Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain

Abstract

In addition to its role in neurotransmission, embryonic serotonin (5-HT) has been implicated in the regulation of neurodevelopmental processes. For example, we recently showed that a subset of 5-HT1-receptors expressed in the fetal forebrain mediate a serotonergic modulation of thalamocortical axons response to axon guidance cues, both in vitro and in vivo. This influence of 5-HT signaling on fetal brain wiring raised important questions regarding the source of the ligand during pregnancy. Until recently, it was thought that 5-HT sources impacting brain development arose from maternal transport to the fetus, or from raphe neurons in the brainstem of the fetus. Using genetic mouse models, we uncovered previously unknown differences in 5-HT accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. 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. These results implicate a new, direct role for placental metabolic pathways in modulating fetal brain development and suggest an important role for maternal-placental-fetal interactions and 5-HT in the fetal programming of adult mental disorders.

Figure 1

Developmental disruptions of 5-HT signaling in utero can lead to abnormal brain function at adult stages. Altering 5-HT signaling in vivo by in utero electroporation of 5-HT1B/1D receptors siRNAs or over-expression plasmids in the dorsal thalamus (DT) affects the formation of the thalamocortical axon (TCA) pathway in the fetal brain. Results suggest that this 5-HT-mediated disruption of fetal brain wiring mechanisms could contribute to long-term alteration of brain function. Abnormal 5-HT signaling in the fetal brain could result from altered function or expression of 5-HT receptors, as described in the text, or from altered availability of the ligand itself, 5-HT. Hyp, hypothalamus; ctx, cortex; ic, internal capsule.

Figure 2

New model of placental contributions to the fetal brain and blood 5-HT. A, the source of 5-HT in the embryonic forebrain changes over time, from an early exogenous (placental) source to a later endogenous (dorsal raphe serotonergic neurons) source. This switch during development allows the embryo brain to progressively become dependent on its own production of 5-HT. DR, dorsal raphe; DT, dorsal thalamus; ctx, cortex. B, The placenta synthesizes 5-HT and 5-HTP from maternal blood tryptophan. This placental 5-HT (red color) is a source of 5-HT to the forebrain during an early phase of development (E10 to E15). Later (E16 to birth), the main source of 5-HT is provided by conversion of maternal tryptophan in hindbrain DR neurons and their axons throughout the forebrain.