All ETDs from UAB

Advisory Committee Chair

Richard S Jope

Advisory Committee Members

Scott R Barnum

Rita M Cowell

Suzanne M Michalek

Harald S Sontheimer

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Neuroinflammation and Fragile X syndrome (FXS) are two particularly devastating neurologic conditions for which no adequate treatment exists and much is still unknown about the underlying cellular and molecular processes. Neuroinflammation contributes to the pathogenesis of many neurologic and psychiatric disorders, thus treatment of the underlying inflammation has broad implications. FXS is the most common cause of inherited intellectual and developmental delay and one of the few known genetic causes of autism. Neuroinflammation and FXS have potential links with glycogen synthase kinase-3 (GSK3) and its inhibitor, lithium. Therefore, the overall goal of this research was to examine the role of GSK3 in neuroinflammation and FXS, as well as the potential therapeutic value of GSK3 inhibitors in these neurologic conditions. Most neuroinflammatory processes result in activation of microglia, the resident immune cells of the brain. Microglial responses include migration to an injury site and the release of pro- and anti-inflammatory factors, which ultimately can affect neuronal survival. Treatment with GSK3 inhibitors attenuated several microglial responses in vitro and in situ after lipopolysaccharide (LPS)-induced activation of microglia, including migration, activation, and production of pro-inflammatory molecules. GSK3 inhibitors also provided protection from inflammation-induced neuronal toxicity. Thus, the utilization of GSK3 inhibitors provides a means to limit the inflammatory actions of microglia and provides neuroprotection after an inflammatory insult. FXS results from an expansion-mutation upstream of the fragile X mental retardation 1 (Fmr1) gene causing loss of the gene product. Together with previous results, it was discovered that impaired inhibitory serine-phosphorylation of GSK3 is a robust phenotype in the brains of Fmr1 knockout mice and two potential therapeutics for FXS, a metabotropic glutamate receptor antagonist and lithium, converge to inhibit GSK3. Chronic lithium treatment reversed the hyperactive GSK3 in the brains of Fmr1 knockout mice and improved many of the tested FXS-associated behaviors. Therefore, impaired inhibitory regulation of GSK3 plays a prominent role in the pathogenesis of FXS and supports GSK3 as a potential therapeutic target. Overall, this work provides novel insight regarding the function of GSK3 in two pathologic processes in the central nervous system, and further supports GSK3 inhibitors as viable therapeutics for both neuroinflammation and FXS.

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