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The Journal of Neuroscience, August 1, 2007, 27(31):8344-8357; doi:10.1523/JNEUROSCI.2399-07.2007
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Cellular/Molecular
Desensitization Properties of AMPA Receptors at the Cerebellar Mossy Fiber–Granule Cell Synapse
David A. DiGregorio,1,2 Jason S. Rothman,1 Thomas A. Nielsen,1 andR. Angus Silver1 1Department of Physiology, University College London, London WC1E 6BT, United Kingdom, and 2Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8118, Laboratoire de Physiologie Cérébrale, Université Paris 5, 75270 Paris Cedex 06, France
Correspondence should be addresssed to R. Angus Silver at the above address. Email: a.silver{at}ucl.ac.uk
Native AMPA receptors (AMPARs) exhibit rapid and profound desensitization in the sustained presence of glutamate. Desensitization therefore contributes to short-term depression at synapses in which glutamate accumulates. At synapses that do not exhibit desensitization-dependent depression, AMPARs are thought to be protected against prolonged or repetitive exposure to synaptically released glutamate. At the cerebellar mossy fiber to granule cell (GC) synapse, in which high release probability and glutamate spillover produce a substantial buildup of glutamate concentration in the cleft ([Glut]cleft) during high-frequency transmission, only moderate desensitization of the phasic AMPAR EPSC occurs. To investigate how such currents are produced, we examined the kinetic properties of synaptic AMPARs in GCs using glutamate uncaging. Photolysis of 4-methoxy-7-nitroindolinyl-caged L-glutamate with large illumination spots produced step-like increases in [Glut]cleft that could be used to systematically probe AMPAR kinetics. At low levels of activation, synaptic AMPARs exhibited little desensitization. With larger activations, the desensitization time course became faster, but the level of desensitization was only weakly dependent on receptor occupancy. Indeed, a substantial desensitization-resistant current component remained (17%) in saturating glutamate. Photolysis with small illumination spots produced brief [Glut]cleft waveforms and transient AMPAR activations, similar to the EPSC current components. Paired-pulse uncaging with such spots revealed little desensitization after spillover-like activations and modest depression after activations that mimicked quantal and spillover components together. Our results show that GC AMPARs exhibit a resistance to desensitization at low occupancies and that this property is crucial for sustaining high-frequency transmission at a synapse in which glutamate accumulates.
Key words: synapse; spillover; AMPA receptor; cerebellum; desensitization; glutamate receptor
Received Dec. 9, 2006; revised June 21, 2007; accepted June 22, 2007.
Correspondence should be addresssed to R. Angus Silver at the above address. Email: a.silver{at}ucl.ac.uk
This article has been cited by other articles:
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[Abstract] [Full Text] [PDF]
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