All ETDs from UAB

Advisory Committee Chair

Farah Lubin

Advisory Committee Members

John Hablitz

Farah Lubin

Michael Wyss

Linda Wadiche

Robert McCullumsmith

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Status epilepticus (SE) triggers molecular mechanisms that underlie the cellular and network changes that occur during the development of temporal lobe epilepsy (TLE). Additionally, gene expression alterations occur during epileptogenesis and in the epileptic brain that contribute to the persistence of the phenotype. However, the underlying epigenetic mechanisms responsible for aberrant gene expression that occur with epilepsy require further investigation. This dissertation investigates how DNA methylation in the hippocampus affects epilepsy and contributes to the memory impairments associated with the disorder. We found that DNA methylation was altered in a hippocampal subregion specific manner in the epileptic brain, displaying altered global and gene-specific DNA methylation. The profound changes to the DNA methylome may greatly affect the epilep-sy phenotype by initiating both pro and anti-epileptic effects via altered gene transcription. Therefore, we hypothesized that disruption in DNA methylation mediated gene transcription necessary for proper memory formation contributes to memory deficits as-sociated with epilepsy. In support of our hypothesis, we found that brain derived neurotrophic factor (bdnf) DNA methylation was significantly decreased in the epileptic hippocampus during memory consolidation that correlated with increased bdnf expression and memory deficits in an animal model. Interestingly, Met supplementation was sufficient to restore bdnf DNA methylation and expression to non-epileptic physiological levels. Met supplementation was also sufficient to reverse hippocampal-dependent memory deficits and decrease interictal spike activity, suggesting an important role for DNA methylation in epilepsy related memory impairments and further suggesting that altered DNA methylation may have both pro and anti-epileptic consequences. Overall, our findings have begun to elucidate a role for DNA methylation in transcriptional regulation in epilepsy and a potential therapeutic tool for reversing memory deficits associated with this disorder.

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