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

  • Sci Rep. 2021 Feb 26;11(1):4746. doi: 10.1038/s41598-021-83957-9.
Heather Mahoney  1  2 ,  Emily Peterson  1  2 ,  Hannah Justin  1  2 ,  David Gonzalez  1  2 ,  Christopher Cardona  1  2 ,  Korey Stevanovic  3 ,  John Faulkner  1  2 ,  Amara Yunus  4 ,  Alexandra Portugues  1  2 ,  Amy Henriksen  1  2 ,  Camden Burns  1  2 ,  Cameron McNeill  5 ,  Joshua Gamsby  1  2 ,  Danielle Gulick  6  7
Affiliations
  • 1. Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA.
  • 2. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
  • 3. National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC, USA.
  • 4. College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • 5. USF Health Informatics Institute, University of South Florida Health, Tampa, FL, USA.
  • 6. Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA. [email protected].
  • 7. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. [email protected].
PMID: 33637777 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.

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