A transient placental source of serotonin for the fetal forebrain

Bonnin, Alexandre
Goeden, Nick
Chen, Kevin
Wilson, Melissa L.
King, Jennifer
Shih, Jean C.
Blakely, Randy D.
Deneris, Evan S.
Levitt, Pat

¹Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, California 90089, USA
²Department of Cell & Neurobiology, Keck School of Medicine of USC, Los Angeles, California 90089, USA
³Department of Pharmacology & Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles, California 90089, USA
⁴Departments of OB/GYN & Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California 90089, USA
⁵Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37221, USA
⁶Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37221, USA
⁷Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA

Received 24 August 2010; accepted 24 February 2011.

Published online 20 April 2011.

Acknowledgements 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.).

Nature 472(7343):p 347-350, April 21, 2011. | DOI: 10.1038/nature09972

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 pregnancybut this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we usedPet1^−/−(also called Fev) mice in which most dorsal raphe neurons lack 5-HT. 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 biologyex vivoand 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.