Disruption of the Placenta-Brain Axis in Transgenic Mice Lacking Serotonin Transporter (SERT) in Trophoblast Cell

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed drugs to pregnant women experiencing depression. While such drugs might be beneficial in combating depression by competitively binding to serotonin transporter (SERT), they can adversely affect the placenta and fetal brain development. Parietal trophoblast giant cells (pTGCs) in the mouse placenta are postulated to internalize maternal serotonin (5-HT) via transport through SERT, encoded by Slc6a4. The placenta provides the initial source of 5-HT to the emerging brain via the placental-brain axis. Disruption of 5-HT acquisition by pTGCs due to genetic deletion of Slc6a4 is hypothesized to impact placental and fetal brain development. A transgenic mouse line with the SERT transporter selectively deleted was created by pairing mice with Cre-recombinase linked to proliferin (Prl2c2) with LoxP sites flanking the Slc6a4 gene. Proliferin is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Sl6a4 KO and WT mice, 5-HT content in the placenta and fetal brains of the mice was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placenta and fetal brain. However, there was significantly lower average number of pTGCs in KO placentas compared to WT (p ≤ 0.05). Sexually dimorphic differences in gene expression were evident in the placenta and fetal brain between KO and WT counterparts with female conceptuses showing the most dramatic responses. Findings suggest that ablation of SERT in pTGC disrupts the placenta-brain axis in a sex-dependent manner. These results might have important clinical ramifications for pregnant women being treated with SSRIs.