Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression

Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4027-32. doi: 10.1073/pnas.1219454110. Epub 2013 Feb 19.

Abstract

NMDA receptor (NMDAR) activation controls long-term potentiation (LTP) as well as long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. A long-standing view proposes that a high level of Ca(2+) entry through NMDARs triggers LTP; lower Ca(2+) entry triggers LTD. Here we show that ligand binding to NMDARs is sufficient to induce LTD; neither ion flow through NMDARs nor Ca(2+) rise is required. However, basal levels of Ca(2+) are permissively required. Lowering, but not maintaining, basal Ca(2+) levels with Ca(2+) chelators blocks LTD and drives strong synaptic potentiation, indicating that basal Ca(2+) levels control NMDAR-dependent LTD and basal synaptic transmission. Our findings indicate that metabotropic actions of NMDARs can weaken active synapses without raising postsynaptic calcium, thereby revising and expanding the mechanisms controlling synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / physiology
  • Chelating Agents / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Kynurenic Acid / analogs & derivatives
  • Kynurenic Acid / pharmacology
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Neuronal Plasticity / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Tissue Culture Techniques

Substances

  • Chelating Agents
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Egtazic Acid
  • Dizocilpine Maleate
  • Kynurenic Acid
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • 7-chlorokynurenic acid