The GSK-3 Inhibitor CT99021 Enhances the Acquisition of Spatial Learning and the Accuracy of Spatial Memory

Yeseul Lee; Zuner A Bortolotto; Clarrisa A Bradley; Thomas M Sanderson; Min Zhuo; Bong-Kiun Kaang; Graham L Collingridge

doi:10.3389/fnmol.2021.804130

The GSK-3 Inhibitor CT99021 Enhances the Acquisition of Spatial Learning and the Accuracy of Spatial Memory

Front Mol Neurosci. 2022 Jan 27:14:804130. doi: 10.3389/fnmol.2021.804130. eCollection 2021.

Authors

Yeseul Lee^{1

2

3}, Zuner A Bortolotto², Clarrisa A Bradley^{1

4

5}, Thomas M Sanderson^{1

2

3}, Min Zhuo^{1

6}, Bong-Kiun Kaang^{1

7}, Graham L Collingridge^{1

2

3

6

8}

Affiliations

¹ Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea.
² Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
³ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
⁴ Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Genes and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁷ Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea.
⁸ Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, Canada.

Abstract

Glycogen synthase kinase 3 (GSK-3) is a Ser/Thr protein kinase that regulates many cellular processes, including synaptic plasticity. Previously, we reported that inhibition of GSK-3 prevents the induction of one of the major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD), in hippocampal slices. In the present study, we have investigated the effects of inhibiting GSK-3 on learning and memory in healthy naïve animals. Systemic administration of a highly selective GSK-3 inhibitor, CT99021, reversibly blocked NMDAR-dependent LTD in the CA1 region of the hippocampus in anesthetized adult mice. In behavioral tasks, CT99021 had no effect on locomotor activity, anxiety, hippocampus-dependent contextual fear memory, and hippocampus-dependent reversal learning. However, CT99021 facilitated the rate of learning in the Morris water maze (MWM) and T-maze and enhanced the accuracy of long-term spatial memory in the MWM. These findings suggest that GSK-3 regulates the accuracy of spatial memory acquisition and recall.

Keywords: CT99021; DMTP T-maze; GSK-3; Morris water maze; NMDAR-dependent LTD; memory enhancement; spatial learning and memory.