The role of glycogen synthase kinase-3beta in schizophrenia.
Glycogen synthase kinase (GSK)-3beta is recognized as a ubiquitous multifunctional enzyme involved in the modulation of many aspects of neuronal function. Inhibitory control of GSK-3beta has been identified to be crucial for the phosphoinositide 3'-kinase (PI3K)-protein kinase B (Akt)-mediated cell survival. Several lines of evidence converge in implicating abnormal GSK-3beta activity in the pathogenesis of schizophrenia. Preclinical evidence showing that both typical and atypical antipsychotics can indirectly inhibit the activity of GSK-3beta, has pointed to GSK-3beta as a possible therapeutic target for schizophrenia. It is well known that GSK-3beta can be indirectly inhibited via regulation of several intracellular signaling cascades, including the canonical Wnt, Reelin and tyrosine kinase receptor (Trk)-PI3K-Akt. Recently, direct inhibition of GSK-3beta 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-3beta inhibitors. This article reviews the evidence supporting the possible role of aberrant GSK-3beta in the pathogenesis of schizophrenia and thus suggesting GSK-3beta to be a potential therapeutic target for this disorder.
Koros
Eliza
E
Department of CNS Research, Boehringer-Ingelheim Pharma GmbH & Co., Biberach, Germany. eliza.koros@boehringer-ingelheim.com
Dorner-Ciossek
Cornelia
C
D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology; D004358:Drug Therapy / Q000639:trends; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D000091042:Reelin Protein; D012559:Schizophrenia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D000091042:Reelin Protein; C000605506:GSK3B protein, human; C000717127:RELN protein, human