Elsevier

Neuroscience

Volume 197, 1 December 2011, Pages 1-7
Neuroscience

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

https://doi.org/10.1016/j.neuroscience.2011.10.005Get rights and content

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.

Highlights

▶Serotonin signaling affects fetal brain development. ▶During an early phase of pregnancy, the placenta provides serotonin to the fetal brain. ▶Placenta-derived serotonin may be important for normal fetal brain development. ▶Results suggest new maternal–fetal–placental contributions to the fetal programming of adult mental disorders.

Section snippets

Role of 5-HT in fetal forebrain wiring

Anatomical studies have shown the early appearance of serotonergic neurons in the developing hindbrain and suggested a role for 5-HT in fetal brain development (Lidov and Molliver, 1982, Aitken and Törk, 1988, Buznikov et al., 2001). These neurons differentiate in the fetal dorsal raphe (DR) as early as embryonic day (E) 10.5 in the mouse and send axons through the ventral forebrain via the medial forebrain bundle; by E14.5 some 5-HT axons are already reaching rostral regions, including the

Sources of 5-HT in the fetal forebrain

Over the past 40 years, the field has embraced the concept that there are both fetal and maternal contributions of 5-HT during pregnancy. Serotonergic neurons appear early in the fetal hindbrain and could provide an endogenous source of 5-HT. Sources of 5-HT other than the fetal brain was assumed because of the observations that 5-HT receptors expression in the rostral forebrain, craniofacial, and peripheral regions is evident several days before serotonergic axons even reach these regions (

Conclusion

The results summarized here provide a mechanism through which alterations of tryptophan metabolic pathways in the placenta can affect placental 5-HT synthesis and fetal forebrain development. We showed that there is a progressive switch from an early dependence on an exogenous (placental) source of 5-HT to a later endogenous brain source. The placental source of 5-HT is provided to the forebrain during developmental periods that include cortical neurogenesis, migration, and initial axon

Acknowledgments

We thank Nick Goeden for technical help. This work was supported by the NICHD (grant 5R21HD065287 to A.B.), NARSAD (to A.B.) and the NIMH (grant 1P50MH078280A1 to P.L.).

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