Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; 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 ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces 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 ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.
Bibliographical noteFunding Information:
We are grateful to Dr Joe Takahashi for the ClockD19 mice. We thank Elizabeth Gordon and Ariel Ketcherside for assistance with mouse husbandry and genotyping, Dr Shari Birnbaum and Ami Petterson for assistance with behavioral testing, and Dr Shibani Mukherjee for assistance with AAV construction and design. We also thank Dr Syann Lee and Dr Joel Elmquist for assistance with laser capture equipment. We also thank Dr R Jude Samulski and the UNC Gene Therapy Vector Core for assistance with AAV preparation. This study was funded by The McKnight Endowment Fund for Neuroscience, The Brain & Behavior Research Foundation (NARSAD) and the NIMH (MH082876).
- Bipolar disorder
- Chromatin structure
- Gene expression