Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

Abstract

Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other’s impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.

Differential serotonin uptake mechanisms at the human maternal-fetal interface

“…This may be result of the influence of various fetal and/or maternal factors that were not controlled for in the present study. Indeed, fetal sex [34] and genotype [52] were reported to influence 5-HT uptake in rat and human placentas, respectively; others and we have found that maternal obesity and glucose tolerance in pregnancy modulate 5-HT system in the human placenta [17, 43, 53, 54], and various other gestational factors, such as maternal genotype, diet, stress, and immune activation, have been shown to influence fetal and placental 5-HT homeostasis [22]. However, it was outside the scope of the present study to understand regulatory influences and factors of the various 5-HT uptake systems in placenta and platelets.…”

“…Indeed, fetal sex 34 and genotype 58 were reported to influence 5-HT uptake in the plasma membrane vesicles isolated from rat and human placentas, respectively. Various other gestational factors such as maternal obesity and glucose tolerance 17,36,59,60 as well as maternal genotype, diet, stress and immune activation 22 have been also reported to influence placental or fetal 5-HT homeostasis. Understanding the regulatory influences of various factors on the 5-HT uptake systems in placenta and platelets, which was beyond the scope of the present study, warrants further investigation in studies employing full kinetic measurements.…”

“…Additionally, in early pregnancy the placenta supplies the developing fetus with maternal and/or placentaderived 5-HT required for a proper (neuro)development [12][13][14]. This wide range of functions may account for different studies associating altered placental 5-HT homeostasis with pregnancy disorders such as preeclampsia [15], fetal growth restriction [16], and gestational diabetes mellitus [17], as well as with mental health implications in the offspring [18][19][20][21][22]. 5-HT exerts its physiological effects by interacting with plasma membrane-bound 5-HT receptors, which include one ligand-gated ion channel and a variety of metabotropic receptors coupled to diverse intracellular signaling pathways [23].…”

“…Additionally, in early pregnancy the placenta supplies the developing fetus with maternal and/or placenta-derived 5-HT required for a proper (neuro)development [12–14]. This wide range of functions may account for different studies associating altered placental 5-HT homeostasis with pregnancy disorders such as preeclampsia [15], fetal growth restriction [16], and gestational diabetes mellitus [17], as well as with mental health implications in the offspring [18–22].…”

Inhibition of ecto-5′-nucleotidase and adenosine deaminase is able to reverse long-term behavioural effects of early ethanol exposure in zebrafish (Danio rerio)

“…The cellular targets underlining the long-lasting cognitive and behavioural outcomes of ethanol exposure include components of serotoninergic, GABAergic, glutamatergic and dopaminergic systems. Data from human and animal studies indicate that ethanol exposure during early brain development is able to block NMDA receptors, to exacerbate GABA A receptor action, to decrease 5-HT-binding and to decrease dopamine levels [8][9][10][11] .…”