Examining etiologies underlying sex bias in autism spectrum disorder using preclinical rodent models: a narrative review

Neurodevelopmental disorders, which manifest early in development, encompass a range of neurological phenotypes and exhibit notable differences in prevalence between sexes. A male bias is particularly pronounced in autism spectrum disorder (ASD). While the exact cause of ASD remains elusive, a combination of genetic variations and environmental influences has been implicated as risk factors. Preclinical ASD models have served as valuable tools in elucidating the mechanisms behind sexual dimorphism in the disorder. In this review, we investigate the potential mechanisms contributing to sex bias by examining both intrinsic differences in neuronal mechanisms and the influence of external factors. Here we categorize the mechanisms into six groups: 1) Sexually dimorphic phenotypes in mice with mutations in genes associated with ASD that are linked to synaptic dysfunction. 2) Sex-specific microglial activity, which may disrupt neural circuit development by over-pruning synapses during critical periods. 3) Sex steroid hormones such as testosterone and allopregnanolone, which differentially shape brain structure and function. 4) Evasion of X chromosome inactivation in the O-linked-N-acetylglucosamine transferase (OGT) gene in the placenta. 5) Sexually dimorphic activation of the integrated stress response pathway in response to maternal immune activation. 6) Immunological responses differentially regulated by sex. Understanding these mechanisms is crucial for unraveling the underlying causes of ASD and may offer insights into other disorders characterized by significant gender disparities.