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.
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We thank H.H. Wu and K. Eagleson for discussions and comments on the manuscript. We thank R. Johnson (Vanderbilt HPLC core facility), L. Zhang for technical help and E. Meng for discussions. This work was supported by the NICHD (grant 5R21HD065287 to A.B.), NARSAD (A.B.) and the NIMH (grant R01MH39085 to J.C.S. and 1P50MH078280A1 to R.D.B. and P.L.).
The authors declare no competing financial interests.
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Bonnin, A., Goeden, N., Chen, K. et al. A transient placental source of serotonin for the fetal forebrain. Nature 472, 347–350 (2011). https://doi.org/10.1038/nature09972
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