Inflammation during pregnancy can disturb brain development and lead to disorders in the progeny, including autism spectrum disorders and schizophrenia. However, the mechanism by which a prenatal, short-lived increase of cytokines results in adverse neurodevelopmental outcomes remains largely unknown. Microglia—the brain’s resident immune-cells—stand as fundamental cellular mediators, being highly sensitive and responsive to immune signals, which also play key roles during normal development.

The fractalkine signaling axis is a neuron-microglia communication mechanism used to regulate neurogenesis and network formation. Previously, we showed hippocampal reduction of fractalkine receptor (Cx3cr1) mRNA at prenatal day (P) 15 in male offspring exposed to maternal immune activation induced with lipopolysaccharide (LPS) during late gestation, which was concomitant to an increased dendritic spine density in the dentate gyrus, a neurogenic niche. The current study sought to evaluate the origin and impact of this reduced hippocampal Cx3cr1 mRNA expression on microglia and cognition. We found that microglial total cell number and density are not affected in the dorsal hippocampus and dentate gyrus, respectively, but that the microglial CX3CR1 protein is decreased in the hippocampus of LPS-male offspring at P15. Further characterization of microglial morphology in the dentate gyrus identified a more ameboid phenotype in LPS-exposed offspring, predominantly in males, at P15. We thus explored maternal plasma and fetal brain cytokines to understand the mechanism behind microglial priming, showing a robust immune activation in the mother at 2 and 4 hrs after LPS administration, while only IL-10 tended towards upregulation at 2 hrs after LPS in fetal brains. To evaluate the functional long-term consequences, we assessed learning and cognitive flexibility behavior during late adolescence, finding that LPS affects only the latter with a male predominance on perseveration. A CX3CR1 gene variant in humans that results in disrupted fractalkine signaling has been recently associated with an increased risk for neurodevelopmental disorders. We show that an acute immune insult during late gestation can alter fractalkine signaling by reducing the microglial CX3CR1 protein expression, highlighting neuron-microglial fractalkine signaling as a relevant target underlying the outcomes of environmental risk factors on neurodevelopmental disorders.

怀孕期间的炎症会干扰大脑发育并导致后代出现疾病，包括自闭症谱系障碍和精神分裂症。然而，产前细胞因子的短期增加导致不良神经发育结果的机制仍然很大程度上未知。小胶质细胞——大脑的常驻免疫细胞——是基本的细胞介质，对免疫信号高度敏感和敏感，在正常发育过程中也起着关键作用。

fractalkine 信号轴是一种神经元-小胶质细胞通讯机制，用于调节神经发生和网络形成。以前，我们在妊娠晚期暴露于脂多糖 (LPS) 诱导的母体免疫激活的雄性后代中，在产前第 15 天 (P)显示海马的 fractalkine 受体 ( Cx3cr1) mRNA 减少，这伴随着齿状体中树突棘密度的增加脑回，一个神经源性生态位。目前的研究试图评估这种减少的海马Cx3cr1的起源和影响小胶质细胞和认知上的 mRNA 表达。我们发现背侧海马和齿状回的小胶质细胞总数和密度分别不受影响，但在 P15 时，LPS 雄性后代海马中的小胶质细胞 CX3CR1 蛋白减少。齿状回中小胶质细胞形态的进一步表征确定了在 P15 暴露于 LPS 的后代（主要是雄性）中更多的变形虫表型。因此，我们探索了母体血浆和胎儿脑细胞因子以了解小胶质细胞启动背后的机制，显示在 LPS 给药后 2 小时和 4 小时，母亲体内的免疫激活很强，而在胎儿脑中 LPS 后 2 小时，只有 IL-10 趋于上调. 为了评估功能性长期后果，我们评估了青春期后期的学习和认知灵活性行为，发现 LPS 仅影响后者，男性在持久性方面占优势。一个CX3CR1基因变异在人类中导致 fractalkine 信号传导中断，最近与神经发育障碍的风险增加有关。我们表明，妊娠晚期的急性免疫损伤可以通过降低小胶质细胞 CX3CR1 蛋白的表达来改变 fractalkine 信号传导，强调神经元-小胶质细胞 fractalkine 信号传导是环境风险因素对神经发育障碍结果的相关目标。