for treating the social impairment present in autism spectrum disorders (ASD); however, its efficacy is still in question and the mechanism(s) by which it improves social behavior in ASD unclear. I propose to investigate the brain circuit abnormalities involving oxytocin neurons as well as the underlying cellular and molecular mechanisms. Results from this study will aid the discovery of not only biomarkers to predict the efficacy of oxytocin, but will also advance our fundamental understanding of the neurobiological mechanisms that underlie the social impairments in ASD.
