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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) is a neurodevelopmental condition with significant heterogeneity, complicating treatment development.
• Effective clinical trials for ASD necessitate patient stratification using robust biomarkers.
• Current research lacks specific molecular markers for stratifying individuals with ASD.

Purpose of the Study:

• To identify and validate molecular markers for stratifying heterogeneous autism spectrum disorder mouse models.
• To investigate the role of oxytocin and immediate early gene families in the social circuit of the brain.
• To assess the potential of identified markers in predicting treatment response and stratifying ASD individuals.

Main Methods:

• Utilized five mouse models exhibiting autism-like behaviors.
• Analyzed gene expression of oxytocin and immediate early gene families in five brain structures.
• Employed integrative analysis to identify discriminant molecular markers for model stratification.

Main Results:

• Immediate early genes showed widespread alterations across models, unlike specific oxytocin family dysregulations.
• Identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as robust molecular markers for stratifying mouse models.
• Stratification using these markers showed predictive value in a fifth model and identified potential responders to oxytocin treatment.

Conclusions:

• Egr1, Foxp1, Homer1a, Oxt, and Oxtr serve as effective molecular markers for stratifying autism spectrum disorder models.
• This study provides a proof-of-concept for molecular stratification in ASD, crucial for personalized medicine.
• Findings have significant implications for enhancing clinical trial design and developing targeted autism therapies.