The Role of O-GlcNAcylation in Synaptic Function

University Of Alabama At Birmingham, Birmingham AL

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Abstract

DESCRIPTION (provided by applicant): Diabetes affects over 20 million people in the US alone. Previous studies show that abnormal insulin and plasma glucose levels in diabetes leads to synaptic dysfunction and cognitive impairment;as such diabetics have an increased risk of Alzheimer's disease and vascular dementia. Under basal conditions, glucose is processed through the glycolytic pathway;while 2-4 % is process via the hexosamine biosynthetic pathway (HBP). The HBP modifies glucose to produce an O-linked N-acetylglucosamine (0-GlcNAc) moiety that can be added to serine/threonine residues. Flux through the HBP is increased when glucose levels are in excess, which leading to a pathologically increase amount of proteins with an O-linked glycosylation tag. Hippocampal neurons have the highest expression of 0-GlcNAc transferase (OGT) and 0-GlcNAcase in forebrain. These two enzymes are responsible for adding and removing, respectively, the 0-GlcNAc moiety to serine/threonine residues in proteins. Thus, the high expression of OGT and 0-GlcNAcase in hippocampus suggests that normal synaptic function in this brain region is modulated by GlcNAc turnover of synaptic proteins. Despite this biochemical information and known cognitive deficits in diabetes where O- GlcNAcylation is increased, no study to date has investigated how O-GlcNAcylation impacts synaptic function required for normal learning and memory. Long-term changes in function of CA3-CA1 synapses underlie hippocampal dependent learning. The possibility exists that abnormal addition of O-GlcNAc on synaptic proteins could interfere with the ability of synapses to express LTP and LTD required for memory processing. In fact, this mechanism could explain deficits in synaptic function in animal models of diabetes. In preliminary experiments, we find that OGT and O-GlcNAcase are tonically active and bidirectionally modulate the strength of basal synaptic transmission, suggesting the natural flux through the HBP sets the level of excitability in the circuit. Furthermore, we find that strongly stimulation of the HBP prevents expression of LTP. The results obtained from this study will launch a new area of investigation aimed at understanding how fluctuations in glucose metabolism by the HBP can directly affect synaptic function in physiological and pathological conditions. This project will help to give some insight into the way the body responds to long-term changes in blood glucose levels and how those changes affect brain homeostasis. The results could lead to new treatments in patients with diabetes as well as even individuals who are pre-disposed to have diabetes.