An inhibitor of casein kinase 1 ε/δ partially normalizes the manic-like behaviors of the ClockΔ19 mouse

Abstract

Bipolar disorder is a terrible and debilitating disease with limited treatment options. Circadian rhythm disruptions are prominent in bipolar subjects, and studies have shown that rhythm stabilization through psychosocial interventions can improve their symptoms. Furthermore, mice with a mutation in one of the central circadian proteins, CLOCK, have severely disrupted rhythms along with a behavioral profile that closely resembles human mania. A compound has been developed (CK01, similar to PF-670462) that inhibits the activity of casein kinase 1 (CK1), a critical protein involved in the timing of the molecular clock. Previous studies have shown that PF-670462 and other similar compounds are capable of entraining and stabilizing rhythms in arrhythmic animals. Here we show that chronic administration of CK01 leads to a reversal of the anxiety-related behavior, and partial reversal of the depression-related phenotypes of the Clock mutant mouse. This drug had no significant effects on the behavior of wild-type mice at the doses tested. These results suggest that CK1ε/δ inhibitors could be viable drugs for the treatment of bipolar disorder.

Fig. 1

CK01 administration has no effect on the locomotor response to novelty. Locomotor activity was measured in the ClockΔ19 mice and the wild-type littermates for 2 h following 10 days of CK01 or lithium administration. Analysis by two-way analysis of variance revealed a significant main effect of genotype [F_(1,90) =145.94, P<0.001]. Bonferroni’s post-hoc tests revealed that there was no significant effect of any treatment on locomotor response to novelty (n=12–14/group). LiCl, lithium chloride. ***P<0.001.

Fig. 2

CK01 administration normalized anxiety-related behavior in the ClockΔ19 mice. (a, b) The ClockΔ19 mice and the wild-type (WT) littermates were assessed for anxiety-related behavior following CK01 and lithium administration in both the elevated plus maze (EPM) (a) and dark/light test (b). Analysis by two-way analysis of variance revealed that ClockΔ19 mice display previously reported decreased anxiety-related behavior by spending more time in the open arms of the EPM [main effect of genotype; F_(1,83) =6.39, P<0.02] and light side of the dark/light box [main effect of genotype; F_(1,85)=21.93, P<0.001]. Bonferroni’s post-tests revealed that 17.8 mg/kg CK01 treatment caused a reduction in open arm time that did not reach significance in the EPM (a) and a significant reduction in time spent in the light side of the dark/light test (b, t =2.553, P<0.05). 32.0 mg/kg CK01 treatment in ClockΔ19 mice caused a significant decrease in EPM open arm time (a, t=2.55, P<0.05) and time spent on the light side of the dark/light test (b, t=3.62, P<0.01). As described previously, lithium had antimanic effects on the ClockΔ19 mice by restoring open-arm time in the EPM (a, t=2.75, P<0.05) and time in the light side of the dark/light test (b, t=3.25, P<0.05) to WT levels. CK01 treatment had no significant effect on the anxiety-related behavior when compared with the vehicle-treated WT mice; however, Bonferroni’s post-hoc tests revealed that lithium treatment caused an anxiolytic effect that differed significantly from mice receiving 32.0 mg/kg CK01 (a, t =3.04, P<0.01), but not vehicle or 17.8 mg/kg CK01 treated mice. LiCl, lithium chloride. *P<0.05, **P<0.01, ***P<0.001.

Fig. 3

CK01 administration has partial effects on ClockΔ19 depression-related behavior. (a) ClockΔ19 and wild-type (WT) mice were assessed for depression-related behavior using the forced swim test following CK01 and lithium treatment. Analysis by two-way analysis of variance (ANOVA) showed that the ClockΔ19 mice have decreased immobility time compared with the WT animals [main effect of genotype; F_(1,88) =21.39, P<0.001]. Bonferroni’s post-hoc tests showed that lithium treatment had previously reported antimanic effects on ClockΔ19 depression-related behavior by increasing the total immobility time (t=2.52, P<0.05). CK01 treatment had no detectable effect on either ClockΔ19 or WT immobile time. (b) Latency to immobility was assessed following CK01 and lithium treatment in ClockΔ19 and WT animals. ClockΔ19 mice had a significantly longer latency to immobility than WT animals by two-way ANOVA [main effect of genotype; F_(1,87) =6.30, P<0.02]. Bonferroni’s post-hoc tests revealed a significant effect of treatment with 17.8 mg/kg CK01 (t=2.82, P<0.05), 32.0 mg/kg CK01 (t =2.80, P<0.05), and lithium (t=3.40, P<0.01) treatment on latency to immobility in ClockΔ19 mice. WT animals were not significantly affected by treatment. LiCl, lithium chloride. *P<0.05, **P<0.01, ***P<0.001.