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Changes in synaptic structure underlie the developmental speeding of AMPA receptor–mediated EPSCs

Nature Neuroscience volume 8, pages 1310–1318 (2005)Cite this article

Abstract

At many excitatory and inhibitory synapses throughout the nervous system, postsynaptic currents become faster as the synapse matures, primarily owing to changes in receptor subunit composition. The origin of the developmental acceleration of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) remains elusive. We used patch-clamp recordings, electron microscopic immunogold localization of AMPARs, partial three-dimensional reconstruction of the neuropil and numerical simulations of glutamate diffusion and AMPAR activation to examine the factors underlying the developmental speeding of miniature EPSCs in mouse cerebellar granule cells. We found that the main developmental change that permits submillisecond transmission at mature synapses is an alteration in the glutamate concentration waveform as experienced by AMPARs. This can be accounted for by changes in the synaptic structure and surrounding neuropil, rather than by a change in AMPAR properties. Our findings raise the possibility that structural alterations could be a general mechanism underlying the change in the time course of AMPAR-mediated synaptic transmission.

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Figure 1: Developmental speeding of the AMPAR-mEPSC at 23 °C and 37 °C.
Figure 2: Voltage dependence of the AMPAR-mediated mEPSC.
Figure 3: Mean single-channel conductance of AMPARs underlying mEPSCs remains constant between P8 and P40.
Figure 4: Cyclothiazide (CTZ) slows the mEPSC decay equally at P8 and P40.
Figure 5: A low-affinity competitive antagonist preferentially accelerates P8 EPSCs.
Figure 6: Electron micrographs showing the differences in AMPA receptor content of mossy fiber–granule cell synapses in P8 and P40 mice.
Figure 7: Analysis by electron microscopy of the cerebellar glomeruli in P8 and P40 mice.
Figure 8: Influence of developmental changes in glomerular structure on simulated EPSCs.

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Acknowledgements

This work was supported by a Wellcome Trust Programme Grant (S.G.C.-C.), a Wellcome Trust Travelling Fellowship (L.C.) and the Centre National de la Recherche Scientifique (L.C. and D.A.D.). S.G.C.-C. holds a Royal Society-Wolfson Award. Z.N. acknowledges receipt of a Wellcome Trust International Senior Research Fellowship, an International Scholarship from Howard Hughes Medical Institute and a Postdoctoral Fellowship from the Boehringer Ingelheim Fund. We thank E. Molnár for providing the anti-pan-AMPA antibody and M. Köllö for his help with the 3D reconstruction. We thank T. Nielsen and J. Rothman for provision of software, S. Brickley, M. Farrant, V. Nägerl and A. Silver for helpful discussions, and B. Barbour, P. DiGregorio, M. Farrant, A. Marty, T. Nielsen, A. Silver and A. Roth for comments on the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK

    Laurence Cathala & Stuart G Cull-Candy

  2. Physiologie Cérébrale, Centre National de la Recherche Scientifique UMR 8118, Université Paris 5, 45, rue des Saint-Pères, Paris, 75006, France

    Laurence Cathala & David A DiGregorio

  3. Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony Street 43, Budapest, 1083, Hungary

    Noemi B Holderith & Zoltan Nusser

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Correspondence to Stuart G Cull-Candy.

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Cathala, L., Holderith, N., Nusser, Z. et al. Changes in synaptic structure underlie the developmental speeding of AMPA receptor–mediated EPSCs. Nat Neurosci 8, 1310–1318 (2005). https://doi.org/10.1038/nn1534

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