Glycogen synthase kinase-3 inhibition is integral to long-term potentiation.
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.
Hooper
Claudie
C
MRC Centre for Neurodegeneration Research, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
Markevich
Vladimir
V
Plattner
Florian
F
Killick
Richard
R
Schofield
Emma
E
Engel
Tobias
T
Hernandez
Felix
F
Anderton
Brian
B
Rosenblum
Kobi
K
Bliss
Tim
T
Cooke
Sam F
SF
Avila
Jesús
J
Lucas
José J
JJ
Giese
Karl Peter
KP
Stephenson
John
J
Lovestone
Simon
S
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D007839:Functional Laterality; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology / Q000528:radiation effects; D017774:Long-Term Potentiation / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000528:radiation effects; D012694:Serine / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors
D016708:Synaptophysin; D012694:Serine; D038362:Glycogen Synthase Kinase 3