Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

中文翻译：

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胎儿脑转录组的母体免疫激活失调与自闭症谱系障碍的病理生理学相关。

众所周知，怀孕期间通过感染激活母体免疫 (MIA) 会增加患自闭症谱系障碍 (ASD) 的风险。然而，目前尚不清楚 MIA 如何以可能解释这种风险增加的方式破坏胎儿大脑基因表达。在这里，我们研究了 MIA 如何以与 ASD 相关的病理生理学相关的方式失调大鼠胎儿脑基因表达（在类似于人类妊娠前三个月结束的时间点）。MIA 下调 ASD 相关基因的表达，其中最大的富集是已知具有罕见的高度外显突变的基因。MIA 还下调许多基因的表达，这些基因也已知在生命后期在 ASD 皮层中持续下调，这些基因在影响突触的产前晚期发育过程中的作用众所周知。作为高度 ASD 渗透性 FMR1 和 CHD8 基因下游靶标的转录和翻译程序也受到 MIA 的严重影响。MIA 强烈上调大量参与翻译起始、细胞周期、DNA 损伤和影响多种关键神经发育功能的蛋白水解过程的基因的表达。翻译起始的上调在 ASD 皮质转录组的基因网络结构中是常见的，并且在整个生命周期中都被保留，并且对细胞周期过程具有下游影响。帽依赖性翻译起始基因 EIF4E 是所有 ASD 相关基因中 MIA 失调最严重的基因之一，靶向网络分析表明 MIA 诱导的 mTOR 转录失调和 EIF4E 依赖性信号传导显着。这种通过改变 Tsc2-mTor-Eif4e 轴引起的翻译起始失调在 MIA 啮齿动物模型中得到了进一步验证。MIA 可能通过失调与影响 ASD 的病理生理学高度相关的胎儿脑基因表达的关键方面来增加患 ASD 的风险。