All ETDs from UAB

Advisory Committee Chair

John D Sweatt

Advisory Committee Members

John J Hablitz

Trygve O Tollefsbol

Linda Wadiche

Jeffrey A Engler

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

An expanding body of literature argues for a pivotal role of molecular epigenetic mechanisms in memory. Defined as mechanisms that regulate gene expression in the absence of DNA sequence modifications, these regulate various stages of memory-associated transcription. These phenomena are present at diverse anatomical subregions of the central nervous system (CNS) and regulate corresponding behaviors. Epigenetic mechanisms comprise a unique category of behavioral and physiological modulators because of their potential to modify the cellular phenotype in a stable manner. Hence, epigenetics offers a novel potential solution to a central paradox in memory retention: the finding that most putative molecular substrates of persisting cognitive traces also experience relatively rapid turnover. DNA methylation appears to be the most suitably co-opted substrate for long-term information propagation in light of its unique robustness. Nevertheless, DNA methylation itself exhibits surprisingly rapid turnover in association with memory consolidation and gene expression, and multiple lines of evidence point to a behavioral role of active methylation. However, until recently, little was known about the agents catalyzing mammalian DNA demethylation and their mechanisms of action. A number of landmark studies addressed this problem and uncovered a role of the Growth Arrest and DNA Damage-Inducible (Gadd45) family in active epigenetic demethylation. In particular, the gene encoding Gadd45ß (Gadd45b) was found to be an immediate-early gene (IEG) with prominent hippocampal expression and to promote activity-related demethylation. Because of these features, I hypothesized that Gadd45b regulates DNA methylation dynamics in the hippocampus in association with memory formation. Utilizing a global knockout (KO) approach, I explored the consequences of a loss of Gadd45b on rodent behavior, hippocampal physiology and transcription. I found that Gadd45b KO mutants displayed enhanced associative fear memory and spatial memory and largely intact baseline behavior in comparison to wildtypes (WT). Likewise, KO mice demonstrate normal baseline physiology in CA1 but enhanced long-term potentiation (LTP). Finally, I show that Gadd45b loss affects activity- and memory-associated gene expression in a temporally specific manner. Collectively, my results show Gadd45b modulates hippocampus-associated behavior, physiology and molecular dynamics and suggest, more broadly, that DNA demethylation is a functional epigenetic mechanism in cognition.

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