Gestational serotonin levels and offspring neurodevelopment

About This Grant

PROJECT SUMMARY Serotonin is an important growth factor during gestation. Animal studies have shown that in early gestation, before the fetus’ own ability to synthesize serotonin develops, the mother’s serotonin system plays an important role in the fetus’ brain development in ways that impact future cognition and behavior. In mice, for example, we found that manipulation of the maternal serotonin system alters placental gene expression, fetal brain serotonin levels, and neuronal projections from the thalamus to the somatosensory cortex. When we initially tested these pathways in humans, we saw a similar initial relationship between maternal whole blood serotonin and offspring symptom severity; however, that study was retrospective, and restricted to a clinical population with autism spectrum disorder, and no study has examined the role of the placenta. Recognizing these limitations, it would be premature to develop a large new study without first testing whether and how the pathways identified in the animal models are conserved in humans. Thus, we propose an Exploratory/Developmental R21 project harnassing the strengths of an ongoing study of 375 mother-infants being followed from early pregnancy to offspring 30-36 months of life (R01MH119510). Because the parent study has already collected the maternal blood in early pregnancy, placenta and cordblood, infant neuroimaging at 2-4 weeks of age, and prospective offspring cognitive and behavioral assessments, there is no data collection in this proposal, and we will be able to test our questions immediately and cost-effectively. Our central hypothesis that lower maternal (but not paternal) whole blood serotonin levels in early (14-18 weeks) pregnancy will be associated with changes in placental transcriptome and diminished cord blood serotonin, reduced infant thalamocortical connectivity (using existing structural connectivity measures) at 2-4 weeks of life, and, ultimately, difficulties in neurocognitive and social functioning at 30-36 months of age. Preliminary analyses of the first twenty maternal blood samples we collected support feasibility and demonstrate a range of serotonin levels consistent with those in the population. This developmental proposal will dissect, for the first time, the effects of maternal and placental serotonergic systems on offspring brain and neurodevelopment. Anchoring this proposal to an established study further provides a rigorous and cost-effective infrastructure. Data from this study can fuel future studies to confirm and test generalizability of mechanisms in larger samples, and test promising interventions. Importantly, serotonin function is modifiable, e.g., through diet, micribiome and pharmacological changes, potentially opening up opportunities for maternal screening and prevention.