Etiologies underlying sex bias in autism spectrum disorder: a narrative review of preclinical rodent models

Abstract

Neurodevelopmental disorders, which emerge early in development, include a range of neurological phenotypes and exhibit marked differences in prevalence between sexes. A male predominance is particularly pronounced in autism spectrum disorder (ASD). Although the precise cause of ASD is still unknown, certain genetic variations and environmental influences have been implicated as risk factors. Preclinical ASD models have been instrumental in shedding light on the mechanisms behind the sexual dimorphism observed in this disorder. In this review, we explore the potential processes contributing to sex bias by examining both intrinsic differences in neuronal mechanisms and the influence of external factors. We organize these mechanisms into six categories: 1) sexually dimorphic phenotypes in mice with mutations in ASD-associated genes related to synaptic dysfunction; 2) sex-specific microglial activity, which may disrupt neural circuit development by excessively pruning synapses during critical periods; 3) sex steroid hormones, such as testosterone and allopregnanolone, that differentially influence brain structure and function; 4) escape from X chromosome inactivation of the O-linked-Nacetylglucosamine transferase gene in the placenta; 5) sexually dimorphic activation of the integrated stress response pathway following maternal immune activation; and 6) immunological responses that are differentially regulated by sex. Understanding these mechanisms is essential for deciphering the underlying causes of ASD and may offer insights into other disorders with notable sex disparities.