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.
Recommended Citation
Abiraman, Kavitha, "O-Glcnac Regulation Of Inhibitory Circuits" (2019). All ETDs from UAB. 949.
https://digitalcommons.library.uab.edu/etd-collection/949
