The role of glycogen synthase kinase-3β in schizophrenia

Glycogen synthase kinase (GSK)-3 beta is recognized as a ubiquitous multifunctional enzyme involved in the modulation of many aspects of neuronal function. Inhibitory control of GSK-3 beta has been identified to be crucial for the phosphoinositide T-kinase (Pl3K)-protein kinase B (Akt)-mediated cell survival. Several lines of evidence converge in implicating abnormal GSK-3 beta activity in the pathogenesis of schizophrenia. Preclinical evidence showing that both typical and atypical antipsychotics can indirectly inhibit the activity of GSK-3 beta, has pointed to GSK-3 beta as a possible therapeutic target for schizophrenia. It is well known that GSK-3 beta can be indirectly inhibited via regulation of several intracellular signaling cascades, including the canonical Wnt, Reelin and tyrosine kinase receptor (Trk)-Pl3K-Akt. Recently, direct inhibition of GSK-3 beta has emerged as a possible option in the pharmacotherapy of several neuropsychiatric disorders. There is, however, a number of issues that need to be considered regarding therapeutic utility of GSK-3 beta inhibitors. This article reviews the evidence supporting the possible role of aberrant GSK-3 beta in the pathogenesis of schizophrenia and thus suggesting GSK-3 beta to be a potential therapeutic target for this disorder. (c) 2007 Prous Science. All rights reserved.