Effect of lithium on the circadian rhythms of locomotor activity and GSK-3 protein expression in the mouse suprachiasmatic nuclei

The suprachiasmatic nucleus (SCN), which is located in hypothalamus regulates the mammalian physiological and behavioral rhythms to approximately 24hr. Lithium is one of the most commonly used drugs in treatment of bipolar disorder. It can also lengthen the period of circadian rhythms in most organisms, although little is known about the underlying mechanism. In our study, we showed that wild-type mice entrained to only an LD 24 hr cycle, whereas Clock gene mutant mice, which is one of the essential circadian gene mutated mouse can entrained to an LD 24, 28, and 32 hr cycle. This result suggested that the circadian oscillator would be possible to entrain to the long period environment by controlling clock genes. In the first study, we examined Drosophila shaggy orhtholog, glycogen synthase kinase-3 (GSK-3) has an important role for regulating mammalian circadian oscillations in lengthened circadian period. After lithium treatment, GSK-3 protein expression in the SCN had been changed its form as inactive. When we assessed locomotor activity, we found an association between the effect of lithium and the period of circadian oscillation as well as the level of GSK-3 protein expression. The decreasing expression of GSK-3 and the increasing expression of phosphorylated GSK-3 (pGSK-3) resulted in an anti-phasic circadian rhythm between the two in the SCN of lithium-treated mice housed under both LD-and DD-cycle conditions. Enzyme activity of GSK-3 in the SCN was low when the level of pGSK-3 protein was high examined by immunoblotting analysis. Thus, GSK-3 enzyme activity has a correlation with the expression of GSK-3 2 protein in the SCN. Although both GSK-3 and pGSK-3 proteins are also expressed in the arcuate nucleus (ARC), lithium did not affect their expression. Based on the association we found between lengthened circadian period and GSK-3 protein and GSK-3 activity in the SCN, we suggest that GSK-3 plays a role in regulating the period of the mammalian circadian pacemaker. In the second study, we show that lithium affects the circadian oscillator in young and old hamster SCN, in an age-dependent manner. In has already known the period gets shorter in age-dependent in hamster. We want to know how lithium work in aged mammalian brain. We found that basal levels of phosphorylated GSK-3 (pGSK-3) protein expression in aged hamsters are much lower than that in young hamsters. Interestingly, in the aged hamsters, lithium did not affect the period of the locomotor activity rhythm and pGSK-3 expression, …