Glutamate transporter studies reveal the pruning of metabotropic glutamate receptors and absence of AMPA receptor desensitization at mature calyx of Held synapses

Robert Renden, Holger Taschenberger, Nagore Puente, Dmitri A. Rusakov, Robert Duvoisin, Lu Yang Wang, Knut P. Lehre, Henrique Von Gersdorff

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69 Scopus citations

Abstract

We examined the effect of glutamate transporter blockade at the calyx of Held synapse. In immature synapses [defined as postnatal day 8 (P8) to P10 rats], transporter blockade causes tonic activation of NMDA receptors and strong inhibition of the AMPA receptor-mediated EPSC amplitude. EPSC inhibition was blocked with a metabotropic glutamate receptor (mGluR) antagonist [1 μM LY341495 (2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid)], suggesting that elevated resting glutamate concentration specifically activates group II and group III mGluRs. Using mGluR subtype-specific agonists and antagonists, we determined that increased glutamate activates presynaptic mGluR2/3 and mGluR8 receptors but not mGluR4, although this receptor is present. Surprisingly, in older animals (P16-P18), transporter blockade had no effect on EPSC amplitude because of a developmental downregulation of group II/III mGluR activation in rats and mice. In contrast to other CNS synapses, we observed no effect of transporter blockade on EPSC decay kinetics, although expression of glutamate transporters was strong in nearby glial processes at both P9 and P17. Finally, using a low-affinity AMPA receptor antagonist (γ-D- glutamylglycine), we show that desensitization occurs at P8-P10 but is absent at P16-P18, even during trains of high-frequency (100-300 Hz) stimulation. We suggest that diffusion and transporter activation are insufficient to clear synaptically released glutamate at immature calyces, resulting in significant desensitization. Thus, mGluRs may be expressed in the immature calyx to help limit glutamate release. In the more mature calyx, there is a far smaller diffusional barrier attributable to the highly fenestrated synaptic terminal morphology, so AMPA receptor desensitization is avoided and mGluR-mediated inhibition is not necessary.

Original languageEnglish (US)
Pages (from-to)8482-8497
Number of pages16
JournalJournal of Neuroscience
Volume25
Issue number37
DOIs
StatePublished - Sep 14 2005

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Keywords

  • AMPA and NMDA receptors
  • Auditory brainstem
  • Desensitization
  • Development
  • Diffusion modeling
  • Glutamate transporters
  • Group II mGluR
  • MNTB
  • TBOA
  • mGluR8
  • γ-DGG

ASJC Scopus subject areas

  • Neuroscience(all)

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