Using a mouse model to investigate male bias in autism spectrum disorder incidence.

Abstract

The review (Chapter 1) overviews our current understanding of the sex bias in autism spectrum disorders (ASD), whereby males are 4 times more likely to develop the condition. The longstanding uncertainty surrounding the etiology of autism can be informed by inclusion of both sexes in future research to better understand the mechanism responsible for this sex bias. Both clinical studies and animal models are useful tools to elucidate the underlying cause(s) of sexual dimorphic morphological, physiological, and behavioral differences in the ASD phenotype.Sex differences in social behaviors are common across species, underscoring the importance of assessing baseline sex differences in behavior, especially when sexually dimorphic effects on behavior are expected. I examined pre-pubertal behavior (Chapter 2) in 3 strains of mice (C57BL/6, CFW, and CF1) using a wheel-running assay developed to be relevant to autism-like behaviors. The results indicated no sex differences in wheel running behaviors or social interaction with all mouse strains displaying typical wheel running behavior, i.e. more time running on the wheel when it would turn and increased performance of other activities when it was jammed. iv Studies have found that elevated levels of fetal testosterone (fT) are correlated with later ASD diagnosis. Prenatal valproic acid (VPA) treatment is a common animal model of ASD in rodents, mimicking many of the features of ASD including increased male vulnerability. I used the VPA model (Chapter 3) to evaluate sex-specific responses to prenatal VPA treatment, and to assess if masculinization of females with perinatal testosterone propionate (TP) after prenatal VPA treatment would masculinize their susceptibility for abnormalities in development relevant to ASD. My findings confirmed that VPA exposure results in impaired motor development abilities, and provide novel evidence that the combined effects of VPA, TP, and maleness (triple hit) led to more severe motor development deficiencies in some tasks. I also present evidence that the triple hit resulted in reduced anxiety, but elevated cognitive rigidity and self-grooming compared to control females. The results provide some evidence for increased vulnerability of triple hit males to behavioral deficits relevant to ASD, but more research is needed to better understand this effect.