The action of neurotransmitters and related substances on early embryogenesis

Serotonin (5-HT) acts as a morphogen influencing embryonic brain development, and as a neurotransmitter regulating multiple biological functions with lifelong effects on animal physical, physiological and mental health, especially during the rapid growth phase prior to birth when embryos face many challenges to reach structural and functional completion. In this study, the development of the serotoninergic (5-HTergic) system and its modulatory effect on the dopaminergic (DAergic) system and related neural circuits were investigated during the mid-late embryogenesis, embryonic day (E)12-E20, in the chicken's brain. During 5-HTergic neuronal maturation, a growth-related anatomical and functional remodeling was highlighted: the 5-HT neurons continuously grew during E12-E20 except for a remarkable regression during E14-E16. Correspondingly, there was a time-dependent change in the 5-HT synthetic capacity. Specifically, 5-HT concentrations in the raphe nuclei increased from E12 to E14, reaching a first plateau during E14-E16, then continuously increased up to E19, and reaching a second plateau between E19-E20. The second plateau of the 5-HT concentration was in correspondence with the establishment of the 5-HTergic autoregulatory loop during E19-E20 and the development of the DAergic system. The DA concentrations remained unchanged from E12 to E16, then started to increase at E16, reaching a maximum at E19, and diminished before hatching. The unique developing time sequence between the 5-HTergic and DAergic systems suggests that the 5-HTergic system may play a critical role in forming the 5-HT – DA neural circuit during chicken embryogenesis. These results provide new insights for understanding the functional organization of the 5-HTergic system during embryonic development and raise the possibility that prenatally modulating the 5-HTergic system may lead to long-lasting brain structural and functional alterations.

During development, the placenta can be said to be the most important organ, however, the most poorly researched. There is currently a broader understanding of how specific insults during development affect the fetal brain, and also the importance of placental signaling in neurodevelopmental programming. Epigenetic responses to maternal and fetal signals are an obvious candidate for transforming early life inputs into long-term programmatic outcomes. As a mediator of maternal and environmental signals to the developing fetus, epigenetic processes within the placenta are particularly powerful such that alterations of placental gene expression, downstream function, and signalling during foetal development have the potential for dramatic changes in developmental programming.

In this article, we reviewed emerging evidence for a placental role in prenatal neurodevelopmental programming with a specific focus on nutrient and prenatal stress signals integration into chromatin changes; this new understanding, we hope will provide the means for lowering developmentally based disorder risk, and new therapeutic targets for treatment in adulthood.

Based on this review, the placenta is a potent micro-environmental player in neurodevelopment as it orchestrates a series of complex maternal–foetal interactions. Maternal insults to this microenvironment will impair these processes and disrupt foetal brain development resulting in the prenatal programming of neurodevelopmental disorders. These findings should inspire advance animal model and human research drive to appraise gene–environment impacts during pregnancy that will target the developmental cause of adult-onset mental disorders.

Serotonin (5-hydroxytryptamine, 5-HT) is known to have a profound impact on fetal development across numerous animal phyla. The presence of a functional serotonergic signal transduction system (serotonin, its receptors, and serotonin transporters) throughout mammalian embryogenesis, in addition to pharmacological and gene knockout studies, both provide evidence for a functional role for serotonin in numerous developmental processes. This chapter provides a brief overview of the cellular aspects of serotonin signaling and placental transfer. Evidence is also presented for a central role for serotonin in neural crest cell function and bone development. This is discussed in the context of contributions to normal and abnormal craniofacial development. Data are further presented that allow the premise that perturbation of serotonin homeostasis during gestation, by either overstimulation or serotonin depletion, can have a deleterious effect on serotonin-dependent processes and subsequent craniofacial development.

The neurotransmitter serotonin (5-HT) plays a central role in brain development, regulation of mood, stress reactivity and risk of psychiatric disorders, and thus alterations in 5-HT signaling early in life have critical implications for behavior and mental health across the life span. Drawing on preclinical and emerging human evidence this narrative review paper will examine three key aspects when considering the consequences of early life changes in 5-HT: (1) developmental origins of variations of 5-HT signaling; (2) influence of genetic and epigenetic factors; and (3) preclinical and clinical consequences of 5-HT-related changes associated with antidepressant exposure (SSRIs). The developmental consequences of altered prenatal 5-HT signaling varies greatly and outcomes depend on an ongoing interplay between biological (genetic/epigenetic variations) and environmental factors, both pre and postnatally. Emerging evidence suggests that variations in 5-HT signaling may increase sensitivity to risky home environments, but may also amplify a positive response to a nurturing environment. In this sense, factors that change central 5-HT levels may act as ‘plasticity’ rather than ‘risk’ factors associated with developmental vulnerability. Understanding the impact of early changes in 5-HT levels offers critical insights that might explain the variations in early typical brain development that underlies behavioral risk.

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.

Altered serotonin (5-hydroxytryptamine, 5-HT) signaling has been implicated in some developmental abnormalities of autism spectrum disorder (ASD). However, the presumed role of 5-HT in ASD raises new questions in fundamental neuroscience. Specifically, it is not clear if the current piecemeal approach to 5-HT signaling in the mammalian body is effective and whether new conceptual approaches may be required. This review briefly discusses 5-HT production and circulation in the central nervous system and outside of it, especially with regard to ASD, and proposes a more encompassing approach that questions the utility of the “neurotransmitter” concept. It then introduces the idea of a generalized 5-HT packet that may offer insights into possible links between serotonergic varicosities and blood platelets. These approaches have theoretical significance, but they are also well positioned to advance our understanding of some long-standing problems in autism research.