Elsevier

Placenta

Volume 48, Supplement 1, December 2016, Pages S66-S71
Placenta

Effects of prenatal maternal stress on serotonin and fetal development

https://doi.org/10.1016/j.placenta.2015.11.013Get rights and content

Abstract

Fetuses are exposed to many environmental perturbations that can influence their development. These factors can be easily identifiable such as drugs, chronic diseases or prenatal maternal stress. Recently, it has been demonstrated that the serotonin synthetized by the placenta was crucial for fetal brain development. Moreover, many studies show the involvement of serotonin system alteration in psychiatric disease during childhood and adulthood. This review summarizes existing studies showing that prenatal maternal stress, which induces alteration of serotonin systems (placenta and fetal brain) during a critical window of early development, could lead to alteration of fetal development and increase risks of psychiatric diseases later in life. This phenomenon, termed fetal programming, could be moderated by the sex of the fetus. This review highlights the need to better understand the modification of the maternal, placental and fetal serotonin systems induced by prenatal maternal stress in order to find early biomarkers of psychiatric disorders.

Introduction

Fetuses are exposed to many environmental factors that can influence their development especially during the very first weeks of gestation since most women do not yet know they are pregnant and so may not have modified their risk behaviors. These factors can be easily identifiable such as drugs (e.g. medication, alcohol), chronic diseases (e.g. depression) but it can also be more subjective like prenatal maternal stress (PNMS), which depends on the type, intensity and duration of stress, and the individual. Thereby, a deregulation of the early life environment can induce not only pregnancy disease (miscarriages, preeclampsia) or fetal development alteration (intrauterine growth restriction, congenital malformations) but also increase the unborn child's risk of a range of diseases including psychiatric disorders (autism, anxiety, and depression) in childhood or adulthood. This concept is termed developmental programming. One of the key components allowing adaptation of fetuses to these conditions is the placenta, and an increasing number studies show its involvement in fetal programming. Recently, it has been demonstrated that the serotonin (or 5-hydroxytryptamine, 5-HT) synthetized by the placenta is essential for fetal brain development. In this review, we highlight the critical role of serotonin, especially placental serotonin, in fetal development. Then we focus on the effect of PNMS on the placental and fetal serotonin system and on fetal brain programming. Finally, we suggest that a deregulation of the tight interaction between placental glucocorticoids and serotonin systems during in utero development could explain the increasing risk to developing psychiatric disease later in life (Fig. 1).

Section snippets

Serotonin system

The identification of serotonin in the brain in the early 1950s [1], [2] led to numerous studies showing its involvement in mental health and psychiatric diseases such as depression, attention deficit hyperactivity disorder, and schizophrenia [3]. The serotonin system is complex including at least 18 subtypes of receptors. Most of them belong to the GPCR (G protein-coupled receptor) family, except for one group, which are ionotropic receptor, the 5-HT3. The serotonin transporter (SERT or 5HTT)

Prenatal maternal stress

The principal effectors of the stress response are commonly referred to as the hypothalamic-pituitary-adrenal (HPA) axis (Fig. 2). Following a stressful event, the hypothalamus produces corticotropin-releasing hormone (CRH) which stimulates the anterior pituitary gland to produce adrenocorticotropic hormone (ACTH). ACTH induces the adrenal glands to produce cortisol, a glucocorticoid often defined as the stress hormone [42]. Cortisol (or corticosterone in rodents) is the end product of the HPA

PNMS effects on serotonin

Accumulating evidence shows a link between PNMS and an increase of behavioral disorders in offspring, including anxiety and depression [75], [76]. In many of these disorders an impairment of serotonin systems was reported. Using animal models, it has been demonstrated that an application of different type of stress (e.g. restraint stress, auditory stress) during pregnancy induces alteration of the central serotonin systems of offspring even later in life. For example, PNMS in mice induced an

Conclusion

The serotonin system is crucial for fetal development, especially for brain development, and many studies show its involvement in psychiatric disease during adulthood. In this review, we group information showing that maternal exposure to environmental factors, including PNMS, which induces alteration of serotonin systems during critical windows of early development, could lead to alterations of fetal development and increase risk of psychiatric diseases such as depression, anxiety, or autism

Competing interests

The authors declare that they have no competing interests.

Acknowledgment

Financially supported by the March of Dimes Foundation Social and Behavioral Sciences Research grant (#12-FY12-179) to CV, and a operating grant from the Canadian Institutes of Health Research (CIHR: MOP-1150067) to SK and CV as well as by studentship awards to JSP from Fonds de recherche du Québec (FRQ)-Santé. Both JSP and LL contributed equally to this review.

References (88)

  • T. Oufkir et al.

    Phosphorylation of JAK2 by serotonin 5-HT (2A) receptor activates both STAT3 and ERK1/2 pathways and increases growth of JEG-3 human placental choriocarcinoma cell

    Placenta

    (2011)
  • K. Sato

    Placenta-derived hypo-serotonin situations in the developing forebrain cause autism

    Med. Hypotheses

    (2013)
  • T.J. Hendricks

    Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior

    Neuron

    (2003)
  • D.J.P. Barker

    Fetal nutrition and cardiovascular disease in adult life

    Lancet

    (1993)
  • C. Tsigos et al.

    Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress

    J. Psychosom. Res.

    (2002)
  • I. Phocas et al.

    Maternal serum total cortisol levels in normal and pathologic pregnancies

    Int. J. Gynaecol. Obstet.

    (1990)
  • A. Charil

    Prenatal stress and brain development

    Brain Res. Rev.

    (2010)
  • S. Avishai-Eliner

    Stressed-out, or in (utero)?

    Trends Neurosci.

    (2002)
  • K.J. O'Donnell

    Maternal prenatal anxiety and downregulation of placental 11​β-HSD2

    Psychoneuroendocrinology

    (2012)
  • J. Dy

    Placental 11β-hydroxysteroid dehydrogenase Type 2 is reduced in pregnancies complicated with idiopathic intrauterine growth restriction: evidence that this is associated with an attenuated ratio of cortisone to cortisol in the umbilical artery

    Placenta

    (2008)
  • B. Börzsönyi

    Gene expression patterns of the 11β-hydroxysteroid dehydrogenase 2 enzyme in human placenta from intrauterine growth restriction: The role of impaired feto-maternal glucocorticoid metabolism

    Eur. J. Obstetrics Gynecol. Reprod. Biol.

    (2012)
  • C. Demendi

    Abnormal fetomaternal glucocorticoid metabolism in the background of premature delivery: placental expression patterns of the 11β-hydroxysteroid dehydrogenase 2 gene

    Eur. J. Obstet. Gynecol. Reprod. Biol.

    (2012)
  • M.A.C. Zijlmans et al.

    Associations between maternal prenatal cortisol concentrations and child outcomes: a systematic review

    Neurosci. Biobehav. Rev.

    (2015)
  • M. Creamer et al.

    Psychometric properties of the impact of event scale – revised

    Behav. Res. Ther.

    (2003)
  • F. Veru

    Prenatal maternal stress predicts reductions in CD4+ lymphocytes, increases in innate-derived cytokines, and a Th2 shift in adolescents: project ice storm

    Physiol. Behav.

    (2015)
  • D.P. Laplante

    Project ice storm: prenatal maternal stress affects cognitive and linguistic functioning in 51/2-year-old children

    J. Am. Acad. Child Adolesc. Psychiatry

    (2008)
  • D.J. Walder

    Prenatal maternal stress predicts autism traits in 61/2 year-old children: project ice storm

    Psychiatry Res.

    (2014)
  • V.L. Clifton

    Review: sex and the human placenta: mediating differential strategies of fetal growth and survival

    Placenta

    (2010)
  • Z. Saif

    Expression of eight glucocorticoid receptor isoforms in the human preterm placenta vary with fetal sex and birthweight

    Placenta

    (2015)
  • M. Weinstock

    The long-term behavioural consequences of prenatal stress

    Neurosci. Biobehav Rev.

    (2008)
  • H. Ishiwata et al.

    Selective serotonin reuptake inhibitor treatment of early postnatal mice reverses their prenatal stress-induced brain dysfunction

    Neuroscience

    (2005)
  • K. Miyagawa

    Prenatal stress induces anxiety-like behavior together with the disruption of central serotonin neurons in mice

    Neurosci. Res.

    (2011)
  • D.L. Van den Hove

    Prenatal stress in the rat alters 5-HT1A receptor binding in the ventral hippocampus

    Brain Res.

    (2006)
  • Y. Huang

    Pre-gestational stress reduces the ratio of 5-HIAA to 5-HT and the expression of 5-HT1A receptor and serotonin transporter in the brain of foetal rat

    BMC Neurosci.

    (2012)
  • L. Booij

    Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

    J. Psychiatry Neurosci.

    (2015)
  • A.H. Amin et al.

    The distribution of substance P and 5-hydroxytryptamine in the central nervous system of the dog

    J. Physiol.

    (1954)
  • A.G. Paquette et al.

    The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes

    J. Cell Biochem.

    (2014)
  • L. Olson et al.

    Early prenatal ontogeny of central monoamine neurons in the rat: fluorescence histochemical observations

    Z Anat. Entwicklungsgesch

    (1972)
  • B.L. Jacobs et al.

    Structure and function of the brain serotonin system

    Physiol. Rev.

    (1992)
  • A. Bonnin

    A transient placental source of serotonin for the fetal forebrain

    Nature

    (2011)
  • G.R. Auda

    Localization of monoamine oxidase mRNA in human placenta

    J. Histochem. Cytochem.

    (1998)
  • C. Vaillancourt

    Labelling of D2-dopaminergic and 5-HT2-serotonergic binding sites in human trophoblastic cells using [3H]-spiperone

    J. Recept. Res.

    (1994)
  • M. Levin et al.

    Of minds and embryos: left-right asymmetry and the serotonergic controls of pre-neural morphogenesis

    Dev. Neurosci.

    (2006)
  • E.S. Petrova et al.

    Serotonin is involved in the regulation of histogenetic processes in rat embryonic neocortex

    Bull. Exp. Biol. Med.

    (2007)
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    Both authors (JSP and LL) contributed equally to this review.

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