All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

John C Chatham

John J Hablitz

Michelle L Olsen

Richard B Marchase

Jerzy P Szaflarski

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Plasticity at central synapses is a vital component of neuronal function and an intensively studied phenomenon thought to underlie learning and memory processes in brain structures including the hippocampus and cerebral cortex. A principle mechanism at work during long-term plasticity is the rapid and heavily regulated post-translational modification of synaptic proteins such as phosphorylation and ubiquitination. A comparatively understudied modification is ‘O-GlcNAcylation’, a distinct form of monoglycosylation with rapid intracellular signaling capacity as opposed to the structural and extracellular signaling roles of O- and N-linked polysaccharide chains on conventionally glycosylated proteins. O-GlcNAcylated proteins are found in every cell type/tissue system in the body, with marked enrichment in brain. Despite high expression, only a handful of studies have begun to characterize the role of protein O-GlcNAcylation in the context of neuronal/synaptic physiology. A previously published study from our lab showed depression of glutamatergic synaptic transmission in hippocampus involving AMPA receptor (AMPAR) GluA2 subunits during acute pharmacological increases in protein O-GlcNAc levels. The first goal of this dissertation was to test the hypothesis that the O-GlcNAc-induced depression of glutamatergic transmission could be used to suppress hyperexcitable activity in acute hippocampal slices and in in vivo EEG recordings. Using GABAAR blockade as a model of epileptiform/seizure activity, I showed that pharmacologically increased protein O-GlcNAcylation dampens in vitro hyperexcitability and alters the dynamics of convulsive seizures measured in vivo. These findings support the potential therapeutic efficacy of O-GlcNAc based treatments in epilepsy and seizure disorders. The second goal of this thesis was to explore the possibility that protein O-GlcNAcylation plays a regulatory role in GABAergic neurotransmission, as no studies to date have examined protein O-GlcNAcylation in the context of inhibitory transmission in the CNS. During analysis of GABAergic transmission onto CA1 pyramidal neurons, it was discovered that pharmacologically increasing protein O-GlcNAcylation caused reductions in both tonic and phasic GABAAR currents, consistently increased E:I ratio, and contributed to an overall reduction in action potential probability at the single cell and population level. These cumulative findings portray protein O-GlcNAcylation as a potent regulator of both excitatory and inhibitory transmission in hippocampus.

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