Date of Award

Spring 2022

Document Type

Thesis

College

College of Natural and Health Sciences

Primary Advisor

Dr. Aimee Franklin

Abstract

The hippocampus is a structure in the brain crucial for learning and memory. This occurs by synaptic remodeling known as long term potentiation and long term depression. Modifications of proteins in the hippocampus can affect its function. One of these modifications is the addition of O-linked β-N-acetylglucosamine, also known as O-GlcNAc. This is a sugar produced from glucose by the hexosamine biosynthetic pathway that is reversibly added onto serine and threonine residues of proteins by O-GlcNAc Transferase, or OGT. It is reversibly removed from these residues by O-GlcNAcAse, or OGA. This modification has been implicated in diabetes, cardiac dysfunction, and neurodegenerative diseases. Furthermore, as the gene coding for OGT is located on the X chromosome, the two copies of this chromosome in females may lead to differential expression of OGT. Connectivity, structure, and hormone differences in male and female brains may likewise impact expression in the brain between sexes. A transgenic, or mutated, mouse model can be generated that prevents OGA expression when the mouse is taking a medication known as doxycycline. This is hypothesized to increase O-GlcNAc levels. Due to the prevalence of O-GlcNAc in various diseases of the brain, this study aimed to validate how levels of OGA, O-GlcNAc, and OGT are related in the hippocampus of mice both on and off doxycycline, and if expression differed between sexes. This was accomplished by western blot analysis. No significant differences were found between wild type and mutant mice, whether male or female and whether on or off doxycycline. These results indicate that the amount of time off doxycycline needed to impact OGA levels was not reached, and that male and female hippocampi express similar amounts of OGA and OGT. Future experiments may investigate how OGA, OGT, and O-GlcNAcylated protein levels differ by sex in other regions of the brain and subregions of the hippocampus. Other future studies may examine if longer time off doxycycline would change OGA and O-GlcNAc levels in the mouse hippocampus.

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