Inhibition of casein kinase 1 δ/ε improves cognitive performance in adult C57BL/6J mice

Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1 delta/epsilon, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1 delta/epsilon, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1 delta/epsilon inhibition in improving time-of-day cognitive performance.

Automated summary

Time-of-day effects have been observed in cognitive behavioral tests, and disruption of the circadian system can impair hippocampus-dependent learning and memory. Modulation of circadian kinases, such as CK1 delta/epsilon, presents a novel approach for improving cognitive deficits. The inhibitor PF-670462 showed potential in enhancing cognitive performance in mice, suggesting the utility of CK1 delta/epsilon inhibition in improving time-of-day cognitive performance.