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The Journal of Neuroscience, December 14, 2005, 25(50):11710-11718; doi:10.1523/JNEUROSCI.4041-05.2005

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Cellular/Molecular
Distinct Subunits in Heteromeric Kainate Receptors Mediate Ionotropic and Metabotropic Function at Hippocampal Mossy Fiber Synapses

Arnaud Ruiz,^1 * Shankar Sachidhanandam,^1 * Jo Kristian Utvik,² Françoise Coussen,¹ and Christophe Mulle¹

¹Laboratoire de Physiologie Cellulaire de la Synapse, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5091, Université Bordeaux 2, 33077 Bordeaux, France, and ²Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway

Heteromeric kainate receptors (KARs) containing both glutamate receptor 6 (GluR6) and KA2 subunits are involved in KAR-mediated EPSCs at mossy fiber synapses in CA3 pyramidal cells. We report that endogenous glutamate, by activating KARs, reversibly inhibits the slow Ca²⁺-activated K⁺ current I_sAHP and increases neuronal excitability through a G-protein-coupled mechanism. Using KAR knockout mice, we show that KA2 is essential for the inhibition of I_sAHP in CA3 pyramidal cells by low nanomolar concentrations of kainate, in addition to GluR6. In GluR6^–/– mice, both ionotropic synaptic transmission and inhibition of I_sAHP by endogenous glutamate released from mossy fibers was lost. In contrast, inhibition of I_sAHP was absent in KA2^–/– mice despite the preservation of KAR-mediated EPSCs. These data indicate that the metabotropic action of KARs did not rely on the activation of a KAR-mediated inward current. Biochemical analysis of knock-out mice revealed that KA2 was required for the interaction of KARs with G_q/11-proteins known to be involved in I_sAHP modulation. Finally, the ionotropic and metabotropic actions of KARs at mossy fiber synapses were differentially sensitive to the competitive glutamate receptor ligands kainate (5 nM) and kynurenate (1 mM). We propose a model in which KARs could operate in two modes at mossy fiber synapses: through a direct ionotropic action of GluR6, and through an indirect G-protein-coupled mechanism requiring the binding of glutamate to KA2.

Key words: hippocampus; CA3; kainate receptors; slow AHP; mossy fiber synapse; excitability; glutamate

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Received June 3, 2005; revised October 28, 2005; accepted November 3, 2005.

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