Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin.
To investigate the role of phosphatases in synaptic plasticity using genetic approaches, we generated transgenic mice that overexpress a truncated form of calcineurin under the control of the CaMKIIalpha promoter. Mice expressing this transgene show increased calcium-dependent phosphatase activity in the hippocampus. Physiological studies of these mice and parallel pharmacological experiments in wild-type mice reveal a novel, intermediate phase of LTP (I-LTP) in the CA1 region of the hippocampus. This intermediate phase differs from E-LTP by requiring multiple trains for induction and in being dependent on PKA. It differs from L-LTP in not requiring new protein synthesis. These data suggest that calcineurin acts as an inhibitory constraint on I-LTP that is relieved by PKA. This inhibitory constraint acts as a gate to regulate the synaptic induction of L-LTP.
Winder
D G
DG
Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York 10032, USA.
Mansuy
I M
IM
Osman
M
M
Moallem
T M
TM
Kandel
E R
ER
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology / Q000502:physiology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D005818:Genetic Engineering; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D017966:Pyramidal Cells / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics; D013268:Stimulation, Chemical; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D019076:Transgenes / Q000235:genetics / Q000502:physiology
D004791:Enzyme Inhibitors; D011506:Proteins; D011994:Recombinant Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases