Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction, communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous ASD mouse models, each exhibiting unique behavioral features along the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes in social plasticity in the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt and Oxtr as five robust and discriminant molecular markers that allowed successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.