SEROTONERGIC MODULATION OF BRAIN DEVELOPMENT: GENETIC AND PHARMACOLOGIC INFLUENCE

(P50MH090966; Gingrich, J., PI; Monk, co investigator)

The current application proposes to create a Silvio O. Conte Center for Basic and Translational Mental Health Research to address the role of serotonin (5HT) signaling in brain development. Before 5HT assumes its canonical role as a neurotransmitter, it acts during early stages of neural growth to exert profound effects on brain structure and function. The Center hypothesizes that two modulators of developmental 5HT signaling include: genetic variants and serotonin selective reuptake inhibitors (SSRIs). In the first case, naturally occurring serotonergic polymorphisms are associated with measurable differences in human brain structure and function. In the second case, the fetus receives incidental exposure from maternal use of SSRI medications. Based on animal models and human imaging, the effects of augmented 5HT signaling on brain development may increase vulnerability to mental disorders as a long-term consequence. The Center will investigate both sources of 5HT signaling modulation and hypothesizes that fetal SSRI exposure and 5HTergic genetic variants will produce convergent effects on brain structure, function, and consequently behavior. The Center includes 4 projects and 4 cores that integrate epidemiology, clinical, and animal models to address the central hypothesis. The Center studies ~11,000 children with in utero exposure to SSRIs by following mental and physical health problems through adolescence. A companion project studies newborns exposed to SSRIs in utero using multi-modal neuroimaging and EEG to assess brain structure and function at the earliest ages. The brain effects of early-life SSRI exposure is studied in mouse models using the same multi-modal imaging measures as well as microscopic analyses of cellular properties that may underlie imaging abnormalities. The Center reasons that the influence of genetic modulators of 5HT is likely encoded during early development. We test this hypothesis through genetically stratified newborns and fetal rhesus macaques, and examining genetics, brain imaging, and EEG in a unique, clinically characterized, population at high and low risk for depression. The Center studies of early-life 5HT signaling and brain development should lead to a better understanding of whether some mental disorders have their origins in development-a question highly relevant to the mission of NIMH.

Shkumbin Mustafa