The etiology of autism spectrum disorder (ASD) is poorly understood; however, emerging clinical and epidemiological data have linked dysregulated immune responses with ASD. Indeed, recent studies increasingly correlate ASD to maternal immune activation (MIA) during pregnancy. In particular, pregnant mothers who suffer from autoimmune disorders, obesity-associated inflammation, or infection are at a significantly higher risk of having children with ASD. Even though mounting evidence clearly demonstrates that hyperactive immune responses during development can disrupt normal brain maturation and cause behavioral abnormalities later in life, the key molecular and cellular pathways responsible for MIA-induced ASD still remain to be identified.

John Lukens and Eli Zunder and their colleagues at the University of Virginia have recently identified an MIA mouse model in which the male, but not female, littermates develop autism-spectrum behaviors, mirroring the higher rates of human ASD in men versus women¹. The fact that male mice are more susceptible to MIA-induced ASD while female littermates are protected suggests that males respond differently to the maternal immune response. The specific cellular and molecular mechanisms that contribute to these sex-based differences in sensitivity to the maternal immune system are poorly characterized. Moreover, the specific biological factors that are responsible for the higher rates of ASD in boys have not been studied in great detail.

Lukens, Zunder and their collaborative research team hypothesize that cutting-edge transcriptomics and mass cytometry approaches will enable an unbiased and comprehensive identification of the cellular and molecular determinants of sex bias in MIA-induced autism. Moreover, they postulate that this line of investigation will help to reveal novel molecular mediators of ASD. Completion of the studies outlined in their proposal will define how sex shapes responsiveness to maternal inflammation. Notably, their analysis will uncover the molecular underpinnings associated with both male bias in autism and sex-based differences in MIA-induced behaviors. This novel resource will provide a much-needed data-driven foundation in which to better define and characterize sexual dimorphism in ASD.