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

Serotonin reuptake inhibitors (SSRIs) are commonly prescribed to pregnant women experiencing depression. Such drugs, however, might adversely affect 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 <i>Slc6a4</i>, and to provide the initial source of 5-HT to the emerging brain via the placental-brain axis. Genetic deletion of <i>Slc6a4</i> in pTGCs has been hypothesized to impact placental and fetal brain development. A transgenic mouse line with high-affinity SERT, encoded by <i>Slc6a4</i>, was selectively deleted by pairing mice with Cre recombinase linked to <i>Prl2c2</i>, with LoxP sites flanking the <i>Slc6a4</i> gene. PRL2C2 is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective <i>Slc6a4</i> KO and WT mice, 5-HT content in the placenta and fetal brains of conceptuses was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placentas or fetal brains. However, there were significantly fewer pTGCs in KO placentas compared to WT (<i>p</i> ≤ 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, including decrease in <i>Prl7a2</i>, <i>Prl5a1</i>, <i>Prl3a1</i>, <i>Slc28a3</i>, and <i>Ceacam 15</i> in female placental samples. These findings suggest that ablation of <i>Slc6a4</i> in pTGC disrupts the placenta-brain axis in a sex-dependent manner. The results might have important clinical ramifications for pregnant women being treated with SSRIs.