Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium.
BACKGROUND
Bipolar disorder (BPD) is a widespread condition characterized by recurring states of mania and depression. Lithium, a direct inhibitor of glycogen synthase kinase 3 (GSK3) activity, and a mainstay in BPD therapeutics, has been proposed to target GSK3 as a mechanism of mood stabilization. In addition to mood imbalances, patients with BPD often suffer from circadian disturbances. GSK3, an essential kinase with widespread roles in development, cell survival, and metabolism has been demonstrated to be an essential component of the Drosophila circadian clock. We sought to investigate the role of GSK3 in the mammalian clock mechanism, as a possible mediator of lithium's therapeutic effects.


METHODS
GSK3 activity was decreased in mouse embryonic fibroblasts (MEFs) genetically and pharmacologically, and changes in the cyclical expression of core clock genes--mPer2 in particular--were examined.


RESULTS
We demonstrate that genetic depletion of GSK3 in synchronized oscillating MEFs results in a significant delay in the periodicity of the endogenous clock mechanism, particularly in the cycling period of mPer2. Furthermore, we demonstrate that pharmacological inhibition of GSK3 activity by kenpaullone, a known antagonist of GSK3 activity, as well as by lithium, a direct inhibitor of GSK3 and the most common treatment for BPD, induces a phase delay in mPer2 transcription that resembles the effect observed with GSK3 knockdown.


CONCLUSIONS
These results confirm GSK3 as a plausible target of lithium action in BPD therapeutics, and suggest the circadian clock mechanism as a significant modulator of lithium's clinical benefits.
Kaladchibachi
Sevag A
SA
Division of Signaling Biology, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ont. M5G 2M9, Canada. 96kaladc@uhnres.utoronto.ca
Doble
Brad
B
Anthopoulos
Norman
N
Woodgett
James R
JR
Manoukian
Armen S
AS