A transient placental source of serotonin for the fetal forebrain

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Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. Dogma states that beyond fetal 5-HT neurons, there are significant maternal contributions to fetal 5-HT during pregnancy ^{1,
2}, but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used the Pet-1 ^−/− mice in which most dorsal raphe (DR) neurons lack 5-HT ³. Measures of 5-HT revealed previously unknown differences in accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. We show that this source 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 and 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 implicates novel maternal-placental-fetal interactions that could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.

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Most cited references 27

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The developmental role of serotonin: news from mouse molecular genetics.

Patricia Gaspar, Olivier Cases, Luc Maroteaux (2004)

New genetic models that target the serotonin system show that transient alterations in serotonin homeostasis cause permanent changes to adult behaviour and modify the fine wiring of brain connections. These findings have revived a long-standing interest in the developmental role of serotonin. Molecular genetic approaches are now showing us that different serotonin receptors, acting at different developmental stages, modulate different developmental processes such as neurogenesis, apoptosis, axon branching and dendritogenesis. Our understanding of the specification of the serotonergic phenotype is improving. In addition, studies have revealed that serotonergic traits are dissociable, as there are populations of neurons that contain serotonin but do not synthesize it.

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Serotonin Regulates Pancreatic β-Cell Mass during Pregnancy

Hail Kim, Yukiko Toyofuku, Francis Lynn … (2010)

During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing β-cells1–3. However, the exact mechanisms by which the lactogenic hormones drive β-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive β-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in β-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked β-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking β-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes4.

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Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.

Mark S. Ansorge, Mingming Zhou, Alena Lira … (2004)

Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 30 March 2011

Publication date (Print): 21 April 2011

Publication date PMC-release: 21 October 2011

Volume: 472

Issue: 7343

Pages: 347-350

Affiliations

[1 ] Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA, 90089, USA

[2 ] Department of Cell & Neurobiology, Keck School of Medicine of USC, Los Angeles, CA, 90089, USA

[3 ] Department of Pharmacology & Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles, CA 90089, USA

[4 ] Departments of OB/GYN & Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA 90089, USA

[5 ] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37221, USA

[6 ] Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37221, USA

[7 ] Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, OH, USA

Author notes

Correspondence and requests for materials should be addressed to A.B. ( bonnin@ 123456usc.edu ) or P.L. ( plevitt@ 123456usc.edu )

Article

Manuscript ID: nihpa276130

DOI: 10.1038/nature09972

PMC ID: 3084180

PubMed ID: 21512572

SO-VID: 04b101bb-5aec-4270-8eb3-029c96aa5b18

License:

Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

History

Funding

Funded by: National Institute of Child Health & Human Development : NICHD

Award ID: R21 HD065287-02 || HD

Funded by: National Institute of Child Health & Human Development : NICHD

Award ID: R21 HD065287-01 || HD