Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A transient placental source of serotonin for the fetal forebrain

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Comparison of fetal 5-HT concentrations in the hindbrain and forebrain of Pet1 −/− and wild type embryos from E10.5 to E17.5.
Figure 2: Placental synthesis of 5-HT in vitro and ex vivo.
Figure 3: HPLC measures of 5-HT concentrations in E14.5 hindbrain, forebrain and placenta of in utero PCPA-injected mice.

Similar content being viewed by others

References

  1. Cote, F. et al. Maternal serotonin is crucial for murine embryonic development. Proc. Natl Acad. Sci. USA 104, 329–334 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Yavarone, M. S., Shuey, D. L., Sadler, T. W. & Lauder, J. M. Serotonin uptake in the ectoplacental cone and placenta of the mouse. Placenta 14, 149–161 (1993)

    Article  CAS  PubMed  Google Scholar 

  3. Hendricks, T. J. et al. Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron 37, 233–247 (2003)

    Article  CAS  PubMed  Google Scholar 

  4. Bonnin, A., Torii, M., Wang, L., Rakic, P. & Levitt, P. Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nature Neurosci. 10, 588–597 (2007)

    Article  CAS  PubMed  Google Scholar 

  5. Ansorge, M. S., Zhou, M., Lira, A., Hen, R. & Gingrich, J. A. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306, 879–881 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Gross, C. et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Taylor, S. E. et al. Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology. Biol. Psychiatry 60, 671–676 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. Bonnin, A., Peng, W., Hewlett, W. & Levitt, P. Expression mapping of 5–HT1 serotonin receptor subtypes during fetal and early postnatal mouse forebrain development. Neuroscience 141, 781–794 (2006)

    Article  CAS  PubMed  Google Scholar 

  9. Anderson, G. M. et al. Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia. Mol. Psychiatry 7, 831–836 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Gaspar, P., Cases, O. & Maroteaux, L. The developmental role of serotonin: news from mouse molecular genetics. Nature Rev. Neurosci. 4, 1002–1012 (2003)

    Article  CAS  Google Scholar 

  11. Buznikov, G. A., Lambert, H. W. & Lauder, J. M. Serotonin and serotonin-like substances as regulators of early embryogenesis and morphogenesis. Cell Tissue Res. 305, 177–186 (2001)

    Article  CAS  PubMed  Google Scholar 

  12. Aitken, A. R. & Tork, I. Early development of serotonin-containing neurons and pathways as seen in wholemount preparations of the fetal rat brain. J. Comp. Neurol. 274, 32–47 (1988)

    Article  CAS  PubMed  Google Scholar 

  13. Lidov, H. G. & Molliver, M. E. Immunohistochemical study of the development of serotonergic neurons in the rat CNS. Brain Res. Bull. 9, 559–604 (1982)

    Article  CAS  PubMed  Google Scholar 

  14. Lebrand, C. et al. Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17, 823–835 (1996)

    Article  CAS  PubMed  Google Scholar 

  15. Lebrand, C. et al. Transient developmental expression of monoamine transporters in the rodent forebrain. J. Comp. Neurol. 401, 506–524 (1998)

    Article  CAS  PubMed  Google Scholar 

  16. Scott, A. L., Bortolato, M., Chen, K. & Shih, J. C. Novel monoamine oxidase A knock out mice with human-like spontaneous mutation. Neuroreport 19, 739–743 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lynn-Bullock, C. P., Welshhans, K., Pallas, S. L. & Katz, P. S. The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats. J. Chem. Neuroanat. 27, 129–138 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Branchek, T. A. & Gershon, M. D. Time course of expression of neuropeptide Y, calcitonin gene-related peptide, and NADPH diaphorase activity in neurons of the developing murine bowel and the appearance of 5-hydroxytryptamine in mucosal enterochromaffin cells. J. Comp. Neurol. 285, 262–273 (1989)

