Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder

Abstract

The male bias in autism spectrum disorder incidence is among the most extreme of all neuropsychiatric disorders, yet the origins of the sex difference remain obscure. Developmentally males are exposed to high levels of testosterone and its byproduct, estradiol. Together these steroids modify the course of brain development by altering neurogenesis, cell death, migration, differentiation, dendritic and axonal growth, synaptogenesis and synaptic pruning, all of which can be deleteriously impacted during the course of developmental neuropsychiatric disorders. Elucidating the cellular mechanisms by which steroids modulate brain development provides valuable insights into how these processes may go awry. An emerging theme is the role of inflammatory signaling molecules and the innate immune system in directing brain masculinization, the evidence for which we review here. Likewise evidence is emerging that the neuroimmune system is over-activated in individuals with autism spectrum disorder. These combined observations lead us to propose that the natural process of brain masculinization puts males at risk by moving them closer to a vulnerability threshold that could more easily be breached by inflammation during critical periods of brain development. Two brain regions are highlighted, the preoptic area and the cerebellum. Both are developmentally regulated by the inflammatory prostaglandin, PGE2, but in very different ways. Microglia, innate immune cells of the brain, and astrocytes are also critical contributors to masculinization and illustrate the importance of non-neuronal cells to the health of the developing brain.

Comorbid epilepsy in autism spectrum disorder: Implications of postnatal inflammation for brain excitability

“…Whereas earlier work from our laboratory conducted in rats has not revealed sex‐dependent effects of early LPS on emotional behaviors, certain other neurological variables may differ . The known sex‐dependent differences in epilepsy and ASD mandated that we determine whether there are hormone‐ or sex‐dependent influences on the interaction between postnatal inflammation and seizure susceptibility in this model. There were no significant sex‐dependent differences in PTZ‐induced seizure thresholds in mice that had been postnatally treated with either saline or LPS (Figure ).…”

Neurobehavioral effects of long‐term maternal fructose intake in rat offspring

“…Genetic modification and environmental factors such as diet, inflammation, hormone therapy or other drugs, may influence brain development by modifying sex hormones and other steroid levels. Furthermore, based on animal and human studies, it has been proposed that females have low levels of neuroimmune activity and inflammatory signaling during fetal life, while masculinization increases inflammation in males and makes them more sensitive to the detrimental effects of early stressors (McCarthy and Wright, 2016).…”

Understanding environmental contributions to autism: Causal concepts and the state of science

“…The literature, however, is contradictory [e.g., Kung et al, 2016]. Alternative more biologically focused frameworks emphasize sexually dimorphic fetal programming of stress responses by the HPA-placental axis [Davis & Pfaff, 2014] and brain masculinization in context of immunoregulatory processes [McCarthy & Wright, 2017].…”