Altered Placental Tryptophan Metabolism: A Crucial Molecular Pathway for the Fetal Programming of Neurodevelopmental Disorders

Abstract : Maternal infections in humans increase the risk for autism spectrum disorders (ASD) in the offspring. In rodents, maternal infections cause behavioral, histological and transcriptional changes in adult offspring that are consistent with those seen in ASD. However, the anatomical and molecular pathways through which inflammation alters fetal brain development are not well understood. Serotonin (5-HT), which is synthesized from the essential amino acid tryptophan (TRP), is a trophic factor for the fetal brain before it acts as a neurotransmitter. In particular, 5-HT 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, 5-HT is thought to be a critical mediator of the fetal programming of mental disorders such as ASD that appear later in life. In early pregnancy the placenta converts maternal TRP to 5-HT, through the tryptophan hydroxylase 1 (TPH1) pathway, thereby providing a source of the amine for the fetal brain. Therefore altering maternal TRP metabolism in the placenta, and consequently placental 5-HT synthesis, may directly affect fetal brain development and constitute a new molecular pathway for the fetal programming of mental disorders. The goal of this project is to characterize the impact of inflammation during pregnancy on placental TRP metabolic pathways and the consequences on fetal brain development