Date of Award

December 2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Advisor(s)

James A. Hewett

Keywords

COX-2, Epilepsy, NMDA, RNA binding protein, Seizure, TIA-1

Subject Categories

Life Sciences

Abstract

Epilepsy is a brain disease defined by having recurrent and spontaneous seizures. The susceptibility to seizure is determined by seizure threshold, which describes the balance between excitatory and inhibitory neurotransmission in the brain. Epileptogenesis, the transition from normal brain to epileptic brain, is accompanied by a progressive reduction of seizure threshold and has been shown to have genetic influences. Expression of neuronal cyclooxygenase-2 (COX-2) gene, PTGS2, a primary gene that regulates prostaglandin synthesis in the normal brain, is enhanced by excitatory neurotransmission and is under tight regulation of N-Methyl-D-Aspartate type glutamate receptor (NMDAR) activity in cortical neurons. The 3’ untranslated region (3’UTR) of PTGS2 gene was found to be a key site of post-transcriptional regulation by NMDAR activity. However, deletion of T-cell intracellular antigen-1 (TIA-1), an RNA binding protein of COX-2 mRNA 3’UTR, did not affect COX-2 protein expression in mouse brain. Although TIA-1 deletion did not alter innate seizure threshold, it facilitated the acquisition of epilepsy and enhanced epileptogenesis-associated mortality. Further investigation revealed that TIA-1 knockout mice have an altered transcriptome in their hippocampi. Together, my findings illustrate an NMDAR-dependent regulatory mechanism of a known modulator of seizure threshold (COX-2) in neurons, and provide insight into the regulation of epileptogenesis by a novel genetic modifier (TIA-1).

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