Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP.
Coincident pre- and postsynaptic activity generates long-term potentiation (LTP), a possible cellular model of learning and memory. LTP has two components: (1) an increase in the excitatory postsynaptic potential (EPSP), and (2) an increase in the ability of the EPSP to generate a spike (E-S coupling of LTP). We have used pharmacological and genetic approaches to address the molecular nature of E-S coupling in CA1 pyramidal neurons. Blockade of the Ca2+-sensitive phosphatase, calcineurin, prevents induction of E-S coupling without interfering with LTP of the EPSP. Calcineurin produces its effect on E-S coupling by inducing a long-lasting depression (LTD) of the GABA(A)-mediated inhibitory postsynaptic potentials (IPSPs). This LTD of the IPSP was prevented by blockade of NMDA receptors. Thus, the tetanus that elicits NMDA-dependent LTP mediates a coordinately regulated double function. It produces LTP of the EPSP and, concomitantly, LTD of the IPSP that leads to enhancement of E-S coupling.
Lu
Y M
YM
Department of Molecular and Medical Genetics, University of Toronto, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Canada.
Mansuy
I M
IM
Kandel
E R
ER
Roder
J
J
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D019703:Calcineurin / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D019319:Okadaic Acid / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D007166:Immunosuppressive Agents; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D019319:Okadaic Acid; D019703:Calcineurin; D016559:Tacrolimus; D001640:Bicuculline