Undergraduate Researcher University of Missouri Branson, Missouri, United States
Abstract Authors: David T. Ellenberger1,2, Rosalind T.B. Herrington1,3, Jessica A. Kinkade8, Sarah E. Seda1,4, Alyssa N. Lambert1,4, and Cheryl S. Rosenfeld1,5,6,7
Departments of:
1Biomedical Sciences. University of Missouri, Columbia, Missouri, 65211. USA
2Microbiology, University of Missouri Columbia, Missouri, 65211. USA
3Biological Sciences, University of Missouri, Columbia, Missouri, 65211. USA
4Animal Sciences, University of Missouri, Columbia, Missouri, 65211. USA.
5MU Institute for Data Science and Informatics, University of Missouri, Columbia, Missouri, 65211. USA
6Department of Genetics Area Program, University of Missouri, Columbia, Missouri, 65211. USA
7Department of Thompson Center for Autism and Neurobehavioral Disorders, University of Missouri, Columbia, Missouri, 65211. USA
8MU Veterinary Medical Diagnostic Laboratory, University of Missouri, Columbia, Missouri, 65211. USA
Abstract Text: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed drugs to combat depression in pregnant women. While such drugs might have beneficial effects in the mother, they can adversely affect the placenta and consequently the fetus through placental insufficiency of serotonin (5-HT). Parietal trophoblast giant cells (pTGCs) in the mouse placenta are at the interface with maternal uterine tissue and are postulated to accumulate maternal 5-HT via internalization through the Slc6a4 (SERT) transporter. The placenta might provide the initial source of 5-HT to the emerging brain via the placental-brain axis. SSRIs may disrupt this axis by binding to SERT transporters within pTGCs. Regulation of 5-HT is important for fetal brain development, as deficiencies have been linked to the development of autism spectrum disorders (ASD) and anxiogenic behaviors. Disruption of 5-HT acquisition by pTGCs due to selective genetic deletion of Slc6a4 within these trophoblast cells is hypothesized to impact placental and fetal brain development, which might manifest in later neurobehavioral deficits. To test this hypothesis, a transgenic mouse line with the SERT transporter selectively knocked out was created by pairing mice with Cre-recombinase linked to proliferin (Prl2c2) with LoxP sites flanking the Slc6a4 gene, which encodes for the SERT protein. Proliferin is exclusively expressed by pTGCs and other giant cells of the placenta. This ensures that only the SERT in these trophoblast (TB) cells are selectively ablated. 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. To analyze spatial learning and memory the Barnes Maze was used, and anxiety-related behaviors were analyzed using the elevated plus maze. We tested four groups of mice for each behavioral test: sixScl6a4fl/flPrl2c2-/- (wild-type, WT) males, four Scl6a4fl/flPrl2c2Cre/- (knockout, KO) males, five Scl6a4fl/flPrl2c2-/- (WT) females, and three Scl6a4fl/flPrl2c2Cre/- (KO) mice females. Results from these studies do not reveal significant differences based on genotypes, sex, or the combination of these two factors for these two behavioral tests. Catecholamine analysis revealed no significant differences (p >0.05) in 5-HT content between KO and WT fetal brain and placenta tissues but significantly elevated levels of epinephrine and metanepenephrine were detected in KO mice fetal brain tissue samples compared to controls. To examine for subtle histopathological and gene expression changes in the placenta and fetal brain, RNAseq and morphometric analyses, respectively, are currently underway. My research addresses a significant gap in understanding the effects of SSRIs on the placenta and fetal neurodevelopment and has the potential to inform clinicians on the safety of these drugs for the mother and her fetus, and thereby, improve outcomes for pregnant women and their offspring.
