Document Type
Article
Publication Date
12-2025
Abstract
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 Slc6a4, and to provide the initial source of 5-HT to the emerging brain via the placental–brain axis. Genetic deletion of Slc6a4 in pTGCs has been hypothesized to impact placental and fetal brain development. A transgenic mouse line with high-affinity SERT, encoded by Slc6a4, was selectively deleted by pairing mice with Cre recombinase linked to Prl2c2, with LoxP sites flanking the Slc6a4 gene. PRL2C2 is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Slc6a4 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 (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, including decrease in Prl7a2, Prl5a1, Prl3a1, Slc28a3, and Ceacam 15 in female placental samples. These findings suggest that ablation of Slc6a4 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.
Recommended Citation
Ellenberger DT, Lyu Z, Herrington RTB, Kinkade JA, Leone GW, Sze JY, Bivens NJ, Baker RF, Roberts RM, Joshi T, et al. Disruption of the Placenta–Brain Axis in Transgenic Mice Lacking Serotonin Transporter (SERT) in Trophoblast Cells. International Journal of Molecular Sciences. 2026; 27(1):436. https://doi.org/10.3390/ijms27010436
Included in
Medical Biochemistry Commons, Medical Pharmacology Commons, Obstetrics and Gynecology Commons
Comments
The copy of record is available from the publisher at https://doi.org/10.3390/ijms27010436. Copyright ©2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.