Inhibition of casein kinase 1 \u03b4/\u03b5 improves cognitive performance in adult C57BL/6J mice

Heather Mahoney,John Faulkner,Hannah Justin,Cameron Mcneill,Joshua Gamsby,Camden Burns,Amara Yunus,Emily Peterson,Danielle Gulick,Christopher Cardona,Alexandra Portugues,David Gonzalez,Korey Stevanovic,Amy Henriksen

doi:10.1038/s41598-021-83957-9

Abstract

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 CK1δ/ε, 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 CK1δ/ε, 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 CK1δ/ε inhibition in improving time-of-day cognitive performance.

Highlights

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 suprachiasmatic nucleus (SCN) or downstream, impairs hippocampus-dependent learning and memory
We focused our investigation on CK1δ inhibition, hypothesizing that cognitive performance rhythms and time-of-day gating of learning and memory in the hippocampus may be altered
Our experimental conditions were modeled after several studies that administered PF-670462 at or near ZT10 to correspond with peak CK1δ/ε activity in the SCN in order to generate the maximum effect on the circadian phase[31,33,36]

Summary

Introduction

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. 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. The SCN conveys time-of-day information to peripheral oscillators, including the hippocampus and amygdala, essential memory processing areas[17,18,19] This master circadian oscillator can be reset or “entrained” by exogenous cues called zeitgebers, which allow the system to adapt to changes in the environment and keep circadian rhythms aligned to their appropriate phase. Mice with mutations in PER1 or PER2 have deficits in long-term memory, and PER2-deficient mice exhibit abnormal long-term potentiation and reduced phosphorylation of cAMP-response-element-binding protein (CREB) in the h ippocampus[19,28]

Methods

Results

Conclusion