title: Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania.
abstract: Lithium is used as treatment for bipolar disorder with particular efficacy in the treatment of mania. Lithium inhibits glycogen synthase kinase 3beta (GSK-3beta) directly or indirectly via stimulation of the kinase Akt-1. We therefore investigated the possibility that transgenic mice overexpressing GSK-3beta could be of relevance to model bipolar disorder. Transgenic mice showed hypophagia, an increased general locomotor activity, and decreased habituation as assessed in an open field, an increased acoustic startle response, and again decreased habituation. The forced swim test revealed a reduced immobility in transgenic mice, but this is probably related to the hyperactivity of the animals. There were no differences in baseline and stress-induced increases of plasma adrenocorticotrophic hormone and corticosterone levels. Molecular analysis suggests compensatory mechanisms in the striatum of these transgenic mice for the overload of active GSK-3beta by dimming the endogenous GSK-3beta signaling pathway via upregulation of Akt-1 expression. Brain-derived neurotrophic factor protein levels were increased in the hippocampus of the transgenic mice. This suggests some kind of compensatory mechanism to the observed reduction in brain weight, which has been related previously to a reduced size of the somatodendritic compartment. Together, in mice overexpressing GSK-3beta, specific intracellular signaling pathways are affected, which is accompanied by altered plasticity processes and increased activity and reactivity, whereas habituation processes seem to be decreased. The behavioral observations led to the suggestion that the model at hand recapitulates hyperactivity as observed in the manic phase of bipolar disorder.
authors.affiliation: Division of Psychiatry, Johnson & Johnson Pharmaceutical Research and Development, B-2340 Beerse, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
authors.forename: Kim
authors.initials: K
authors.lastname: Cryns
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.forename: Hansfried
authors.initials: H
authors.lastname: van Craenendonck
authors.forename: Ilse
authors.initials: I
authors.lastname: Goris
authors.forename: Guy
authors.initials: G
authors.lastname: Daneels
authors.forename: J Adriaan
authors.initials: JA
authors.lastname: Bouwknecht
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001714:Bipolar Disorder / Q000209:etiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D004326:Drinking / Q000502:physiology; D004435:Eating / Q000502:physiology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D006948:Hyperkinesis / Q000209:etiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D017440:Photoperiod; D013216:Reflex, Startle; D015398:Signal Transduction; D013550:Swimming
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000324:Adrenocorticotropic Hormone; D004247:DNA; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D003345:Corticosterone