Antidepressant Interactions of Ketamine and Glycogen Synthase Kinase-3 (GSK3) in Mice

of a thesis at the University of Miami. Thesis supervised by Dr. Eleonore Beurel No. of pages in text. (58) Depression is a prevalent and debilitating mood disorder afflicting nearly one in five people in the United States. Current medications used for treatment of depression are inadequate because they have a delayed onset of therapeutic benefit, low efficacy, several side effects, and require chronic administration. This presents the need for improved antidepressant therapies. Ketamine, a general anesthetic, was recently shown to have rapid-acting antidepressant effects at a sub-anesthetic dose. It is unknown how ketamine elicits an antidepressant effect, but several mechanisms have been proposed, including glycogen synthase kinase-3 (GSK3) inhibition and α-amino-3-hydroxy-5-methylospxazol-4-propionic acid (AMPA) receptor activation. This thesis focuses on the role of GSK3 in the ketamine antidepressant effect by expanding previous findings to additional depressive-like behavior models in mice and examines the molecular role of GSK3 and AMPA receptors in response to ketamine in order to further understand the signaling that leads to ketamine’s antidepressant effect. I provide evidence that the antidepressant effect of ketamine requires the inhibition of GSK3 and the activation of AMPA receptors and support a mechanism involving interaction between GSK3 and AMPA receptor trafficking that leads to the antidepressant effect of ketamine. This will provide possible strategies to develop much needed new antidepressant therapies.