Kainate Receptor Subunit GluR6 Research Articles

Epigenetic Regulation of Glutamic Acid Decarboxylase 67 in a Hippocampal Circuit.

GABAergic dysfunction in hippocampus, a key feature of schizophrenia (SZ), may contribute to cognitive impairment in this disorder. In stratum oriens (SO) of sector CA3/2 of the human hippocampus, a network of genes involved in the regulation of glutamic acid decarboxylase GAD67 has been identified. Several of the genes in this network including epigenetic factors histone deacetylase 1 (HDAC1) and death-associated protein 6 (DAXX), the GABAergic enzyme GAD65 as well as the kainate receptor (KAR) subunits GluR6 and7 show significant changes in expression in this area in SZ. We have tested whether HDAC1 and DAXX regulate GAD67, GAD65, or GluR in the intact rodent hippocampus. Stereotaxic injections of lentiviral vectors bearing shRNAi sequences for HDAC1 and DAXX were delivered into the SO of CA3/2, followed by laser microdissection of individual transduced GABA neurons. Quantitative PCR (QPCR) analyses demonstrated that inhibition of HDAC1 and DAXX increased expression of GAD67, GAD65, and GluR6 mRNA. Inhibition of DAXX, but not HDAC1 resulted in a significant increase in GluR7 mRNA. Our data support the hypothesis that HDAC1 and DAXX play a central role in coordinating the expression of genes in the GAD67 regulatory pathway in the SO of CA3/2.

Perturbed Hippocampal Synaptic Inhibition and γ-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism.

SummaryLoss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.

Novel spliced variants of ionotropic glutamate receptor GluR6 in normal human fibroblast and brain cells are transcribed by tissue specific promoters

The members of the ionotropic glutamate receptor family, namely, a-amino-3-hydroxy-S-methyl-4-isoxazole propionate (AMPA), kainate, and N-methyl- d-aspartate (NMDA) receptors, are important mediators of the rapid synaptic transmission in the central nervous system. We have investigated the splicing pattern and expression of the kainate receptor subunit GluR6 in human fibroblast cell lines and brain tissue. We demonstrate the expression of GluR6A variant specifically in brain, and four variants, namely, GluR6B, GluR6C, GluR6D and GluR6E in fibroblast cell lines. The variants GluR6D and GluR6E have not been described before, and appear to be specific for non-neuronal cells. Genomic analysis and cloning of the sequence preceding the transcribed region led to the identification of two tissue specific promoters designated as neuronal promoter P N and non-neuronal promoter P NN. We have used RNA ligase mediated RACE and in silico analyses to locate two sets of transcription start sites, and confirmed specific transcripts initiated by P N and P NN in brain cells and fibroblasts, respectively. The domain structure of variants GluR6D and GluR6E revealed the absence of three transmembrane domains. The lack of these domains suggests that the mature receptors arising from these variant subunits may not function as active channels. Based on these structural features in GluR6D and GluR6E, and the observations that GluR6B, GluR6C, GluR6D and GluR6E are exclusively expressed in non-neuronal cells, it is likely that these receptor subunits function as non-channel signaling proteins.

Intrathecal injection of GluR6 antisense oligodeoxynucleotides alleviates acute inflammatory pain of rectum in rats.

To investigate whether the kainate (KA) receptor subunit GluR6 is involved in the acute inflammatory pain. Formalin was injected into the mucosa of rectum in Sprague-Dawley rats to induce visceral pain. The antisense oligodeoxynucleotides (ODNs) of GluR6 were injected once per day for 3 d before formalin injection, after which GluR6 protein level was examined by immunoblotting method. The change of visceral pain was also investigated. The expression of GluR6 in the spinal cord of rats increased after the formalin injection. Moreover, pre-treatment of GluR6 antisense ODNs could suppress GluR6 expression in the spinal cord of rats and decrease the scores of visceral pain at 45 min following formalin injection. Kainate receptor subunit GluR6 plays an important role in the visceral pain induced by injection of formalin into the wall of rectum. GluR6 may serve as a potential target for the treatment of acute inflammatory visceral pain.

