Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder.
Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder.
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DOI：
10.1016/j.biopsych.2016.10.004
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发表时间：
2017-03-01
影响因子：
10.6
通讯作者：
Wright CL
中科院分区：
文献类型：
--
作者：
McCarthy MM;Wright CL
自闭症谱系障碍发病率的男性偏见是所有神经精神障碍中最极端的，但性别差异的起源仍然不清楚。发育中的男性暴露于高水平的睾丸激素及其副产品雌二醇。这些类固醇一起通过改变神经发生、细胞死亡、迁移、分化、树突和轴突生长、突触发生和突触修剪来改变大脑发育的过程，所有这些都可以在发育性神经精神障碍的过程中受到不利影响。阐明类固醇调节大脑发育的细胞机制为这些过程如何出错提供了有价值的见解。一个新出现的主题是炎症信号分子和先天免疫系统在引导大脑雄性化中的作用，我们在这里回顾了这些证据。同样，有证据表明，自闭症谱系障碍患者的神经免疫系统被过度激活。这些综合观察使我们提出，大脑男性化的自然过程使男性处于危险之中，因为他们更接近脆弱的阈值，在大脑发育的关键时期，炎症更容易突破这个阈值。两个大脑区域被突出显示，视前区和小脑。两者都是由炎症性前列腺素PGE2调节的，但方式非常不同。小胶质细胞、大脑的先天免疫细胞和星形胶质细胞也是男性化的关键因素，并说明了非神经元细胞对发育中大脑健康的重要性。
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.