Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse.
We have identified an excitatory synapse in cerebellar molecular layer interneurons at which the level of presynaptic activity determines the receptor type involved in the postsynaptic response. When small numbers of parallel fibers are activated, EPSCs are mediated solely by AMPA receptors (AMPARs), despite our finding that NMDA receptors (NMDARs) are present in the dendrites of these cells. The EPSC kinetics are fast (tau decay = 0.82 +/- 0.05 msec at room temperature), consistent with the role these interneurons are thought to play in precisely timed inhibitory control of Purkinje cells. NMDARs are activated only when glutamate release is increased either by facilitation with brief high-frequency trains or by recruiting more presynaptic fibers with higher stimulus intensities. Under these conditions, EPSCs consist of a fast-rising AMPAR-mediated current followed by a slow component mediated by both NMDARs and AMPARs. Inhibitors of glutamate transport increase the amplitude and prolong the time course of the compound EPSCs. In contrast, the properties of fast AMPAR EPSCs resulting from the activation of few inputs remain unchanged when glutamate uptake is blocked. Our results suggest that, at these synapses, the postsynaptic density contains AMPARs alone. It is only when transmitter release is high enough for glutamate to diffuse to the extrasynaptic space and to reach concentrations sufficient to activate extrasynaptic receptors that NMDARs are involved in the postsynaptic response. We suggest that such a spatial separation of receptor types may provide a mechanism for rapid changes in EPSC properties, depending on the amount of synaptic activity.
Clark
Beverley A
BA
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom. b.clark@ucl.ac.uk.
Cull-Candy
Stuart G
SG
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004058:Diffusion; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005456:Fluorescent Dyes; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007478:Iontophoresis; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011999:Recruitment, Neurophysiological / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D027322:Amino Acid Transport System X-AG; D003998:Dicarboxylic Acids; D005456:Fluorescent Dyes; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D005998:Glycine