Gumusoglu Serena Banu, Hing Benjamin Wen Qing, Chilukuri Akanksha Sri Satya, Dewitt Jessica Jolynn, Scroggins Sabrina Marie, Stevens Hanna Elizabeth
Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA, USA.
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
Neuropsychopharmacology. 2020 May;45(6):1008-1017. doi: 10.1038/s41386-020-0640-0. Epub 2020 Feb 19.
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.
孕期慢性炎症（如先兆子痫、糖尿病）与后代患神经发育障碍（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期炎症模型经过测试，尚不清楚哪些可通过母体干预来靶向的此类暴露介质。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期疾病有关的促炎细胞因子。为了测试母体慢性IL-17对后代的影响，在整个孕期持续给C57BL/6J母鼠注射IL-17A。对后代进行体重、皮质体积、基因表达和细胞组成以及成年行为的评估。IL-17A处理的后代在胚胎第18天（E18）和成年时，躯体和皮质大小均减小。E18皮质的mRNA测序显示，雄性中有320个差异表达基因，而雌性中没有。这些基因在ASD（西蒙斯基金会自闭症研究倡议）、突触和细胞周期基因中显著富集。到成年时，新皮质神经胶质细胞密度和基因表达降低，而雄性中GABA能突触基因表达增加。此外，IL-17A处理的雄性而非雌性后代表现出焦虑样行为减少。雄性的社交接近缺陷与新皮质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且持续地引起ASD样表型。这与ASD中的男性偏向、皮质发育改变和行为学发现相呼应，表明母体慢性IL-17促成了后代ASD的发病机制。此外，从胚胎期突触和细胞周期基因失调到成年神经胶质细胞、抑制性突触和行为紊乱的轨迹，提示了母体慢性IL-17对后代产生影响的一种机制。
