Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 50, Pages 11710-11718Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4041-05.2005
Keywords
hippocampus; CA3; kainate receptors; slow AHP; mossy fiber synapse; excitability; glutamate
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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 alpha(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.
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