All ETDs from UAB

Advisory Committee Chair

Xiaohua Li

Advisory Committee Members

John Hablitz

Richard Jope

Anne Theibert

Scott Wilson

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mood disorders are devastating psychiatric illnesses that will affect as many as one in every five persons worldwide over the course of their lifetime. Significant gaps still remain in our understanding of these illnesses and outcomes for many patients are far from optimal. Glycogen Synthase Kinase 3 (GSK3) is a protein kinase that is increasingly recognized as playing an important role in a number of neuronal functions, as well as in pathological states such as mood disorders. GSK3 is inhibited in the brain by phosphorylation on an N-terminal serine. Several treatments for mood disorders, including lithium, antidepressants, and atypical antipsychotics increase this inhibitory phosphorylation, suggesting that it may be an important mechanism for the regulation of mood. In these studies, we investigate the role of serine phosphorylation of GSK3 in the treatment and pathophysiology of mood disorders. To investigate the mechanisms of mood disorder treatment, we first examined activation of Akt, an upstream regulating kinase of GSK3, in response to serotonin. Both an acute increase in serotonin and chronic antidepressant treatment result in a functional activation of the Akt signaling pathway. Similarly, activation of 5-HT1A receptors were found to increase phosphorylation of GSK3 through activation of the PI3K/Akt pathway, and phosphorylation of GSK3 was found to be necessary for 5-HT1A receptor-mediated inhibition of conditioned fear memories. Antagonism of 5-HT2A receptors was found to inhibit GSK3 through activation of Akt, while activation of 5-HT2A receptors was found to increase inhibitory phosphorylation of GSK3 only in the absence of ß-arrestin2. Furthermore, loss of ß-arrestin2 potentiates the antidepressant-induced increase in phosphorylated GSK3 as well as the behavioral response to antidepressants. Finally, we investigated the behavioral effects of decreased serine-phosphorylation of GSK3 using knock-in mice with GSK3 that is immune to serine phosphorylation. We found that loss of this phosphorylation resulted in increased behavioral susceptibility to induction of both manic- and depressive-like states. The studies presented here demonstrate that serine phosphorylation of GSK3 plays a critical role in mood disorder pathology. This gives us novel insights into the regulation of mood, and may provide avenues for the development of more effective treatments for mood disorders.

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