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

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

doi:10.3389/fnmol.2021.804130

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.

Highlights

Consistent with earlier observations, we found that Low frequency stimulation (LFS) induced a moderate, but robust long-term depression (LTD) (80.5 ± 1.2% of baseline, measured at 104 min; Figure 1B) that was not observed when LFS was applied 15 min after injection of the non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, at 20 mg/kg i.p. (95.0 ± 4.3% measured at 120 min; p < 0.01, one-way ANOVA, LTD under control conditions vs. in the presence of ketamine; Figure 1C)
We tested whether inhibition of Glycogen synthase kinase 3 (GSK-3) activity can block the induction of NMDAR-LTD in vivo using a dose (25 mg/kg, i.p.) previously determined to be effective in behavioral experiments (Pan et al, 2011)
The principal finding of the present study is that a GSK-3 inhibitor, CT99021, blocks the induction of NMDAR-LTD in the CA1 region of the hippocampus in vivo and improves hippocampus-dependent learning and memory

Summary

Introduction

GSK-3 is a Ser/Thr kinase that is involved in multiple signaling pathways including glucose regulation (Embi et al, 1980; Parker et al, 1983), cell proliferation and migration (Jope et al, 2007; Beurel et al, 2010) and inflammation and apoptosis (Jope et al, 2007, 2017; Beurel et al, 2010). The learning deficits caused by over-expression of GSK-3 are ameliorated in Tau-knockout mice (Gomez de Barreda et al, 2010). These observations strongly implicate altered GSK-3 activity in the etiology of AD (Cohen and Goedert, 2004; Hooper et al, 2008; Kremer et al, 2011; Llorens-Martin et al, 2014). Given the involvement of GSK-3 in AD and other major brain disorders it is important to understand its normal functions in the CNS

Methods

Results

Conclusion