Delineating the effects of sex on microglia in neurodevelopmental disorders

摘要 许多神经发育障碍的发病率，包括自闭症，精神分裂症和脑瘫， 男性比女性高得多。在自闭症谱系障碍（ASD）的情况下，最近的估计 表明自闭症在男性中的发病率是女性的4到5倍。男性脆弱的原因 和女性自闭症保护目前仍然知之甚少。更好地理解分子 神经发育障碍中性别偏见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， 神经发育疾病的治疗靶点。在我们的初步研究中，我们发现， 母体免疫激活（MIA）的程度影响自闭症相关行为异常的发展 以一种特定于性别的方式。更具体地说，我们证明了低水平的妊娠炎症 促进男性后代而不是女性后代自闭症相关表型的发展。与此相反， 将MIA提高到阈值以上促进神经发育障碍的女性特异性诱导， 男性后代的胎儿重吸收。有趣的是，在我们的男性偏好的神经发育疾病模型中， 我们观察到小胶质细胞通路在雄性后代中而不是雌性后代中过度活化。此外，我们发现， 在妊娠早期，小胶质细胞和其他髓样细胞的抗CSF1R敲低提供了大量的 防止MIA模型中行为异常的发展。小胶质细胞是组织驻留的 中枢神经系统（CNS）的巨噬细胞，其帮助清除碎片和病原体，并且还 已经报道参与突触修剪、轴突引导和神经发生。最近的研究 开始揭示小胶质细胞活性的性别差异，这可能有助于不同的疾病结果， 成人大脑相比之下，目前对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导致性别特异性 小胶质细胞活动的改变可能影响神经发育。对于这个探索性的项目，我们建议 两个目标是定义性别如何塑造小胶质细胞的动力学和功能（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的领域 在我们对妊娠期暴露于炎症如何改变性别中小胶质细胞反应的理解中， 这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.