title: Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors.
abstract: Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is unclear if this inhibition and its downstream effects on specific signaling pathways are relevant to the treatment of bipolar disorder and depression. One of the targets of GSK-3 is the transcription factor beta-catenin. Normally active GSK-3 phosphorylates beta-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases beta-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS beta-catenin overexpression. Transgenic mice overexpressing beta-catenin demonstrated behavioral changes similar to those observed following the administration of lithium, including decreased immobility time in the forced swim test (FST). Further, we show that although acute administration of lithium and overexpression of the beta-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the beta-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithium-treated and beta-catenin mice had an elevated response to d-amphetamine following multiple administrations of the stimulant, though the difference in absolute locomotion was maintained throughout the sensitization time-course. Neither acute lithium nor beta-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which beta-catenin transgenic mice exhibited behaviors identical to those observed in lithium-treated mice, are consistent with the hypothesis that the behavioral effects of lithium in these models are mediated through its direct inhibition of GSK-3 and the consequent increase in beta-catenin. By associating the behavioral effects of lithium with beta-catenin levels, these data suggest that increasing beta-catenin might be a novel therapeutic strategy for mood disorders.
authors.affiliation: Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-3711, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Gould
authors.forename: Haim
authors.initials: H
authors.lastname: Einat
authors.forename: Kelley C
authors.initials: KC
authors.lastname: O'Donnell
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Picchini
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schloesser
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D019964:Mood Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D011595:Psychomotor Agitation / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D018692:Antimanic Agents; D051176:beta Catenin; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3