Hypoxia activates glycogen synthase kinase-3 in mouse brain in vivo: Protection by mood stabilizers and imipramine

Background: Glycogen synthase kinase-3 (GSK3), which is primarily regulated by an inhibitory phosphorylation of all N-terminal serine, has been implicated as contributing to mood disorders by the finding that it is inhibited by the mood stabilizer lithium. Methods: This study tested if the antidepressant imipramine or the mood stabilizers lithium and sodium valproate regulated pathophysiological serine-dephosphorylation of GSK3 caused by hypoxia in mouse brain in vivo. Results: Hypoxia caused rapid serine-dephosphorylation of both isoforms of GSK3, GS3beta and GSK3alpha, in mouse cerebral cortex, hippocampus, and striatum. Pretreatment of mice with imipramine, sodium valproate, or lithium attenuated hypoxia-induced serine-dephosphorylation of GSK3beta and GSK3alpha in all three brain regions. Conclusions: These results demonstrate that imipramine and mood stabilizers are capable of blocking pathophysiologically induced serine-dephosphorylation of GSK3, supporting the hypothesis that stabilization of serine-phosphorylation of GSK3 contributes to their therapeutic effects.