Abstract
Perturbations to the in utero environment can dramatically change the trajectory of offspring neurodevelopment. Insults commonly encountered in modern human life such as infection, toxins, high-fat diet, prescription medications, and others are increasingly linked to behavioral alterations in prenatally-exposed offspring. While appreciation is expanding for the potential consequence that these triggers can have on embryo development, there is a paucity of information concerning how the crucial maternal-fetal interface (MFI) responds to these various insults and how it may relate to changes in offspring neurodevelopment. Here, we found that the MFI responds both to an inflammatory state and altered serotonergic tone in pregnant mice. Maternal immune activation (MIA) triggered an acute inflammatory response in the MFI dominated by interferon signaling that came at the expense of ordinary development-related transcriptional programs. The major MFI compartments, the decidua and the placenta, each responded in distinct manners to MIA. MFIs exposed to MIA were also found to have disrupted sex-specific gene expression and heightened serotonin levels. We found that offspring exposed to MIA had sex-biased behavioral changes and that microglia were not transcriptionally impacted. Moreover, the combination of maternal inflammation in the presence of pharmacologic inhibition of serotonin reuptake further transformed MFI physiology and offspring neurobiology, impacting immune and serotonin signaling pathways alike. In all, these findings highlight the complexities of evaluating diverse environmental impacts on placental physiology and neurodevelopment.