Activation of Glycogen Synthase Kinase-3 Inhibits Long-Term Potentiation with Synapse-Associated Impairments

Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2007; 27(45):12211-20. DOI: 10.1523/JNEUROSCI.3321-07.2007
Source: PubMed


Activation of glycogen synthase kinase-3 (GSK-3) can cause memory deficits as seen in Alzheimer's disease, the most common age-associated dementia, but the mechanism is not understood. Here, we found that activation of GSK-3 by wortmannin or transient overexpression of wild-type GSK-3beta could suppress the induction of long-term potentiation (LTP) in rat hippocampus, whereas simultaneous inhibition of GSK-3 by lithium or SB216763 or transient expression of a dominant-negative GSK-3beta mutant (dnGSK-3beta) preserved the LTP. After high-frequency stimulation (HFS), the presynaptic release of glutamate and the expression/clustering of synapsin I, a synaptic vesicle protein playing an important role in neurotransmitter release, decreased markedly after upregulation of GSK-3. In vitro studies further demonstrated that GSK-3 inhibited the expression of SynI independent of HFS. In postsynaptic level, the expression of PSD93 and NR2A/B proteins decreased significantly when GSK-3 was activated. The LTP-associated synapse impairments including less presynaptic active zone, thinner postsynaptic density, and broader synaptic cleft were also prominent in the hippocampal slices after HFS with activation of GSK-3. These synaptic impairments were attenuated when GSK-3 was simultaneously inhibited by LiCl or SB216763 or transient expression of dnGSK-3. We conclude that upregulation of GSK-3 impairs the synaptic plasticity both functionally and structurally, which may underlie the GSK-3-involved memory deficits.

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    • "GSK-3 phosphorylation reduces the capability of tau to promote microtubule assembly in vitro and in cells [33] [34] . GSK-3 together with the activity of other kinases such as CK1, Cdk5, and MARK, has the ability to signifi cantly affect tau phosphorylation and modulate its neuronal function [35] [36] [37] [38] . "
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    • "The Akt/GSK3 signalling pathway has been implicated in the downstream regulation of ionotropic glutamate receptor functions [Beaulieu et al. 2009]. Notably, activation of GSK3 has been shown to inhibit the development of glutamatergic N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP), causing changes to neuronal synaptic plasticity and contributing to learning and memory deficits [Zhu et al. 2007]. In addition, GSK3 inhibition has been shown to prevent the development of long-term depression (LTD) in rat hippocampal slices [Peineau et al. 2007], reducing the efficacy of neuronal synapses. "
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