Different pools of glutamate receptors mediate sensitivity to ambient glutamate in the cochlear nucleus

J Neurophysiol. 2015 Jun 1;113(10):3634-45. doi: 10.1152/jn.00693.2014. Epub 2015 Apr 8.


Ambient glutamate plays an important role in pathological conditions, such as stroke, but its role during normal activity is not clear. In addition, it is not clear how ambient glutamate acts on glutamate receptors with varying affinities or subcellular localizations. To address this, we studied "endbulb of Held" synapses, which are formed by auditory nerve fibers onto bushy cells (BCs) in the anteroventral cochlear nucleus. When ambient glutamate was increased by applying the glutamate reuptake inhibitor TFB-TBOA, BCs depolarized as a result of activation of N-methyl-D-aspartate receptors (NMDARs) and group I metabotropic glutamate receptors (mGluRs). Application of antagonists against NMDARs (in 0 Mg(2+)) or mGluRs caused hyperpolarization, indicating that these receptors were bound by a tonic source of glutamate. AMPA receptors did not show these effects, consistent with their lower glutamate affinity. We also evaluated the subcellular localization of the receptors activated by ambient glutamate. The mGluRs were not activated by synaptic stimulation and thus appear to be exclusively extrasynaptic. By contrast, NMDARs in both synaptic and extrasynaptic compartments were activated by ambient glutamate, as shown using the use-dependent antagonist MK-801. Levels of ambient glutamate appeared to be regulated in a spike-independent manner, and glia likely play a major role. These low levels of ambient glutamate likely have functional consequences, as even low concentrations of TBOA caused significant increases in BC spiking following synaptic stimulation. These results indicate that normal resting potential appears to be poised in the region of maximal sensitivity to small changes in ambient glutamate.

Keywords: ambient glutamate; excitability; extrasynaptic.

Publication types

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

MeSH terms

  • Action Potentials / drug effects*
  • Aging
  • Animals
  • Animals, Newborn
  • Cochlear Nucleus / cytology*
  • Cochlear Nucleus / drug effects
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Excitatory Amino Acid Agents / pharmacology*
  • Glutamic Acid / pharmacology*
  • In Vitro Techniques
  • Mice
  • Mice, Inbred CBA
  • Receptors, Glutamate / classification
  • Receptors, Glutamate / metabolism*
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology


  • Excitatory Amino Acid Agents
  • Receptors, Glutamate
  • Sodium Channel Blockers
  • Glutamic Acid
  • Tetrodotoxin