Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain

Abstract

Accumulating evidences suggest that serotonin (5-HT) contributes to the developmental programming of childhood- and adult-onset mental illnesses. This is thought to occur through the capacity of 5-HT to modulate developmental processes such as cell proliferation, migration and circuit wiring. For instance, genetic studies in mice show that disruption of 5-HT signaling during a restricted period of pre- and postnatal development results in long-term behavioral abnormalities such as increased anxiety in adulthood (Gaspar et al., 2003, Oberlander et al., 2009). The developmental programming of adult anxiety can be triggered either by a transient knockdown of a single 5-HT receptor [5-HT1A, (Gross et al., 2002)] or by a transient developmental exposure to specific serotonin reuptake inhibitors (SSRIs) (Ansorge et al., 2004, Ansorge et al., 2008). The recent discovery of a role for 5-HT in fetal forebrain wiring in utero (Bonnin et al., 2007, Bonnin et al., 2011) suggests a potential mechanism by which 5-HT signaling disruption can have long-term consequences on brain function. 5-HT signaling through two receptors (htr1b/1d; 5-HT1B/1D) switches the response of thalamic axons to netrin-1 from attraction to repulsion in vitro (Bonnin et al., 2007). Targeted disruption in vivo of 5-HT1B/1D receptors expression in the dorsal thalamus led to abnormal thalamocortical axons (TCAs) pathways in the internal capsule and cortex (Bonnin et al., 2007). Thus, the level 5-HT signaling through the number and/or type of 5-HT receptors activated is critical for normal brain development. The concentration of 5-HT available for receptors activation is likely another important parameter for normal brain development. We recently demonstrated that the fetal forebrain selectively accumulates placenta-derived 5-HT during the initial axon growth period (Bonnin et al., 2011). These data suggest that certain developing circuits in the fetal brain are sensitive to placental 5-HT during their initial ontogeny, which could be impacted by both genetic and environmental disturbances that are known to increase risk for mental illnesses. The role of 5-HT signaling in fetal brain wiring and the potential importance of placental metabolism in 5-HT-mediated fetal programing are discussed below.

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

“…Recent human studies have associated maternal stress with increased levels of serotonin and norepinephine transporters, and a downregulation of MAO in villous trophoblasts at term (Blakeley et al, 2013;Ponder et al, 2011). As these cells reside between the maternal and fetal vasculature, such changes in transport would increase their intrauterine availability, especially that of serotonin, which is synthesized in maternal, placental, and fetal compartments (Bonnin and Levitt, 2011;Nguyen et al, 1999;Verhaagh et al, 2001). Subsequent fetal overexposure may have deleterious effects on brain development, where, eg, serotonin excess impaired embryonic cortical interneuron migration in mice (Riccio et al, 2009;Velasquez et al, 2013).…”

“…These cells synthesize and secrete growth factors, immunomodulators, sex steroids, metabolic mediators such as leptin and lactogen, and neuromodulators such as corticotropinreleasing factor (CRF) and serotonin (reviewed in Bonnin and Levitt, 2011;Bowen et al, 2002;Fowden et al, 2014;Reis et al, 2001;Sagawa et al, 2002;Sandman, 2015). Placental hormones act as endocrine, paracrine, and autocrine modulators of maternal and fetal physiology throughout pregnancy, in particular during implantation, at parturition, and in response to intrauterine conditions including stress signals.…”

Serotonin controlling feeding and satiety

“…Placental 5-HT pathways from maternal tryptophan contribute to the fetal programming of the brain. Later in in development, there will be a switch to an endogenous brain source of 5-HT [387]. However, as in any case the availability of the 5-HT precursor tryptophan depends on dietary supply [388], an impact of the early nutritional environment on brain development can be expected [389].…”

PlacentalHTR2Amethylation is associated with infant neurobehavioral outcomes

“…10 Alterations to serotonergic tone have also been shown to alter brain development in vivo. 11 The fetus develops a full serotonin response pathway before it can produce its own serotonin 12 and relies on maternal-and placental-derived serotonin during early development, 13 suggesting an important role for this neurotransmitter within the placenta in during early neurodevelopment.…”