Glycogen synthase kinase-3 inhibition is integral to long-term potentiation.

Claudie Hooper, V Markevich, Florian Plattner, Richard Killick, E Schofield, T Engel, F Hernandez, Brian Henry Anderton, K Rosenblum, Timothy V. P. Bliss, Samuel Frazer Cooke, J Avila, J J Lucas, Karl Peter Giese, John David Stephenson, Simon H Lovestone

Research output: Contribution to journalArticlepeer-review

297 Citations (Scopus)

Abstract

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-3beta 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-3beta phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3beta. 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-3beta in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer's and other dementias.
Original languageEnglish
Pages (from-to)81 - 86
Number of pages6
JournalEuropean Journal of Neuroscience
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 2007

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