Chronic inflammation during pregnancy (e.g., preeclampsia, diabetes) is linked to increased risk for offspring neurodevelopmental disorders such as autism spectrum disorder (ASD). However, mediators of such exposures that could be targeted with maternal intervention are unclear, as few chronic gestational inflammation models have been tested. One potential mediator is interleukin-17 (IL-17), a pro-inflammatory cytokine implicated in neurodevelopmental disorders and gestational disease. To test chronic maternal IL-17 impacts on offspring, C57BL/6J dams were administered IL-17A continuously throughout pregnancy. Offspring were assessed for body weight; cortical volume, gene expression, and cellular composition; and adult behavior. IL-17A-condition offspring exhibited decreased somatic and cortical size at embryonic day 18 (E18) and as adults. mRNA sequencing of E18 cortex revealed 320 differentially expressed genes in males, but none in females. These were significantly enriched for ASD (Simons Foundation Autism Research Initiative), synaptic, and cell cycle genes. By adulthood, neocortical glial cell density and gene expression were decreased, while GABAergic synaptic gene expression was increased in males. Furthermore, IL-17A-condition male but not female offspring exhibited reduced anxiety-like behavior. Social approach deficits in males were negatively correlated with neocortical GABAergic synaptic gene expression. Chronic gestational IL-17A was sufficient to cause ASD-like phenotypes early and persistently in male offspring. This echoes the male bias, altered cortical development, and behavioral findings in ASD, suggesting that chronic maternal IL-17 contributes to offspring ASD pathogenesis. Furthermore, the trajectory from embryonically dysregulated synaptic and cell cycle genes to disrupted adult glia, inhibitory synapses, and behavior suggests a mechanism for chronic maternal IL-17 effects on offspring.

中文翻译：

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慢性母体白细胞介素 17 和自闭症相关的皮层基因表达、神经生物学和行为。

怀孕期间的慢性炎症（例如先兆子痫、糖尿病）与后代神经发育障碍（例如自闭症谱系障碍 (ASD)）的风险增加有关。然而，由于很少有慢性妊娠炎症模型经过测试，母体干预可能针对的此类暴露的介质尚不清楚。一种潜在的介质是白细胞介素 17 (IL-17)，一种与神经发育障碍和妊娠疾病有关的促炎细胞因子。为了测试慢性母体 IL-17 对后代的影响，C57BL/6J 水坝在整个怀孕期间连续施用 IL-17A。评估后代的体重；皮质体积、基因表达和细胞组成；和成人行为。IL-17A 条件后代在胚胎第 18 天 (E18) 和成年时表现出体细胞和皮质尺寸减小。E18 皮质的 mRNA 测序揭示了 320 个差异表达的基因在男性中，但在女性中没有。这些基因显着丰富了 ASD（西蒙斯基金会自闭症研究计划）、突触和细胞周期基因。到成年期，新皮质神经胶质细胞密度和基因表达降低，而男性的 GABAergic 突触基因表达增加。此外，IL-17A 条件雄性而非雌性后代表现出减少的焦虑样行为。男性的社交方法缺陷与新皮质 GABA 能突触基因表达呈负相关。慢性妊娠期 IL-17A 足以在雄性后代中早期和持续地引起 ASD 样表型。这与 ASD 中的男性偏见、皮质发育改变和行为发现相呼应，表明慢性母体 IL-17 有助于后代 ASD 发病机制。此外，从胚胎失调的突触和细胞周期基因到破坏的成人神经胶质、抑制性突触和行为的轨迹表明了慢性母体 IL-17 对后代影响的机制。