GluR6‐containing KA receptor mediates the activation of p38 MAP kinase in rat hippocampal CA1 region during brain ischemia injury

Our previous study showed that kainate (KA) receptor subunit GluR6 played an important role in ischemia-induced MLK3 and JNK activation and neuronal degeneration through the GluR6-PSD95-MLK3 signaling module. However, whether the KA receptors subunit GluR6 is involved in the activation of p38 MAP kinase during the transient brain ischemia/reperfusion (I/R) in the rat hippocampal CA1 subfield is still unknown. In this present study, we first evaluated the time-course of phospho-p38 MAP kinase at various time-points after 15 min of ischemia and then observed the effects of antagonist of KA receptor subunit GluR6, GluR6 antisence oligodeoxynucleotides on the phosphorylation of p38 MAP kinase induced by I/R. Results showed that inhibiting KA receptor GluR6 or suppressing the expression of KA receptor GluR6 could down-regulate the elevation of phospho-p38 MAP kinase induced by I/R. These drugs also reduced the phosphorylation of MLK3, MKK3/MKK6, MKK4, and MAPKAPK2. Additionally, our results indicated administration of three drugs, including p38 MAP kinase inhibitor before brain ischemia significantly decreased the number of TUNEL-positive cells detected at 3 days of reperfusion and increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion after 15 min of ischemia. Taken together, we suggest that GluR6-contained KA receptors can mediate p38 MAP kinase activation through a kinase cascade, including MLK3, MKK3/MKK6, and MKK4 and then induce increased phosphorylation of MAPKAPK-2 during ischemia injury and ultimately result in neuronal cell death in the rat hippocampal CA1 region.

Mutations to the Kainate Receptor Subunit GluR6 Binding Pocket That Selectively Affect Domoate Binding

Kainate receptor responses to domoate are characterized by large steady-state currents and slow deactivation kinetics. To improve our understanding of these responses, we mutated residues at the mouth of the agonist binding pocket of GluR6 using whole-cell electrophysiology to characterize the effects of the mutants. We identified two residues where mutations had significant ligand-specific effects. One, Met691, forms a hydrogen bond that seems to facilitate domoate binding by affecting the main-chain conformation. We found that mutation of Met691 to alanine significantly attenuated responses to domoate but had no effect on responses to glutamate, confirming the importance of this main-chain interaction in GluR6. The second residue, Val685, is located at the mouth of the binding pocket, adjacent to the domoate side-arm. Mutation of Val685 to glutamine increased the rate of decay from steady-state responses to domoate by more than 50-fold but had no effect on the rate or extent of desensitization or on the kinetics of responses to either glutamate or kainate. The V685Q mutant also significantly reduced the potencies of both glutamate (peak) and domoate (peak and steady-state). Empirical analysis using a basic kinetic model indicated that the V685Q phenotype could be fully explained by faster ligand dissociation. The V685Q mutant accelerated receptor deactivation without affecting either desensitization or gating, making it a potentially useful tool for further dissection of ligand binding and gating in kainate receptors.

Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania.

The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with bipolar disorder (BPD), but its function in affective regulation is unknown. Compared with wild-type (WT) and GluR5 knockout (KO) mice, GluR6 KO mice were more active in multiple tests and super responsive to amphetamine. In a battery of specific tests, GluR6 KO mice also exhibited less anxious or more risk-taking type behavior and less despair-type manifestations, and they also had more aggressive displays. Chronic treatment with lithium, a classic antimanic mood stabilizer, reduced hyperactivity, aggressive displays and some risk-taking type behavior in GluR6 KO mice. Hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. The membrane levels of other glutamatergic receptors were not significantly altered by GluR6 ablation or chronic lithium treatment. Together, these biochemical and behavioral results suggest a unique role for GluR6 in controlling abnormalities related to the behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggressiveness, driven or increased goal-directed pursuits, risk taking and supersensitivity to psychostimulants. Whether GluR6 perturbation is involved in the mood elevation or thought disturbance of mania and the cyclicity of BPD are unknown. The molecular mechanism underlying the behavioral effects of lithium in GluR6 KO mice remains to be elucidated.

