A transient placental source of serotonin for the fetal forebrain

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Abstract
Although it is widely assumed that a maternal contribution to fetal serotonin (5-hydroxytryptamine or 5-HT) levels during pregnancy is important in neurodevelopment, there is little direct experimental evidence to support the idea. Bonnin et al. use new techniques to determine that during early pregnancy the placenta is a significant source of 5-HT, made from maternal tryptophan precursors in both mice and humans. Later in pregnancy, an endogenous 5-HT source in the fetus takes over. Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal–fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy1,2 but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1−/− (also called Fev) mice in which most dorsal raphe neurons lack 5-HT3. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal–placental–fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.