This repository contains source code for analysis of snRNA sequening data for the paper "Maternal-Fetal Immune Conflict in a Mouse Model of Neurodevelopmental Disorders."

Abstract:

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and cognitive impairments that arises through a combination of genetic and environmental risk factors. One environmental risk factor is maternal immune activation (MIA), wherein pathogenic infections in pregnant individuals increase the risk of ASD in the offspring by three times. ASD is more prevalent in males than in females, and mounting evidence suggests that males are more likely to exhibit poor neurodevelopmental outcomes following MIA. However, the reasons that males exhibit this heightened sensitivity to MIA, and the inflammatory pathways through which MIA leads to lifelong impairments in brain function in vulnerable males, remain largely mysterious. Here, we harness a mouse model of MIA-driven neurodevelopmental disorders to uncover changes in fetal health that occur within twenty-four hours of exposure of the pregnant dam the viral mimetic poly(I:C). We identify a vulnerable subset of 25% of embryos that exhibit large-scale teratogenic abnormalities—including decreased fetal weight, craniofacial malformations, a lack of external sensory organ development, and vascular hemorrhaging—while 75% of embryos maintain a normal developmental trajectory. Strikingly, these developmental abnormalities only occurred in a subset of males. Single-nucleus transcriptomics revealed the robust induction of antigenic, pro-inflammatory responses across numerous cell types within the placentas of males exhibiting deficits following MIA, especially within fetally derived spongiotrophoblasts, the cells that form the border between the maternal and fetal compartments of the placenta. In parallel with MIA increasing the expression of genes involved in antigen presentation within this cell class, spongiotrophoblasts simultaneously downregulated extracellular matrix and hormone biosynthesis pathways, leading to a breakdown in the structural integrity of the placenta only in male embryos that exhibited developmental abnormalities following MIA. This loss of placental integrity increased the levels of maternally derived innate and adaptive immune cells, including T cells, and pro-inflammatory cytokines within the amniotic fluid of MIA-exposed male embryos that exhibited developmental abnormalities. At the mechanistic level, we show that one of these maternally derived cytokines, IL-6, is necessary for the MIA-evoked abnormalities in male fetal development. Our data reveal that MIA induces a transition from an immunosuppressive placental and amniotic microenvironment toward a pro-inflammatory, antigenic state only at the maternal-fetal interfaces of a subset of male embryos, leading to developmental deficits that are restricted to this vulnerable cohort. These data provide experimental support for the hypothesis that some males may be more likely to acquire ASD downstream of MIA because they express paternally derived antigens that, when coupled with a loss of placental immunosuppression due to maternal infection, derails embryonic development selectively in males.