Delineating the effects of sex on microglia in neurodevelopmental disorders

摘要 许多神经发育障碍（包括自闭症、精神分裂症和脑瘫）的发病率 男性明显高于女性。就自闭症谱系障碍 (ASD) 而言，最近的估计 表明男性自闭症患病率是女性的 4 至 5 倍。男性脆弱的原因 目前对自闭症女性保护仍知之甚少。加深对分子的理解 神经发育障碍中性别偏见背后的细胞因素将提供重要的新见解 研究这些复杂疾病的病因，最终将有助于揭示急需的生物标志物和 神经发育疾病的治疗靶点。在我们的初步研究中，我们发现改变 母体免疫激活（MIA）的程度影响自闭症相关行为异常的发展 以特定性别的方式。更具体地说，我们证明妊娠期炎症水平较低 促进男性而非女性后代自闭症相关表型的发展。相比之下， 将 MIA 提高到阈值以上会促进女性特有的神经发育障碍的诱导 男性后代的胎儿重吸收。有趣的是，在我们偏向男性的神经发育疾病模型中， 我们观察到，雄性后代而非雌性后代的小胶质细胞通路过度活跃。此外，我们发现 妊娠早期小胶质细胞和其他骨髓细胞的抗 CSF1R 敲低提供了大量 防止 MIA 模型中出现行为异常。小胶质细胞是组织驻留的 中枢神经系统 (CNS) 的巨噬细胞有助于清除碎片和病原体，并且 据报道参与突触修剪、轴突引导和神经发生。最近的研究有 开始揭示小胶质细胞活性的性别差异，这些差异可能导致不同的疾病结果 成人的大脑。相比之下，目前对于性别如何调节小胶质细胞反应知之甚少。 神经发育障碍。鉴于我们的初步发现，我们假设 MIA 会导致性别特异性 小胶质细胞活动的改变会影响神经发育。对于这个探索性项目，我们建议 两个目标是定义性别如何影响小胶质细胞的动态和功能（目标 1）以及基因表达（目标 2） MIA 驱动的神经发育障碍模型。完成拟议的研究将开辟新天地 在我们对妊娠期炎症暴露如何改变性别中小胶质细胞反应的理解中 具体方式将为神经发育障碍的基础提供新的见解。

ABSTRACT The incidence of many neurodevelopmental disorders including autism, schizophrenia, and cerebral palsy are considerably higher in males than females. In the case of autism spectrum disorder (ASD), recent estimates indicate that autism is 4 to 5 times more prevalent in males than females. The reason(s) for male vulnerability and female protection in autism currently remain poorly understood. Improved understanding of the molecular and cellular factors that underlie sex-bias in neurodevelopmental disorders will provide important new insights into the etiologies of these complex disorders and will ultimately help to reveal much-needed biomarkers and therapeutic targets for neurodevelopmental disease. In our preliminary studies, we have found that altering the extent of maternal immune activation (MIA) influences development of autism-related behavioral abnormalities in a sex-specific manner. More specifically, we demonstrate that low levels of gestational inflammation promotes the development of autism-related phenotypes in male but not female offspring. In contrast, enhancing MIA above a threshold promotes female-specific induction of neurodevelopmental disorders and fetal reabsorption of male offspring. Interestingly, in our male-biased model of neurodevelopmental disease, we observe that microglial pathways are hyperactivated in male offspring and not females. Moreover, we find that anti-CSF1R knockdown of microglia and other myeloid cells during early gestation provides substantial protection against the development of behavioral abnormalities in the MIA model. Microglia are tissue-resident macrophages of the central nervous system (CNS) that aid in the clearance of debris and pathogens, and also have been reported to participate in synaptic pruning, axon guidance, and neurogenesis. Recent studies have begun to reveal sex-based differences in microglia activity that can contribute to distinct disease outcomes in the adult brain. In contrast, little is currently known in regard to how sex modulates microglia responses in neurodevelopmental disorders. Given our preliminary findings, we hypothesize that MIA results in sex-specific alterations in microglia activities that can affect neurodevelopment. For this exploratory project, we propose two aims to define how sex shapes microglia dynamics and function (Aim 1), and gene expression (Aim 2) in a neurodevelopmental disorder model driven by MIA. Completion of the proposed studies will break new ground in our understanding of how gestational exposure to inflammation can alter microglia responses in a sex- specific manner and will provide new insights into the underpinnings of neurodevelopmental disorders.