Neurosciences
Program

Blackwell, R.A., Gould, T.D., and Brady, A.M.  (2008, November).  Cognitive and behavioral deficits in beta-catenin knockout mice: an endophenotype approach to modeling bipolar disorder.  Poster presented at the Society for Neuroscience Annual Meeting, Washington, DC.

Abstract 

Developing novel medications to treat bipolar disorder has been difficult, with lithium being the main drug used to treat the disorder for over three decades in spite of severe side effects. Increasing levels of beta-catenin produces behavioral effects similar to lithium administration, suggesting that low beta-catenin levels may be involved in bipolar disorder. Reproducing the cyclicity of bipolar disorder is a major obstacle in developing valid animal models of the condition, and may be unnecessary. Instead, the current study investigated multiple behavioral and cognitive endophenotypes of bipolar disorder in a beta-catenin knockout mouse model. Female C57BL/6 wild-type (WT) and Cre-mediated conditional forebrain beta-catenin knockout (KO) mice were used. Subjects were tested for depressive-like behaviors in the tail suspension test (TST) and forced swim test (FST); for increased locomotion in standard activity chambers; and for spatial learning in a six-arm radial arm maze (RAM). As cognitive deficits have been linked with reduced dendritic spine density in other animal models, hippocampal tissue (stained using the Golgi-Cox method) was examined for spine density. Preliminary data indicates that KO animals had a tendency to spend more time in immobility in the TST (but not the FST), suggesting an increase in depressive-like behavior. However, KO mice did not show increases in locomotor activity, which has been suggested as a correlate of manic-like behavior. Additionally, KO mice took significantly more days to reach criterion in the RAM than WT mice, suggesting that spatial learning is impaired in mice with low levels of beta-catenin. The greater immobility time in the TST in female beta-catenin KO mice mirrors previous findings in male beta-catenin KO mice, and the finding of impaired spatial memory extends the characterization of these mice to include cognitive deficits as observed in patients with bipolar disorder. Overall, these findings provide preliminary support for the validity of the beta-catenin knockout model in female mice. However, as there were no significant differences in activity or in the FST, further study will be required before the model may be considered fully valid for bipolar disorder.