The Journal of Neuroscience, September 14, 2005, 25(37):8482-8497; doi:10.1523/JNEUROSCI.1848-05.2005
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Cellular/Molecular
Glutamate Transporter Studies Reveal the Pruning of Metabotropic Glutamate Receptors and Absence of AMPA Receptor Desensitization at Mature Calyx of Held Synapses
Robert Renden,1
Holger Taschenberger,2
Nagore Puente,3,4
Dmitri A. Rusakov,5
Robert Duvoisin,6
Lu-Yang Wang,7
Knut P. Lehre,3 and
Henrique von Gersdorff1
1The Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, 2Abteilung Membranbiophysik, Max-Planck-Institut für Biophysikalische Chemie, D-37077 Göttingen, Germany, 3Centre for Molecular Biology and Neuroscience, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway, 4Department of Neurosciences, Faculty of Medicine and Dentistry, Basque Country University, 699-48080 Bilbao, Spain, 5Institute of Neurology, University College London, London WC1N 3BG, United Kingdom, 6Neurological Sciences Institute, Oregon Health and Science University, Beaverton, Oregon 97006, and 7The Program for Brain and Behavioral Research and Division of Neurology, The Hospital for Sick Children and Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X8
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 [1µM 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 (
-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.
Key words: auditory brainstem; MNTB; development; glutamate transporters; desensitization ; AMPA and NMDA receptors; -DGG ; diffusion modeling; group II mGluR; mGluR8; TBOA
Received May 9, 2005;
revised June 29, 2005;
accepted July 21, 2005.
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