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

Eur J Neurosci. 2007 Jan;25(1):81-6. doi: 10.1111/j.1460-9568.2006.05245.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western / methods
  • Dose-Response Relationship, Radiation
  • Electric Stimulation / methods
  • Functional Laterality
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / physiology*
  • Hippocampus / physiology
  • Hippocampus / radiation effects
  • Long-Term Potentiation / physiology*
  • Long-Term Potentiation / radiation effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation / radiation effects
  • Serine / metabolism
  • Synaptophysin / metabolism
  • Synaptosomes / metabolism
  • Time Factors


  • Synaptophysin
  • Serine
  • Glycogen Synthase Kinase 3