Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP

Neuron. 2000 Apr;26(1):197-205. doi: 10.1016/s0896-6273(00)81150-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bicuculline / pharmacology
  • Calcineurin / drug effects
  • Calcineurin / physiology*
  • Enzyme Inhibitors / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • GABA Antagonists / pharmacology
  • Immunosuppressive Agents / pharmacology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Mice
  • Mice, Transgenic
  • Okadaic Acid / pharmacology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / physiology*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Tacrolimus / pharmacology


  • Enzyme Inhibitors
  • GABA Antagonists
  • Immunosuppressive Agents
  • Receptors, GABA-A
  • Receptors, N-Methyl-D-Aspartate
  • Okadaic Acid
  • Calcineurin
  • Tacrolimus
  • Bicuculline