Serotonin (5HT) is a multifunctional signaling molecule best known as a neurotransmitter of the central nervous system. In addition, 5HT also plays important extra-cerebral roles, both in adulthood and during development. Disturbances in 5HT homeostasis are associated with many mental health conditions and also appear to play an important role in obesity and diabetes. There is growing evidence that DNA methylation modulates the expression of 5HT-regulating genes and may contribute to 5HT dysfunction. DNA methylation is a dynamic process that responds to environmental cues, especially during early development. Our recent findings suggest that DNA methylation of the 5HT transporter gene (SLC6A4) in the placenta is sensitive to maternal metabolic perturbations associated with gestational diabetes mellitus (GDM). Therefore, this project aims to better understand the influence of maternal metabolic status during pregnancy on the 5HT system of the placenta and the newborn. Using placental tissue and primary placental cells obtained from clinically well-defined normoglycemic and GDM pregnancies, we will investigate the relationship of maternal pre-pregnancy body mass index (pBMI) and gestational glycemia with DNA methylation and expression of SLC6A4, 5HT receptor type 2A (HTR2A) and other serotonin-regulating genes in the placenta. Furthermore, through in vitro studies in placental cell models, we will investigate how exposure to glucose affects methylation and expression of SLC6A4 as well as the function of the corresponding gene product. Finally, we will investigate the relationship of pBMI and gestational glycemia with the neonatal 5HT system by measuring DNA methylation of 5HT-regulating genes and 5HT-related biochemical parameters (5HT levels, platelet 5HT uptake) in cord blood samples.