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; Tom 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

Yeseul Lee, Zuner A Bortolotto, Clarrisa A. Bradley, Tom M Sanderson, Min Zhuo, Bong-Kiun Kaang^*, Graham L Collingridge^*

^*Corresponding author for this work

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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.

Original language	English
Article number	804130
Number of pages	13
Journal	Frontiers in Molecular Neuroscience
Volume	14
Early online date	27 Jan 2022
DOIs	https://doi.org/10.3389/fnmol.2021.804130
Publication status	E-pub ahead of print - 27 Jan 2022

Bibliographical note

Funding Information:
The behavioral study was supported by the World-Class University Program, the Creative Research Initiative Program of the Ministry of Science and Technology in Korea, and the National Honor Scientist Program of the National Research Foundation funded by the Korea Government (B-KK). The electrophysiological study was supported by the European Research Council (GC), the Medical Research Council (GC), and the Biotechnology and Biological Science Research Council (GC). GC was also supported by the Krembil Family Chair in Alzheimer’s Research and the Canadian Institute of Health Research.

Publisher Copyright:
Copyright © 2022 Lee, Bortolotto, Bradley, Sanderson, Zhuo, Kaang and Collingridge.

Keywords

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

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title = "The GSK-3 inhibitor CT99021 enhances the acquisition of spatial learning and the accuracy of spatial memory",

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 na{\"i}ve 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.",

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author = "Yeseul Lee and Bortolotto, {Zuner A} and Bradley, {Clarrisa A.} and Sanderson, {Tom M} and Min Zhuo and Bong-Kiun Kaang and Collingridge, {Graham L}",

note = "Funding Information: The behavioral study was supported by the World-Class University Program, the Creative Research Initiative Program of the Ministry of Science and Technology in Korea, and the National Honor Scientist Program of the National Research Foundation funded by the Korea Government (B-KK). The electrophysiological study was supported by the European Research Council (GC), the Medical Research Council (GC), and the Biotechnology and Biological Science Research Council (GC). GC was also supported by the Krembil Family Chair in Alzheimer{\textquoteright}s Research and the Canadian Institute of Health Research. Publisher Copyright: Copyright {\textcopyright} 2022 Lee, Bortolotto, Bradley, Sanderson, Zhuo, Kaang and Collingridge.",

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AU - Zhuo, Min

AU - Kaang, Bong-Kiun

AU - Collingridge, Graham L

N1 - Funding Information: The behavioral study was supported by the World-Class University Program, the Creative Research Initiative Program of the Ministry of Science and Technology in Korea, and the National Honor Scientist Program of the National Research Foundation funded by the Korea Government (B-KK). The electrophysiological study was supported by the European Research Council (GC), the Medical Research Council (GC), and the Biotechnology and Biological Science Research Council (GC). GC was also supported by the Krembil Family Chair in Alzheimer’s Research and the Canadian Institute of Health Research. Publisher Copyright: Copyright © 2022 Lee, Bortolotto, Bradley, Sanderson, Zhuo, Kaang and Collingridge.

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N2 - 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.

AB - 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.

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KW - Morris water maze

KW - DMTP T-maze

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DO - 10.3389/fnmol.2021.804130

M3 - Article (Academic Journal)

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SN - 1662-5099

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JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

M1 - 804130

ER -

The GSK-3 inhibitor CT99021 enhances the acquisition of spatial learning and the accuracy of spatial memory

Abstract

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