Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment

Abstract

Genomic studies suggest an association of circadian clock genes with bipolar disorder (BD) and lithium response in humans. Therefore, we tested mice mutant in various clock genes before and after lithium treatment in the forced swim test (FST), a rodent behavioral test used for evaluation of depressive-like states. We find that expression of circadian clock components, including Per2, Cry1 and Rev-erbα, is affected by lithium treatment, and thus, these clock components may contribute to the beneficial effects of lithium therapy. In particular, we observed that Cry1 is important at specific times of the day to transmit lithium-mediated effects. Interestingly, the pathways involving Per2 and Cry1, which regulate the behavior in the FST and the response to lithium, are distinct as evidenced by the phosphorylation of GSK3β after lithium treatment and the modulation of dopamine levels in the striatum. Furthermore, we observed the co-existence of depressive and mania-like symptoms in Cry1 knock-out mice, which resembles the so-called mixed state seen in BD patients. Taken together our results strengthen the concept that a defective circadian timing system may impact directly or indirectly on mood-related behaviors.

• Bipolar disorder
• Cry1
• cryptochrome
• depression
• mixed state
• neurogenesis

ACKNOWLEDGEMENTS

We would like to thank Stéphanie Baeriswyl-Aebischer and Antoinette Hayoz for technical assistance and Drs. Bert van der Horst and Ueli Schibler for initially providing Cry and Rev-erbα knock-out mice for our breeding colony.

DECLARATION OF INTEREST

The authors declare they have no competing financial interests.

All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AS, FS, VR, LA, UA. Acquisition of data: AS, FS, VR, JAR, EB. Analysis and interpretation of data: AS, FS, LA, VR, GR, UA. Writing of the manuscript: AS, UA. Obtained funding: UA. Support from the Swiss National Science Foundation, the Velux Foundation and the State of Fribourg is gratefully acknowledged.

Supplementary material available online.

Supplementary Figures S1 and S2, Table S1.