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PNAS 98 (20): 11003-11008

Copyright © 2001 by the National Academy of Sciences.

Colloquium Paper


Presynaptic kainate receptors at hippocampal mossy fiber synapses

Dietmar Schmitz*, Jack Mellor*, Matthew Frerking{dagger},{ddagger}, and Roger A. Nicoll*,§

*Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, CA 94143; and {dagger}Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

Abstract: Hippocampal mossy fibers, which are the axons of dentate granule cells, form powerful excitatory synapses onto the proximal dendrites of CA3 pyramidal cells. It has long been known that high-affinity binding sites for kainate, a glutamate receptor agonist, are present on mossy fibers. Here we summarize recent experiments on the role of these presynaptic kainate receptors (KARs). Application of kainate has a direct effect on the amplitude of the extracellularly recorded fiber volley, with an enhancement by low concentrations and a depression by high concentrations. These effects are mediated by KARs, because they persist in the presence of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-selective antagonist GYKI 53655, but are blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/KAR antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and the KAR antagonist SYM2081. The effects on the fiber volley are most likely caused by a depolarization of the fibers via the known ionotropic actions of KARs, because application of potassium mimics the effects. In addition to these effects on fiber excitability, low concentrations of kainate enhance transmitter release, whereas high concentrations depress transmitter release. Importantly, the synaptic release of glutamate from mossy fibers also activates these presynaptic KARs, causing an enhancement of the fiber volley and a facilitation of release that lasts for many seconds. This positive feedback contributes to the dramatic frequency facilitation that is characteristic of mossy fiber synapses. It will be interesting to determine how widespread facilitatory presynaptic KARs are at other synapses in the central nervous system.

{ddagger} Present address: Neurological Sciences Institute, Oregon Health Sciences University, Beaverton, OR 97006.

§ To whom reprint requests should be addressed. E-mail: nicoll{at}

This paper results from the Inaugural Arthur M. Sackler Colloquium of the National Academy of Sciences, "Neural Signaling," held February 15–17, 2001, at the National Academy of Sciences in Washington, DC.

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