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The Journal of Neuroscience, November 7, 2007, 27(45):12211-12220; doi:10.1523/JNEUROSCI.3321-07.2007
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Neurobiology of Disease
Activation of Glycogen Synthase Kinase-3 Inhibits Long-Term Potentiation with Synapse-Associated Impairments
Ling-Qiang Zhu,1 * Shao-Hui Wang,1 * Dan Liu,1 Yang-Yang Yin,1 Qing Tian,1 Xiao-Chuan Wang,1 Qun Wang,1 Jian-Guo Chen,2 andJian-Zhi Wang1,2 1Department of Pathophysiology and 2Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
Correspondence should be addressed to Dr. Jian-Zhi Wang, Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China. Email: wangjz{at}mails.tjmu.edu.cn
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-3ß 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-3ß mutant (dnGSK-3ß) 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.
Key words: glycogen synthase kinase-3; long-term potentiation; glutamate; synapse; synapsin I; postsynaptic density
Received April 21, 2007; revised Aug. 24, 2007; accepted Sept. 9, 2007.
Correspondence should be addressed to Dr. Jian-Zhi Wang, Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China. Email: wangjz{at}mails.tjmu.edu.cn
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