期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 25, 期 1, 页码 81-86出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1460-9568.2006.05245.x
关键词
Alzheimer's disease; GSK-3; mice; Notch; Wnt
资金
- MRC [MC_U117512674, G0400983] Funding Source: UKRI
- Medical Research Council [G0400983, MC_U117512674] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3 beta is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3 beta phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3 beta. The LTP deficits can be attenuated/rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3 beta in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer's and other dementias.
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