A transient placental source of serotonin for the fetal forebrain

Serotonin (5-hydroxytryptamine; 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. Dogma states that beyond fetal 5-HT neurons, there are significant maternal contributions to fetal 5-HT during pregnancy(1,2), but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used the Pet-1(−/−) mice in which most dorsal raphe (DR) neurons lack 5-HT(3). Measures of 5-HT revealed previously unknown differences in accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. We show that this source 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 and 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 implicates novel maternal-placental-fetal interactions that could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.