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

Abstract

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.

Keywords: 5-HT; SERT; SSRI; anti-depressants; autism; gestation; giant cells; pre-eclampsia; trophoblast.

Figure 1

Synthesis and metabolism of 5-HT. TPH1/2 catalyzes the hydroxylation of L-tryptophan to 5-HTP. AAAD stimulates the decarboxylation of 5-HTP to yield 5-HT. MAO-A metabolizes 5-HT to 5-HIAA. Chemical structures are from www.chemspider.com/.

Figure 2

Normal 5-HT signaling in the placenta and effects of SSRI on this signaling pathway. (A) In normal TB cells, 5-HT binds to SERT and is translocated into the cell, whereupon its actions are terminated. (B) In TB cells exposed to SSRI, this pharmaceutical agent competitively binds to SERT, which prevents 5-HT from binding to this protein. Consequently, an increase in extracellular concentrations of 5-HT are available to bind to 5HT(2A)R and other similar receptors residing within the plasma membrane that may mediate 5-HT signaling pathways.

Figure 3

Histopathological changes in embryonic day (E)18 placenta of SERT-KO vs. WT mice. Low magnification (2X) images of SERT-KO (A) and WT (B) placenta at this stage. The spongiotrophoblast region of the junctional zone is designated with an asterisk. Higher magnification (20X) of this region is included as an inset to the right of the initial image. Considerable necrosis is evident in this region of SERT-KO mice placenta. Panels A and B are H & E stained images. Panels C and D (10X magnification) are trichrome stained to show extensive fibrosis and necrosis evident within the junctional zone for SERT-KO mice relative to WT individuals who lack such pathological changes. (C) SERT-KO mouse placenta at E18 and (D) WT mouse placenta at E18. Adapted from [34] with permission from Wiley publications.