  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 explored molecular markers within the oxytocin and immediate early
gene families across five interconnected brain structures of the social circuit
in four distinct 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. Through integrative analysis,
we identified Egr1, Foxp1, Homer1a, Oxt and Oxtr as five robust and
discriminant molecular markers facilitating 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. The implications extend to enhancing the success of clinical trials
and guiding personalized medicine for distinct subgroups of individuals with
autism.
