Transgenic Mice Overexpressing Glycogen Synthase Kinase 3β: 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 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.

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…It was reported that transgenic mice overexpressing GSK3b recapitulate hyperactivity as observed in the manic phase of bipolar disorder. 99 Our result suggests that the decreased GM05926 GM05932 GM05988 GM05990 GM06028 GM06024 GM05984 GM05915 GM05897 pGSK3β (S9)…”

Circadian genes, rhythms and the biology of mood disorders

“…Interestingly, transgenic mice overexpressing the circadian modulator, GSK3β, are hyperactive, have reduced immobility in the forced swim test (indicative of lower depression-like behavior), and an increased startle response (Prickaerts et al, 2006). These behaviors are reminiscent of bipolar patients in the manic state.…”

Disruption of the Circadian Output Molecule Prokineticin 2 Results in Anxiolytic and Antidepressant-like Effects in Mice

“…Single-nucleotide polymorphism analysis and studies with animal models that have disrupted circadian rhythms have indicated a molecular link between circadian rhythms and mood regulation (Curtis et al, 2007;McClung, 2007;Prickaerts et al, 2006;Roybal et al, 2007). Our findings here indicate that PK2, as an SCN circadian output factor, also plays a critical role in the regulation of stress-related traits.…”

“…Furthermore, mice harboring a mutation in the Clock gene were shown to display reduced depression-like behavior in the forced swimming and learned helplessness tests, as well as reduced anxiety or increased risk-taking behavior in several measures (Easton et al, 2003;Roybal et al, 2007). Transgenic mice overexpressing GSK3b, a circadian modulator, are hyperactive and have reduced immobility in the forced swimming test, indicating lower depression-like behavior (Prickaerts et al, 2006). Thus, these studies have implicated the link between mood regulation and certain circadian genes.…”