β-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 b-catenin. Normally active GSK-3 phosphorylates b-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases b-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS b-catenin overexpression. Transgenic mice overexpressing b-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 b-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the b-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithiumtreated and b-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 b-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which b-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 b-catenin. By associating the behavioral effects of lithium with b-catenin levels, these data suggest that increasing b-catenin might be a novel therapeutic strategy for mood disorders.

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

“…Consistent with results reported previously for time points between 10 and 35 days (Bersudsky et al, 2007;Cryns et al, 2006;Gould et al, 2007a;O'Brien et al, 2004;Shaldubina et al, 2006), in our experiments 10 days of lithium administration resulted in decreased immobility time in the mouse FST (t(14) = 7.98, p < 0.001; Figure 2a). We have previously reported that i.p.…”

“…administration to rats (Eroglu and Hizal, 1987), acute i.p. administration to mice , and in mice following long-term administration in the chow (Bersudsky et al, 2007;Cryns et al, 2006;Gould et al, 2007a;O'Brien et al, 2004;Shaldubina et al, 2006). To the best of our knowledge, our report is the first to show that lithium by itself has antidepressant-like effects in the TST.…”

“…We have previously reported that i.p. administration of LiCl 30 minutes prior to the FST did not result in antidepressant-like effects (Gould et al, 2007a). However, this administration paradigm results in whole brain lithium levels lower than those necessary to result in antidepressant-like effects in the FST (Bersudsky et al, 2007;Gould et al, 2007a).…”

“…However, limited data exist to suggest that the behavioral effects of lithium in rodent models of mood disorders may be linked to any actions of lithium on AMPA receptor function. Multiple groups have recently shown that long-term administration of lithium in rodent chow results in robust antidepressant-like effects in the FST (Bersudsky et al, 2007;Cryns et al, 2006;Gould et al, 2007a;O'Brien et al, 2004;Shaldubina et al, 2006). The tail suspension test, another measure of antidepressant efficacy, was established in 1985 by Steru and colleagues (Steru et al, 1985), but limited evidence exists for the effects of lithium on this behavioral model.…”

Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation

“…However, they are very consistent with an important new study showing that lithium administration and b-catenin activation produce a similar behavioral phenotype. 42 Adult vs embryonic neural progenitors Previous in vitro studies have focused on lithium's neurogenic effects in ENPs, 13,43 rather than adult progenitors, which often behave differently than their embryonic counterparts. 14 Our findings are in general agreement with previous reports in ENPs.…”