Biological Drivers of Sex Differences in Autism Spectrum Disorder

Objective

It becomes increasingly clear that male and female brains do not develop along the same path. These inherent biological distinctions can lead to sex-specific vulnerabilities and variations in how neurodevelopmental conditions manifest. A prime example is Autism Spectrum Disorder (ASD), where a consistently higher number of males are diagnosed compared to females (approximately four males for every female), thereby emphasizing the significant impact of sex. While diagnostic practices may contribute, compelling evidence suggests that intrinsic biological factors are key drivers of these differences. Previous research, including work from the Novarino Lab using ASD mouse models, has shown that female brains exhibit more pronounced changes in gene activity compared to those of males. These results highlight the importance of sex as a factor, but the underlying causes, whether they're linked to sex chromosomes or hormonal effects, are still unclear. This project aims to dissect sex-specific effects during a critical postnatal developmental period. By building on the existing ASD mutant mouse cohort in the Novarino lab and combining it with the Four Core Genome mouse model, we'll create a one-of-a-kind transcriptomic dataset that can separate the effects of genetic sex (XX vs. XY chromosomes) from those of gonadal hormones on brain development. By achieving these goals, the project will yield the first genome-wide, cell-type-specific analysis of sex bias in ASD mutants, thereby advancing the field toward a mechanistic, sex-informed understanding of the disorder that ultimately could pave the way for sex-informed therapeutic strategies, moving beyond a one-size-fits-all approach.