Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder - PubMed (original) (raw)

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

Margaret M McCarthy et al. Biol Psychiatry. 2017.

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. Evidence is also emerging that the neuroimmune system is overactivated 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 E2, but in different ways. Microglia, innate immune cells of the brain, and astrocytes are also critical contributors to masculinization and illustrate the importance of nonneuronal cells to the health of the developing brain.

Keywords: Androgens; Autism spectrum disorder; Cerebellum; Estrogens; Masculinization; Microglia; Preoptic area; Prostaglandins.

Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Masculinization of the brain converges with inflammation and enhances male vulnerability to ASD

Feminization and masculinization are distinct developmental processes. In rodents normal masculinization of some brain regions involves inflammatory signaling molecules such as prostaglandins which are derived from activated innate immune cells, the microglia, as well as reactive astrocytes. Inflammation during pregnancy in humans is a putative risk factor for development of ASD, with evidence that the greater the inflammation the more severe the disorder(20). Whether in utero inflammation increases the risk for ASD disproportionately in males is unknown. Based on research in rodents and correlational evidence in humans(37) we propose that females have very low levels of inflammatory signaling in the brain (green) while the natural process of masculinization increases inflammation in males (yellow-orange) and pushes males closer to a threshold of vulnerability which can be more easily breached if inflammation occurs during a developmental sensitive period (orange-red).

Figure 2

Figure 2. The preoptic area is sexually dimorphic and impacts multiple behaviors with relevance to ASD

The POA (red box) is a small but complex brain region that contains the medial preoptic nucleus (MPN) and hosts multiple neuroanatomical sex differences and is central to the control of motivated, affiliative and nurturing behaviors as well as sleep and fever generation, all of which are central to the phenotype of ASD. The POA is also the embryonic source of GABA neurons to the amygdala, hippocampus and prefrontal cortex and shares reciprocal connections with components of the reward pathway and those areas regulating fear and social behaviors.

Figure 3

Figure 3. Purkinje neuron development is regulated by PGE2 during a sensitive window

The principle neurons of the cerebellum show dramatic growth and differentiation during the first 3 postnatal weeks of life in the laboratory rat. Endogenous PGE2 is elevated during the 2nd postnatal week and is a critical regulator of normal Purkinje neuron growth. If PGE2 production is increased by inflammation during that week, the Purkinje neuron growth is stunted. If PGE2 production is decreased by treatment with NSAID inhibitors of cyclooxygenase, the Purkinje neurons show excessive growth of the dendritic tree. Changes in PGE2 levels in either the 1st or 3rd postnatal week has no impact on Purkinje neuron growth and this appears to be due to an intrinsic gene expression program in which the transducers of the PGE2 signal are up regulated during the 2nd week but expressed only at low levels during the 1st and 3rd weeks. Thus there is a narrowly defined sensitive window during which inflammation or treatment with NSAIDs dysregulates cerebellar development.

Figure 4

Figure 4. Different sensitive periods at different life stages of rats and humans

The developmental profile of the rat is shifted from humans in that a newborn pup is roughly equivalent to a mid- to late-gestation human fetus. The sensitive period for sexual differentiation of the preoptic area in the rat is operationally defined by the onset of testicular androgen production in male fetuses on embryonic day 18 and the loss of sensitivity of females to exogenous hormone treatment by the end of the first postnatal week. In humans the sensitive period for the preoptic area begins during the 2nd trimester with fetal androgen production and probably ends prior to birth although this conclusion is constrained by a lack of experimental data. The sensitive period we have identified in cerebellar development is during the second postnatal week in the rat which corresponds to the peripartum period in the human. The factors constraining the sensitive period in the rat are the onset and offset of gene expression profiles. Whether a similar profile exists in humans is currently unknown.

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