Abstract

Kainate (KA) receptors (KAR) have important modulatory roles of synaptic transmission. In the cerebellum, the action mechanisms of KAR-mediated glutamatergic depression are unknown. We studied these mechanisms by recording evoked excitatory postsynaptic currents (eEPSCs) from cerebellar slices using the whole-cell configuration of the patch-clamp technique. We observed that 3 μM KA decreased the amplitude of eEPSCs and increased the number of failures at the synapses established between parallel fibers (PF) and Purkinje neurons, and the effect was antagonized by NBQX under the condition where AMPA receptors were previously blocked. The inhibition of protein kinase A (PKA) suppressed the effect of KAR activation on eEPSC, and effect was not prevented by protein kinase C inhibitors. Furthermore, in the presence of Pertussis toxin, the depression of glutamate release mediated by KAR activation was prevented, invoking the participation of a Gi/o protein in this modulation. Finally, the KAR-mediated depression of glutamate release was not prevented by blocking calcium-permeable KARs or by treatments that affect calcium release from intracellular stores. We conclude that KARs present at these synapses mediate an inhibition of glutamate release through a mechanism that involves the activation of G-protein and protein kinase A.

Highlights

  • Kainate-type glutamate receptors are well-established mediators of canonical, ionotropic postsynaptic transmission and, presynaptically, these receptors support a modulatory regulation of neurotransmitter release

  • Following the observation that glutamatergic transmission at parallel fibers (PF)-PuC synapses of juvenile rat pups is modulated by kainate receptors (KARs) in a biphasic manner [17], as is the case in the hippocampus [2,3,4,5], we established the parallel fiber-Purkinje (PF-PuC) synapse paradigm in slices from early adult mouse cerebellum to study the mechanisms involved in glutamate release modulation mediated by KAR-activation

  • Because AMPA receptors were previously antagonized in the presence of the selective blocker GYKI53655 in the bath, the observation of full antagonism by NBQX invoked the modulation to be due to KARs

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Summary

Introduction

Kainate-type glutamate receptors are well-established mediators of canonical, ionotropic postsynaptic transmission and, presynaptically, these receptors support a modulatory regulation of neurotransmitter release. At several excitatory glutamatergic synapses, the KAR-mediated modulation is found to be biphasic, such that low agonist concentrations facilitate glutamate release, as opposed to higher agonist concentrations, which inhibit neurotransmitter release (see [2,3,4,5,9,10] for reviews). How this diametrically opposite modulation is mechanistically manifest is the subject of considerable debate and investigation, as is the question of the subcellular location of KARs responsible for presynaptic modulation [2,3,4,5,6,7].

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