Glycogen synthase kinase-3β haploinsufficiency lengthens the circadian locomotor activity period in mice

• GSK3β+/− mice have a lengthened intrinsic circadian locomotor activity as compared to WT mice.
• No significant difference in locomotor activity was observed between both groups.
• GSK3β haploinsufficiency mimics the circadian phenotype observed with lithium treatment.

The mood stabiliser drug lithium has been reported to impact circadian rhythms in vertebrates. Among several putative therapeutic molecular targets, direct inhibition of glycogen synthase kinase-3 beta (GSK3β) by lithium has been proposed to underlie its effects on circadian physiology. Here we study the effect of GSK3β haploinsufficiency on the circadian locomotor activity in mice during a free-running period in comparison to wildtype littermates (WT). Mice were housed individually to record their circadian wheel running activity and were entrained to a 12 h light/12 h dark cycle for 14 days and then placed under constant darkness for 14 days to allow free-running. During the free-running phase, the circadian locomotor activity period of GSK3β+/− was significantly lengthened (23.83 ± 0.05 h) when compared to the WT mice (23.54 ± 0.10 h; p = 0.0374). No significant difference in locomotor activity was observed. Knowing that GSK3β interacts with most of the core clock components, these data suggest that GSK3β acts as a critical intrinsic regulator of the circadian clock and plays an important role in regulating its period in response to lithium treatment.