Identification of Molecular Mechanisms That Underlie the Development and Treatment of Manic-Like Behaviors in Mice: the Importance of Cholecystokinin and Chromatin Modifications

Bipolar disorder (BPD) is a severe and chronic psychiatric disease that is defined by the occurrence of one or more manic or mixed episodes. The underlying cause of BPD, as well as the mechanisms of action of current pharmacological treatments for BPD, are poorly understood. Mice with a mutation in the Clock gene (ClockDelta19) have been identified as a model of mania that respond to lithium treatment; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium’s effectiveness on these mice remain unclear. Here we find that Cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockDelta19 mice. Selective knock-down of Cck expression via RNA interference (RNAi) in the VTA of wild type mice is sufficient to produce a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockDelta19 mice is due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. We also found that another mood stabilizer, valproate (VPA), has mood stabilizing effects in the ClockDelta19 mice, and that VPA causes a restoration of Cck levels in the VTA, similar to lithium. Further investigation into the regulation of the Cck gene by VPA identified a role for histone acetylation in the therapeutic actions of mood stabilizers in the ClockDelta19 mice. Both lithium and VPA cause increases in histone acetylation at the Cck promoter, though potentially through different mechanisms. Lithium treatment may cause recruitment of specific chromatin remodeling complexes, while VPA appears to regulate the Cck gene through HDAC inhibition. The importance of HDAC inhibition in VPA’s therapeutic actions was strengthened by the finding that administration of the specific Class I and IIb HDAC inhibitor suberoylanilide hydroxamic acid was sufficient to rescue manic-like behaviors in the ClockDelta19 mice. These studies identify a key role for Cck in the development and treatment of mania, and for regulation of chromatin modifications in the therapeutic actions of mood stabilizers.