Maternal infections in humans increase the risk for autism in the offspring. In rodents, maternal infections cause behavioral, histological, and transcriptional changes in adult offspring that are consistent with those seen in autism. However, the anatomical and molecular pathways through which inflammation alters fetal brain development are not well understood.

The goal of this project is to characterize the impact of inflammation during pregnancy on placental tryptophan metabolic pathways and the consequences on fetal brain development. In the prenatal period, maternal-fetal interactions are critically important for the establishment of initial fetal brain structures and circuitry. Disruption of these interactions may increase risk for neuropsychiatric disorders in the offspring, including autism. Serotonin, which is synthesized from the essential amino acid tryptophan, is a trophic factor for the fetal brain before it acts as a neurotransmitter. In particular, serotonin signaling modulates fetal brain wiring mechanisms, and its disruption at early stages of pre- and postnatal development has long-term consequences on adult brain function and behavior. Thus, serotonin is thought to be a critical mediator of the fetal programming of mental disorders that appear later in life. We recently discovered that during early pregnancy the placenta converts maternal tryptophan to serotonin, through the TPH1 pathway, thereby providing a source of the amine for the fetal brain. Therefore, altering maternal tryptophan metabolism in the placenta, and consequently placental serotonin synthesis, may affect fetal brain development and constitute a new molecular pathway for the fetal programming of mental disorders.

During maternal infections, protection of the fetus from maternal immunity requires metabolism of maternal tryptophan by placental indoleamine deoxygenase (IDO), leading to kynurenine production. Thus, in early gestation simultaneous alternative pathways for maternal tryptophan metabolism in the placenta provide not only a critical immune protection for the fetus, but also a source of trophic support (serotonin) for the fetal brain. We propose to test the hypothesis that inflammation compromises serotonergic modulation of fetal brain development by affecting the simultaneous metabolism of maternal tryptophan through IDO and TPH1 pathways within the placenta. The proposed aims rely on a new technology, the ex vivo perfusion of live mouse placentas, that can be applied to understanding the molecular underpinnings of maternal-fetal relationships at different times of gestation. Through unique collaborations planned in this grant application, the proposed aims will advance our understanding of the impact of inflammation on maternal-fetal interactions and consequences on the development of serotonin-relevant and other fetal brain circuits that have been implicated in autism.