LTP inhibits LTD in the hippocampus via regulation of GSK3beta.
Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information.
Peineau
Stéphane
S
MRC Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, University Walk, Bristol, BS8 1TD, United Kingdom.
Taghibiglou
Changiz
C
Bradley
Clarrisa
C
Wong
Tak Pan
TP
Liu
Lidong
L
Lu
Jie
J
Lo
Edmond
E
Wu
Dongchuan
D
Saule
Emilia
E
Bouschet
Tristan
T
Matthews
Paul
P
Isaac
John T R
JT
Bortolotto
Zuner A
ZA
Wang
Yu Tian
YT
Collingridge
Graham L
GL
D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D049229:Dendritic Spines / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008301:Maleimides / Q000494:pharmacology; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3