Human GluR6c, a functional splicing variants of GluR6, is mainly expressed in non-nervous cells

Kainate-type glutamate receptors (KARs) are receptor channels with a variety of distinct physiological functions in synaptic transmission, depending on their sub-cellular location in functional neuronal compartments. The kainate receptor subunit GluR6 presents different splice variants involving the C-terminal domain, namely GluR6a, GluR6b and GluR6c. In this study, we report the analysis of the three human splicing isoforms and in particular of the uncharacterized hGluR6c. When expressed in COS-7 cells, hGluR6a receptor subunit was highly present on the surface of the plasma membrane, whereas hGluR6b and hGluRc were poorly transported to the membrane. Electrophysiological studies of homomeric receptors showed that hGluR6c subunit can generate functional receptors with characteristics similar to the GluR6b variant. mRNA expression analysis demonstrated that hGluR6c variant is mainly expressed in non-neuronal cells and barely expressed in neuronal ones. Interestingly, undifferentiated NT2 cells expressing only the hGluR6c isoform, during neuronal differentiation induced by retinoic acid, increased the expression level of the neuronal form hGluR6a with a parallel decreased of hGluR6c. Overall, our data indicate that hGluR6c might have unique properties in non-nervous cells and in the first stages of CNS development.

SUMOylation regulates kainate-receptor-mediated synaptic transmission

The small ubiquitin-like modifier protein (SUMO) regulates transcriptional activity and the translocation of proteins across the nuclear membrane. The identification of SUMO substrates outside the nucleus is progressing but little is yet known about the wider cellular role of protein SUMOylation. Here we report that in rat hippocampal neurons multiple SUMOylation targets are present at synapses and we show that the kainate receptor subunit GluR6 is a SUMO substrate. SUMOylation of GluR6 regulates endocytosis of the kainate receptor and modifies synaptic transmission. GluR6 exhibits low levels of SUMOylation under resting conditions and is rapidly SUMOylated in response to a kainate but not an N-methyl-D-aspartate (NMDA) treatment. Reducing GluR6 SUMOylation using the SUMO-specific isopeptidase SENP-1 prevents kainate-evoked endocytosis of the kainate receptor. Furthermore, a mutated non-SUMOylatable form of GluR6 is not endocytosed in response to kainate in COS-7 cells. Consistent with this, electrophysiological recordings in hippocampal slices demonstrate that kainate-receptor-mediated excitatory postsynaptic currents are decreased by SUMOylation and enhanced by deSUMOylation. These data reveal a previously unsuspected role for SUMO in the regulation of synaptic function.

Block of Kainate Receptor Desensitization Uncovers a Key Trafficking Checkpoint

A prominent feature of ionotropic glutamate receptors from the AMPA and kainate subtypes is their profound desensitization in response to glutamate-a process thought to protect the neuron from overexcitation. In AMPA receptors, it is well established that desensitization results from rearrangements of the interface formed between agonist-binding domains of adjacent subunits; however, it is unclear how this mechanism applies to kainate receptors. Here we show that stabilization of the binding domain dimer by the generation of intermolecular disulfide bonds apparently blocked desensitization of the kainate receptor GluR6. This result establishes a common desensitization mechanism in both AMPA and kainate receptors. Surprisingly, however, surface expression of these nondesensitizing mutants was drastically reduced and did not depend on channel activity. Therefore, in addition to its role at the synapse, we now propose an intracellular role for desensitization in controlling maturation and trafficking of glutamate receptors.

Investigation via ion pore transplantation of the putative relationship between glutamate receptors and K + channels

The pore domains of ionotropic glutamate receptors (iGluRs) and potassium channels (K + channels) show several structural similarities. To test for functional compatibility, we transferred pore regions from prokaryotic, invertebrate, and vertebrate K + channels into pharmacologically representative iGluRs and vice versa. Although the chimeric proteins were expressed on the cell surface, only one of 45 pore chimeras showed ion channel function: The kainate receptor subunit GluR6, carrying the pore loop plus adjacent transmembrane domains of the prokaryotic, glutamate-gated, K +-selective GluR0, adopted several electrophysiological properties of the donor pore upon pore transplantation. This suggests that, despite structural similarities between iGluR and K + channel pores, there is a lack of functional compatibility so that K + channel pores cannot be gated by the iGluR gating machinery, and vice versa. However, K +-selective pores can be gated in an iGluR sequence environment, given a similar signal transduction mechanism as appears to be present in GluR0.

