Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice

Abstract

L-glutamate, the neurotransmitter of the majority of excitatory synapses in the brain, acts on three classes of ionotropic receptors: NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors. Little is known about the physiological role of kainate receptors because in many experimental situations it is not possible to distinguish them from AMPA receptors. Mice with disrupted kainate receptor genes enable the study of the specific role of kainate receptors in synaptic transmission as well as in the neurotoxic effects of kainate. We have now generated mutant mice lacking the kainate-receptor subunit GluR6. The hippocampal neurons in the CA3 region of these mutant mice are much less sensitive to kainate. In addition, a postsynaptic kainate current evoked in CA3 neurons by a train of stimulation of the mossy fibre system is absent in the mutant. We find that GluR6-deficient mice are less susceptible to systemic administration of kainate, as judged by onset of seizures and by the activation of immediate early genes in the hippocampus. Our results indicate that kainate receptors containing the GluR6 subunit are important in synaptic transmission as well as in the epileptogenic effects of kainate.

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

“…It has been suggested that CA3 neurons of the hippocampus are among the most responsive neurons to KA since these neurons degenerate following local or distal KA injections (Nadler et al, 1978, Nadler et al, 1980. In support of this, a considerable amount of work has clearly demonstrated the presence of postsynaptic KARs at the mossy fiber-CA3 synapse, and GluR6-deficient mice are less susceptible to KA-induced seizures and excitotoxic neuronal death in the CA3 region of the hippocampus (Mulle et al, 1998, Fisahn et al, 2004. Furthermore, the intracerebroventricular injection of a peptide that disrupts GluR6-PSD95-MLK3 signaling can prevent kainate-induced neuronal loss in CA3 neurons (Liu et al, 2006).…”

“…CA3 pyramidal neurons of the hippocampus are particularly sensitive since these neurons degenerate following injection of kainate (Nadler et al, 1978). Other models of TLE that lead to excessive activation of mossy fibers and a sustained release of glutamate can cause similar damage to CA3 neurons (for example see (Sloviter and Damiano, 1981)), and it is clear that KARs are involved in this excitotoxicity since GluR6-deficient mice have been shown to be less susceptible to kainate-induced degeneration of these neurons (Mulle et al, 1998).…”

KRIP6: A novel BTB/kelch protein regulating function of kainate receptors

“…Kainate receptors mediate a component of synaptic transmission at mossy fiber to CA3 inputs (Castillo et al, 1997;Vignes and Collingridge, 1997) and are required for short-and long-term synaptic remodeling at hippocampal and cortical synapses (Bortolotto et al, 1999;Contractor et al, 2001;Park et al, 2006;Rodriguez-Moreno and Lerma, 1998). Kainate receptor activation contributes to developmental regulation of GABAergic transmission , to seizure generation (Ben-Ari and Cossart, 2000;Mulle et al, 1998) and epileptiform burst activity (Fisahn et al, 2004).…”

SUMOylation of the kainate receptor subunit GluK2 contributes to the activation of the MLK3–JNK3 pathway following kainate stimulation

“…Knockdown of GluK2 by antisense oligodeoxynucleotides protects against ischemic neuronal loss in the rat hippocampal CA1 region [14]. In addition, GluK2-deficient mice exhibit resistance to neuronal degeneration and seizures induced by kainate acid [19]. These studies indicate that signaling via GluK2-containing kainate receptors is an important event in the induction of neuronal toxicity.…”