    Article  CAS  PubMed  Google Scholar 

  19. Chen, J. J. et al. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: Abnormal intestinal motility and the expression of cation transporters. J. Neurosci. 21, 6348–6361 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Howd, R. A., Nelson, M. F. & Lytle, L. D. L-tryptophan and rat fetal brain serotonin. Life Sci. 17, 803–811 (1975)

    Article  CAS  PubMed  Google Scholar 

  21. Balkovetz, D. F., Tiruppathi, C., Leibach, F. H., Mahesh, V. B. & Ganapathy, V. Evidence for an imipramine-sensitive serotonin transporter in human placental brush-border membranes. J. Biol. Chem. 264, 2195–2198 (1989)

    CAS  PubMed  Google Scholar 

  22. Robson, J. M. & Senior, J. B. The 5-hydroxytryptamine content of the placenta and foetus during pregnancy in mice. Br. J. Pharmacol. Chemother. 22, 380–391 (1964)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim, H. et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nature Med. 16, 804–808 (2010)

    Article  CAS  PubMed  Google Scholar 

  24. Jawerbaum, A. & White, V. Animal models in diabetes and pregnancy. Endocr. Rev. 31, 680–701 (2010)

    Article  PubMed  Google Scholar 

  25. Suzuki, S. et al. Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti. Biochem. J. 355, 425–429 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kanai, M. et al. Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol. Brain 2 8 10.1186/1756-6606-2-8 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Miller, C. L. et al. Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder. Schizophr. Res. 113, 259–267 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nabi, R., Serajee, F. J., Chugani, D. C., Zhong, H. & Huq, A. H. Association of tryptophan 2,3 dioxygenase gene polymorphism with autism. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 125B, 63–68 (2004)

    Article  PubMed  Google Scholar 

  29. Brown, A. S. & Derkits, E. J. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am. J. Psychiatry 167, 261–280 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  30. Oberlander, T. F., Gingrich, J. A. & Ansorge, M. S. Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence. Clin. Pharmacol. Ther. 86, 672–677 (2009)

    Article  CAS  PubMed  Google Scholar 

  31. Johansen, P. A., Jennings, I., Cotton, R. G. & Kuhn, D. M. Tryptophan hydroxylase is phosphorylated by protein kinase A. J. Neurochem. 65, 882–888 (1995)

    Article  CAS  PubMed  Google Scholar 

  32. Kuhn, D. M., Ruskin, B. & Lovenberg, W. Tryptophan hydroxylase. The role of oxygen, iron, and sulfhydryl groups as determinants of stability and catalytic activity. J. Biol. Chem. 255, 4137–4143 (1980)

    CAS  PubMed  Google Scholar 

  33. Chen, K. et al. Forebrain-specific expression of monoamine oxidase A reduces neurotransmitter levels, restores the brain structure, and rescues aggressive behavior in monoamine oxidase A-deficient mice. J. Biol. Chem. 282, 115–123 (2007)

    Article  CAS  PubMed  Google Scholar 

  34. Nagai, A., Takebe, K., Nio-Kobayashi, J., Takahashi-Iwanaga, H. & Iwanaga, T. Cellular expression of the monocarboxylate transporter (MCT) family in the placenta of mice. Placenta 31, 126–133 (2010)

    Article  CAS  PubMed  Google Scholar 

  35. Koe, B. K. & Weissman, A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J. Pharmacol. Exp. Ther. 154, 499–516 (1966)

    CAS  PubMed  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Contributions

A.B. conducted the experiments with assistance from N.G. in placenta studies, K.C. and J.C.S. in providing mutant mouse strains and in MAOA enzymatic assays. R.D.B. and E.S.D. provided mutant mouse strains and M.L.W. and J.K. provided human tissue. A.B. and P.L. conceived this study, interpreted the data and wrote the manuscript. All authors commented on the paper.

Corresponding authors

Correspondence to Alexandre Bonnin or Pat Levitt.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-2, a Supplementary Discussion with additional references and Supplementary Figures 1-5 with legends. (PDF 2230 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09972

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing