TY - JOUR
T1 - Glutamate transporter studies reveal the pruning of metabotropic glutamate receptors and absence of AMPA receptor desensitization at mature calyx of Held synapses
AU - Renden, Robert
AU - Taschenberger, Holger
AU - Puente, Nagore
AU - Rusakov, Dmitri A.
AU - Duvoisin, Robert
AU - Wang, Lu Yang
AU - Lehre, Knut P.
AU - Von Gersdorff, Henrique
PY - 2005/9/14
Y1 - 2005/9/14
N2 - 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.
AB - 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.
KW - AMPA and NMDA receptors
KW - Auditory brainstem
KW - Desensitization
KW - Development
KW - Diffusion modeling
KW - Glutamate transporters
KW - Group II mGluR
KW - MNTB
KW - TBOA
KW - mGluR8
KW - γ-DGG
UR - http://www.scopus.com/inward/record.url?scp=24944568133&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=24944568133&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1848-05.2005
DO - 10.1523/JNEUROSCI.1848-05.2005
M3 - Article
C2 - 16162930
AN - SCOPUS:24944568133
SN - 0270-6474
VL - 25
SP - 8482
EP - 8497
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 37
ER -