Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors

Nature. 1997 Feb 13;385(6617):630-4. doi: 10.1038/385630a0.


The classical view of fast chemical synaptic transmission is that released neurotransmitter acts locally on postsynaptic receptors and is cleared from the synaptic cleft within a few milliseconds by diffusion and by specific reuptake mechanisms. This rapid clearance restricts the spread of neurotransmitter and, combined with the low affinities of many ionotropic receptors, ensures that synaptic transmission occurs in a point-to-point fashion. We now show, however, that when transmitter release is enhanced at hippocampal mossy fibre synapses, the concentration of glutamate increases and its clearance is delayed; this allows it to spread away from the synapse and to activate presynaptic inhibitory metabotropic glutamate receptors (mGluRs). At normal levels of glutamate release during low-frequency activity, these presynaptic receptors are not activated. When glutamate concentration is increased by higher-frequency activity or by blocking glutamate uptake, however, these receptors become activated, leading to a rapid inhibition of transmitter release. This effect may be related to the long-term depression of mossy fibre synaptic responses that has recently been shown after prolonged activation of presynaptic mGluRs (refs 2, 3). The use-dependent activation of presynaptic mGluRs that we describe here thus represents a negative feedback mechanism for controlling the strength of synaptic transmission.

Publication types

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

MeSH terms

  • Animals
  • Evoked Potentials
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamates / metabolism*
  • Guinea Pigs
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Pimelic Acids / pharmacology
  • Quinoxalines / pharmacology
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism*


  • Excitatory Amino Acid Antagonists
  • Glutamates
  • Pimelic Acids
  • Quinoxalines
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline