All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

Lynn E Dobrunz

Mark O Bevensee

Rita M Cowell

John C Chatham

Kazutoshi Nakazawa

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Post translational modification of proteins plays a crucial role in regulating their function, and the role of one such modification, termed O-GlcNAcylation, is understudied. O-GlcNAcylation involves the dynamic cycle of adding and removing an O-linked N-acetylglucosamine (O-GlcNAc) by the enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which are highly expressed in the hippocampus. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. We have shown that acute and selective increase in O-GlcNAcylation of AMPAR GluA2 subunits underlies expression of a novel form of LTD at CA3-CA1 synapses (O-GlcNAc LTD), as well as the dampening of pathological hyperexcitability in seizure models. Yet, no study has investigated if O-GlcNAcylation modulates the strength of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable effect on the excitation/inhibition balance. The overall effect of increased O-GlcNAc on principal cells is reduced synaptically-driven spike probability via excitatory synaptic depression and decreased intrinsic excitability. Additionally, we show that O-GlcNAc depresses inhibitory input from dendrite- and soma-targeting interneurons, suggesting that O-GlcNAc is a generalized mechanism whereby the strength of inhibition can be “turned down”. Taken together, our results position O-GlcNAcylation as a novel regulator of inhibitory circuits, the overall excitation/inhibition balance, and neuronal output.

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