Deciphering autism heterogeneity: a molecular stratification approach in four mouse models

Déchiffrer l'hétérogénéité de l'autisme : une approche de stratification moléculaire dans quatre modèles murins

Caroline Gora (1) , Ana Dudas (1) , Océane Vaugrente (1) , Lucile Drobecq (1) , Emmanuel Pecnard (1) , Gaëlle Lefort (1) , Lucie P. Pellissier (1)

1 PRC - Physiologie de la reproduction et des comportements [Nouzilly]

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.

Mots clés: Autism spectrum disorder; social interaction; molecular markers; oxytocin; synaptic plasticity; stratification of individuals with autism

Domaines: Neurosciences [q-bio.NC]

Caroline Gora, Ana Dudas, Océane Vaugrente, Lucile Drobecq, Emmanuel Pecnard, et al.. Deciphering autism heterogeneity: a molecular stratification approach in four mouse models. 2024. ⟨hal-04522001⟩