All ETDs from UAB

Advisory Committee Chair

Sarah M Clinton

Advisory Committee Members

Gwendalyn King

Merida Grant

Farah Lubin

Michelle Olsen

Richard Shelton

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Selective serotonin reuptake inhibitors (SSRIs) have been a mainstay pharmacological treatment for women experiencing depression during pregnancy and postpartum for nearly three decades. Recently, though, growing evidence indicates that early-life SSRI exposure triggers long-lasting behavioral abnormalities. Clinically, children exposed to SSRIs in early life exhibit increased internalizing behavior, reduced social behavior, and increased risk for depression in adolescence. Similarly, in rodents, perinatal SSRI exposure leads to increased traits of anxiety- and depression-like behavior. Interestingly, certain individuals are more susceptible to early-life SSRI exposure than others, suggesting that perinatal SSRI exposure poses greater risks for negative outcome within certain populations; however, few studies have investigated factors contributing to susceptibility to SSRI exposure. The present studies began by establishing a rodent model of individual differences in susceptibility to perinatal SSRI exposure. We show that rats bred for Low Response to novelty (Low Responders, LRs) naturally exhibit high levels of inhibition/anxiety and are susceptible to perinatal SSRI-induced behavioral abnormalities (increased adult depression-like behavior) while High Novelty Responder (HR) rats were resistant. We used this rodent model in combination with transcriptome profiling and next-generation sequencing approaches to interrogate molecular mechanisms in the developing brain that may underlie the adverse behavioral consequences of perinatal SSRI exposure. Perinatal SSRI exposure induced robust gene expression changes in the early postnatal hippocampus; including reduced expression of the DNA methylating enzyme Dnmt3a. Sequencing analyses identified numerous hypomethylated genomic regions in the perinatal SSRI-exposed hippocampus, leading us to hypothesize that transiently suppressing DNA methylation in the developing hippocampus would mimic perinatal SSRI-associated behavioral effects. We found that, indeed, siRNA-mediated knockdown of hippocampal Dnmt3a in neonatal rats increased adult depression-like behavior. Overall these data suggest that perinatal SSRI exposure perturbs limbic system development and long-term emotional behavior, in part, by suppressing DNA methylation in the early postnatal hippocampus. Identifying molecular mechanisms that contribute to the deleterious behavioral effects of perinatal SSRI exposure may highlight biological mechanisms in the etiology of mood disorders. Moreover, understanding mechanisms that drive individual differences in susceptibility to perinatal SSRI exposure could lead to individualized treatment strategies for depressed women who are or plan to become pregnant.

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