Date of Award
Doctor of Philosophy (PhD)
William A. Falls
Diane M. Jaworski
Stress associated psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder affect a large proportion of the population. Reductions in the complexity of neuronal morphology and reduced neurogenesis are commonly observed outcomes following stress exposure in rodent models and may represent a mechanism for the reduced brain volume in stress sensitive regions such as the hippocampus observed in individuals diagnosed with stress associated disorders. Multiple lines of evidence suggest that glycogen synthase kinase (GSK)-B may play a role in the neurodegenerative phenotype observed following stress exposure. GSK3B is atypical in that it is inhibited by phosphorylation. This inhibitory phosphorylation has typically been studied by examining the phosphorylation state of the serine 9 (S9) site. Inhibition of GSK3B is implicated in synaptic stabilization, increased expression of trophic factors that support dendritic complexity and neurogenesis, reduced apoptosis, and the antidepressive effects of currently implemented therapeutics. It is surprising then that little research has examined the regulation of GSK3B by stress. A novel GSK3B phosphorylation site, serine 389 (S389), has recently been described that is regulated by p38 mitogen activated protein kinase (MAPK) and is independent of S9 phosphorylation by AKT. p38 MAPK is implicated in the behavioral effects of stress exposure making an understanding of its interaction with GSK3B S389 phosphorylation during stress a compelling research target. The current studies examine GSK3B regulation following variate stress exposure in stress reactive brain regions, describe the anatomical specificity of GSK3B S389 phosphorylation in the brain, and detail the behavioral phenotype of a novel mutant mouse that cannot inhibit GSK3B by S389 phosphorylation (GSK3B KI). Region specific changes in GSK3B phosphorylation were observed following stress exposure, as well as voluntary exercise, a behavior that confers stress resistance. Elevated GSK3B S389 phosphorylation was associated with increased levels of phosphorylated p38 MAPK. This pathway is implicated in the response to DNA damage, and, surprisingly, we observed that histone H2A-variant-X (H2A.X), a marker of DNA damage, was elevated following stress and exercise. Accumulated DNA damage is a proposed driver of neurodegeneration suggesting that the pathway activated by stress may be engaged to protect against such decline. Consistent with a role in the response to DNA damage, we observed a primarily nuclear localization of GSK3B S389 phosphorylation in the brain while S9 phosphorylation was found in nuclear and cytosolic compartments. Further, we observed neurodegeneration in hippocampal and cortical regions of GSK3B KI mice supporting the idea that the inhibition of GSK3B by S389 phosphorylation observed following stress and exercise may be protective. Though largely similar to wild type mice in behavioral tests, increased auditory fear conditioning was evident in GSK3B KI mice. Contextual and cued freezing was prolonged in GSK3B KI mice, a phenotype that is commonly observed in stress models. Together these findings suggest that GSK3B S389 phosphorylation is playing a critical role in neuronal integrity that is independent of GSK3B S9 phosphorylation, and that the subset of neurons protected by GSK3B S389 phosphorylation may play an important role in preventing a portion of the maladaptive behavioral changes observed following stress exposure.
Number of Pages
Hare, Brendan Deegan, "Glycogen Synthase Kinase-3β: An Investigation Of The Novel Serine 389 Phosphorylation Site" (2015). Graduate College Dissertations and Theses. 357.
Available for download on Sunday, April 02, 2017