Effects of prenatal maternal stress on serotonin and fetal development
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.
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Both authors (JSP and LL) contributed equally to this review.