Characterizing the Placenta-Brain Axis in Transgenic Mice Lacking Serotonin Transporter (SERT) in Trophoblast Cells

During pregnancy, the mouse and human placenta contain appreciable quantities of serotonin (5- hydroxytryptamine; 5-HT), but a scant amount is known about the actions of this catecholamine within the placenta. In the mouse, 5-HT is concentrated in parietal trophoblast giant cells (pTGCs) at the periphery of the spongiotrophoblast layer and at the interface of the placenta and maternal decidua and may have local and as yet uncharacterized paracrine effects. Concentrations of placenta 5-HT can be affected by extrinsic factors, including selective serotonin reuptake inhibitors (SSRI) and endocrine disrupting chemicals, that can detrimentally affect placental architecture and may render the fetus prone to diseases later in life. Thus, it is essential to understand the source of 5-HT and paracrine actions of this compound within the placenta. In mouse conceptuses where the 5-HT transporter gene (Scl6a4/SERT) is mutated, we have recently shown that the pTGCs also appear to be targeted, but in this case, there is marked expansion, rather than shrinkage of the pTGC layer, and upregulation of gene-sets involved in nutrient acquisition and metabolism and those linked to blood clotting. We hypothesize that 5-HT exerts key paracrine actions within the placenta, pTGCs acquire it via SERT from maternal sources, and disruption in pTGC accrual of 5-HT leads to placental dysfunction and compromises fetal brain development. Relevant to these observations is that selective serotonin-reuptake inhibitors (SSRIs), which block SLC6A4/SERT transport activity, are commonly prescribed anti-depressants for pregnant women, and women using SSRI have been reported to deliver lower birthweight infants and have placental-fetal vascular mal-perfusion, consistent with the inference that 5-HT might play a role in placental homeostasis in the human. Based on these facts, we surmise that compromised SLC6A4/SERT activity affects allocation of 5-HT within the placenta, thereby interfering with placental function, including the ability to supply 5-HT to the fetal forebrain. To test our hypothesis that the pTGCs play a central role in 5-HTapportionment, we have created conditional knockout (KO) mice that lack Slc6a4 /SERT selectively in pTGCs and spiral artery TGC (Spa-TGCs), which may also be important for 5-HT accumulation by the placenta. Specific Aim: We will determine whether disturbances in pTGC/Spa-TGC 5-HT acquisition via SLC6A4 affect placental and subsequent brain development and function. This aim will address whether mice that conditionally lack Scl6a4/SERT in pTGCs and Spa-TGCs have lowered accumulation of 5-HT and develop placental and neural transcriptomic and histopathological changes. Experiments will confirm the role of pTGCs in 5-HT accrual in the rodent placenta, help us understand how 5-HT availability affects the placenta and brain, and whether maternal treatment with SSRI could obstruct such processes. Results may offer insight into how placental abnormalities contribute to later-in-life diseases with a fetal origin, presumably paving the way for novel early diagnostic and remediation strategies to prevent such disorders. Project Number: 1R03HD114968-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Cheryl Rosenfeld | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $156,500 | Activity Code: R03 | Study Section: Obstetrics and Maternal-Fetal Biology Study Section[CHHD-B] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03HD11496801A1