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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE304347 | GEO | 2025/08/02

REPOSITORIES: GEO

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Project description:The serotonin transporter (SERT, SLC6A4), belonging to Na+ and Cl- dependent transporters, functions to regulate the availability of serotonin (5-HT) in various tissues including brain, platelets, and intestine. Alterations in 5-HT levels and/or SERT expression have been implicated in pathophysiological conditions including anxiety-like behavior, obesity, cardiovascular disorders and GI disorders such as IBD, IBS, and diarrhea. Accordingly, SERT deficiency in mice is pleiotropic with many different phenotypic traits. Transgenic mice with global deletion of SERT exhibit increased anxiety, abnormal GI motility, and obesity associated with hyperglycemia. Additionally, these mice are more susceptible to intestinal inflammation. The mechanism by which SERT deficiency underlies GI related disturbances and exacerbates the severity of gut inflammation is not known. Thus, we evaluated the ileal mRNA expression to identify potential intestinal targets that contribute to disease pathogenesis when the SERT gene is non-functional. For these studies, RNA was extracted from ileum mucosa from age matched (9-10 wk) control and SERT KO mice by Trizol and was subjected to Mouse mRNA and OneArray Profiling. Our microarray data revealed 492 significantly upregulated and 293 downregulated genes in SERT KO ileum. Pathway analysis revealed significant enrichment in cell cycle, signaling, chemotaxis, and epithelial transporters. Genes of interest were validated by RT-PCR, which included CYP1A1 (~20 fold decrease, p < 0.05), CLDN8 (~30% decrease, p < 0.05), and HMGCS2 (~7 fold increase, p < 0.05). Similar changes were found in colon. A remarkable decrease in expression of Cyp1a1, which encodes a cytochrome P450 enzyme, provides a novel role of serotonergic pathways in drug and xenobiotic detoxification. CLDN8 encodes for claudin 8, which is downregulated in patients with Crohn’s disease. Deficiency of HMGCS2, the mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase, is linked to hypoglycemia. Our data provides novel clues for differential expression of genes affected by 5-HT and/or SERT deficiency in the intestine.

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

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