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

Several important milestones were reached during the second year of this award. First, we were able to demonstrate that maternal inflammation during pregnancy, triggered by the viralmimic poly(I:C), induces a significant increase of tryptophan metabolism in the placenta. This leads to a direct increased output of serotonin from the placenta to the fetal forebrain. Elevation of serotonin at these early stages of fetal brain development alters the development of the serotonergic system (blunting of axonal growth) and neuronal progenitor cell proliferation in specific forebrain regions. Thus our results demonstrate a direct molecular link between placental tryptophan metabolism and fetal brain development. A manuscript reporting these findings was submitted to the Journal of Neuroscience and is currently under review. In the second year of this award, we also started to investigate the possibility of pharmacologically interfering with this molecular pathway in order to potentially protect the fetal brain from the effects of maternal inflammation. Prepared in collaboration with Zilkha Neurogenetic Institute, Keck School of Medicine of California. The original document contains color images.