A transient placental source of serotonin for the fetal forebrain

Abstract

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 pregnancy1,2, 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-HT3. 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.

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

“…Using HPLC, we measured forebrain, hindbrain, and placenta tissue levels of 5-HT at embryonic day E14.5, when the placenta predominantly supplies 5-HT to the fetal forebrain (Bonnin et al, 2011). Forebrain 5-HT levels were significantly decreased in SERT Ala56 embryos from SERT Ala56 dams compared with wild-type embryos from wild-type dams (t = 2.32, p = 0.029; Figure 1a); whereas hindbrain levels were not different (t = 0.077, p = 0.94; Figure 1b).…”

“…The impact of maternal SERT genotype on forebrain 5-HT levels is surprising because previous work found that 5-HT does not cross the maternal-fetal barrier (Robson and Senior, 1964), and its synthesis in the placenta is dependent upon embryo genotype (Bonnin et al, 2011). The observed developmental trajectory of forebrain 5-HT, however, suggests that altered maternal 5-HT homeostasis impacts the placenta.…”

“…The observed developmental trajectory of forebrain 5-HT, however, suggests that altered maternal 5-HT homeostasis impacts the placenta. At E14.5, during a developmental time period when the placenta provides the main source of forebrain 5-HT (Bonnin et al, 2011), 5-HT levels were specifically decreased in the forebrain of embryos from Ala56 dams. Furthermore, E14.5 placentas from Ala56 dams also showed parallel decreases in 5-HT, suggesting altered placental 5-HT synthesis, handling, or release caused reduced forebrain 5-HT levels.…”

“…Tryptophan Hydroxylase (TPH) Activity Assay TPH activity was assayed from in vitro placenta preparations as previously described (Bonnin et al, 2011) with slight modifications. Frozen placental tissue was homogenized in 350 μl of extraction buffer containing 0.05 M Tris-HCL buffer pH 7.5, 1 mM EGTA, and 1 mM DTT.…”

“…Several key proteins in the 5-HT system are transiently expressed in the developing forebrain before the arrival of 5-HT projections from the midbrain raphe nuclei (Bonnin et al, 2006;Gaspar et al, 2003), suggesting that exogenous sources of 5-HT have a role in development. Notably, the placenta synthesizes and delivers 5-HT to the fetal forebrain (Bonnin et al, 2011). Although disruptions in this placental 5-HT synthetic pathway appear poised to impact fetal neurodevelopment, this possibility has yet to be examined in genetic animal models of ASD.…”