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The Journal of Neuroscience, August 30, 2006, 26(35):9022-9029; doi:10.1523/JNEUROSCI.5216-05.2006

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Behavioral/Systems/Cognitive
Transgenic Mice Overexpressing Glycogen Synthase Kinase 3: A Putative Model of Hyperactivity and Mania

Jos Prickaerts,^1,3 * Dieder Moechars,^2 * Kim Cryns,² Ilse Lenaerts,¹ Hansfried van Craenendonck,¹ Ilse Goris,² Guy Daneels,² J. Adriaan Bouwknecht,¹ and Thomas Steckler¹

¹Division of Psychiatry and ²Functional Genomics, Johnson & Johnson Pharmaceutical Research and Development, B-2340 Beerse, Belgium, and ³Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD, Maastricht, The Netherlands

Correspondence should be addressed to Dr. Thomas Steckler, Division of Psychiatry, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. Email: tsteckle{at}prdbe.jnj.com

Lithium is used as treatment for bipolar disorder with particular efficacy in the treatment of mania. Lithium inhibits glycogen synthase kinase 3 (GSK-3) directly or indirectly via stimulation of the kinase Akt-1. We therefore investigated the possibility that transgenic mice overexpressing GSK-3 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-3 by dimming the endogenous GSK-3 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-3, 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.

Key words: Akt-1; mania; lithium; bipolar disorder; schizophrenia; dopamine

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Received Dec. 7, 2005; revised July 7, 2006; accepted July 28, 2006.

Correspondence should be addressed to Dr. Thomas Steckler, Division of Psychiatry, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. Email: tsteckle{at}prdbe.jnj.com

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