Placental serotonin signaling, pregnancy outcomes, and regulation of fetal brain development

• Published in: Biology of reproduction 2020-03, Vol.102 (3), p.532-538
• Main Author: Rosenfeld, Cheryl S
• Format: Article
• Language: English
• Subjects: 5-HT; anti-depressants; Antidepressants; Autism; Brain; Cellular signal transduction; Fetal brain; Fetus; Fetuses; gestation; giant cells; Growth; Mental depression; Observations; Patient outcomes; Physiological aspects; Placenta; pre-eclampsia; Preeclampsia; Pregnancy; Prenatal development; Reproductive health; Review; REVIEWS; Serotonin; SERT; SSRI; trophoblast
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1093/biolre/ioz204

The placenta is a transient organ but essential for the survival of all mammalian species by allowing for the exchanges of gasses, nutrients, and waste between maternal and fetal placenta. In rodents and humans with a hemochorial placenta, fetal placenta cells are susceptible to pharmaceutical agents and other compounds, as they are bathed directly in maternal blood. The placenta of mice and humans produce high concentrations of serotonin (5-HT) that can induce autocrine and paracrine effects within this organ. Placental 5-HT is the primary source of this neurotransmitter for fetal brain development. Increasing number of pregnant women at risk of depression are being treated with selective serotonin-reuptake inhibitors (SSRIs) that bind to serotonin transporters (SERT), which prevents 5-HT binding and cellular internalization, allowing for accumulation of extracellular 5-HT available to bind to 5-HT(2A) receptor (5-HT(2A)R). In vitro and in vivo findings with SSRI or pharmacological blockage of the 5-HT(2A)R reveal disruptions of 5-HT signaling within the placenta can affect cell proliferation, division, and invasion. In SERT knockout mice, numerous apoptotic trophoblast cells are observed, as well as extensive pathological changes within the junctional zone. Collective data suggest a fine equilibrium in 5-HT signaling is essential for maintaining normal placental structure and function. Deficiencies in placental 5-HT may also result in neurobehavioral abnormalities. Evidence supporting 5-HT production and signaling within the placenta will be reviewed. We will consider whether placental hyposerotonemia or hyperserotonemia results in similar pathophysiological changes in the placenta and other organs. Lastly, open ended questions and future directions will be explored. Summary sentence The fetal placenta produces serotonin (5-HT) that can induce autocrine/paracrine effects, but disruptions in this signaling pathway may lead to placental pathological changes and increase risk for fetal diseases, including autism spectrum disorders.