What can a clock mutation in mice tell us about bipolar disorder?

Abstract

Bipolar disorder, also known as manic-depressive illness, is characterized by episodes of mania and episodes of depression usually interspersed with periods of relatively normal mood (1). During the manic phase, affected individuals exhibit elevated mood, irritability, increased activity, reduced sleep, hypersexuality, and increased goal-directed activities. Bipolar disorder in its various forms affects >3% of the population and is associated with a high risk for suicide, substance abuse, and vocational disability (2). Although several animal models for major depressive disorder have been developed, there are no plausible models for bipolar disorder (3). In this issue of PNAS, Roybal et al. (4) describe the results of a systematic analysis of the behavior of a mouse with a deletion of exon 19 in the Clock gene, which shows remarkable parallels to the symptoms observed in individuals in an episode of mania (1). The Clock mutant mice exhibit hyperactivity, decreased sleep, reduced anxiety, and increased response to cocaine, sucrose, and medial forebrain bundle stimulation. Furthermore, many of these behaviors can be reversed by transfection of the ventral tegmental area (VTA) dopaminergic neurons with WT Clock gene or by treatment with therapeutic doses of lithium (Li+), a commonly prescribed mood stabilizer.