Cited by 341Bipolar Disorder and TreatmentNeuroscience and Neuropharmacology ResearchTreatment of Major Depression

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Transgenic Mice Overexpressing Glycogen Synthase Kinase 3β: A Putative Model of Hyperactivity and Mania

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Prickaerts, Jos, Moechars, Dieder, Cryns, Kim, Lenaerts, Ilse, van Craenendonck, Hansfried, Goris, Ilse, Daneels, Guy, Bouwknecht, J. Adriaan, Steckler, Thomas·2006·The Journal of Neuroscience

DOI 10.1523/jneurosci.5216-05.2006PMC PMC6675350

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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.

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Authors: Prickaerts, J., Moechars, D., Cryns, K., Lenaerts, I., van Craenendonck, H., Goris, I., Daneels, G., Bouwknecht, J. A., & Steckler, T.
Affiliations: Janssen Research & Development (United States) (US)
Corresponding author: Steckler, Thomas
ORCID: Prickaerts, Jos
Lenaerts, Ilse
Steckler, Thomas
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2006-08-30
Volume: 26
Issue: 35
Pages: 9022-9029
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.5216-05.2006
PMC: PMC6675350
OpenAlex: W1963600261
Cited by: 341
References: 59
Citations by year: 2026: 5 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 13 · 2021: 14 · 2020: 17 · 2019: 7 · 2018: 11 · 2017: 13 · 2016: 22 · 2015: 20 · 2014: 27 · 2013: 27 · 2012: 21
FWCI: 11.04
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 182 d)
Locations: Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Research Publications (Maastricht University) (publishedVersion, cc-by-nc-sa)
Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders: European Commission
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords: glycogen synthase kinase-3β, transgenic mice, hyperactivity, mania, bipolar disorder, lithium, AKT1, brain-derived neurotrophic factor, striatum, hippocampus, locomotor activity, acoustic startle response, habituation, ACTH, compensatory signaling, neuroplasticity
MeSH terms: Glycogen Synthase Kinase 3 beta, Adrenocorticotropic Hormone, Animals, Bipolar Disorder, Corticosterone, Disease Models, Animal, DNA, Drinking, Eating, Female, Hippocampus, Hyperkinesis, Male, Mice, Transgenic, Motor Activity, Reflex, Startle, Swimming, Signal Transduction, Photoperiod, Brain-Derived Neurotrophic Factor, Glycogen Synthase Kinase 3, Mice

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Transgenic Mice Overexpressing Glycogen Synthase Kinase 3β: A Putative Model of Hyperactivity and Mania

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