Neuroprotective effects of GluR6 antisense oligodeoxynucleotides on transient brain ischemia/reperfusion‐induced neuronal death in rat hippocampal CA1 region

To investigate whether the kainate (KA) receptors subunit GluR6 is involved in the neuronal cell death induced by cerebral ischemia followed by reperfusion, the antisense oligodeoxynucleotides (ODNs) of GluR6 were used to suppress the expression of GluR6 by intracerebroventricular infusion once per day for 3 days before ischemia. Transient brain ischemia was induced by four-vessel occlusion in Sprague-Dawley rats. The effects of GluR6 antisense ODNs on the phosphorylation of MLK3 and JNK and the interactions of MLK3 and PSD-95 with GluR6 were examined by immunoprecipitation and immunoblotting. Our results show that GluR6 antisense ODNs can knock down the expression of GluR6 and suppress the assembly of the GluR6.PSD-95.MLK3 signaling module and, therefore, inhibit JNK activation and phosphoralation of c-jun. On the other hand, the GluR6 antisense ODNs also show a protective role against neuronal cell death induced by cerebral ischemia/reperfusion. Administration of GluR6 antisense ODNs once per day for 3 days before cerebral ischemia significantly decreased neuronal degeneration. In conclusion, our results demonstrate that kainate receptor subunit GluR6 plays an important role in neuronal death induced by cerebral ischemia followed by reperfusion.

The Effect of Three Inhaled Anesthetics in Mice Harboring Mutations in the GluR6 (Kainate) Receptor Gene

Combinations of GluR5-GluR7, KA1, and KA2 subunits form kainate receptors, a subtype of excitatory ionotropic glutamate receptors. Isoflurane enhances the action of kainate receptors comprising GluR6 subunits expressed in oocytes. To test whether alterations of the GluR6 subunit gene affect the actions of inhaled anesthetics in vivo, we measured the minimum alveolar concentration of desflurane, isoflurane, and halothane in mice lacking the kainate receptor subunit GluR6 (GluR6 knockout mice) and mice with a dominant negative glutamine/arginine (Q/R) editing mutation in membrane domain 2 of the GluR6 receptor (GluR6 editing mutants), which increases the calcium permeability of kainate receptors containing GluR6Q. We also measured the capacity of isoflurane to interfere with Pavlovian fear conditioning to a tone and to context. Absence of the GluR6 subunit did not change the minimum alveolar concentration of isoflurane, desflurane, or halothane. Possibly, kainate receptors assembled from the remaining kainate receptor subunits compensate for the absent subunits and thereby produce a normal minimum alveolar concentration. A Q/R mutation that dominantly affects kainate receptors containing the GluR6 subunit in mice increased isoflurane minimum alveolar concentration (by 12%; P < 0.01), decreased desflurane minimum alveolar concentration (by 18%; P < 0.001), and did not change halothane minimum alveolar concentration (P = 0.25). These data may indicate that kainate receptors containing GluR6Q subunits differently modulate, directly or indirectly, the mechanism by which inhaled anesthetics cause immobility. The mutations of GluR6 that were studied did not affect the capacity of isoflurane to interfere with fear conditioning.

Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid

We report the crystal structure of the glycosylated ligand-binding (S1S2) domain of the kainate receptor subunit GluR6, in complex with the agonist domoate. The structure shows the expected overall homology with AMPA and NMDA receptor subunit structures but reveals an unexpected binding mode for the side chain of domoate, in which contact is made to the larger lobe only (lobe I). In common with the AMPA receptor subunit GluR2, the GluR6 S1S2 domain associates as a dimer, with many of the interdimer contacts being conserved. Subtle differences in these contacts provide a structural explanation for why GluR2 L483Y and GluR3 L507Y are nondesensitizing, but GluR6, which has a tyrosine at that site, is not. The structure incorporates native glycosylation, which has not previously been described for ionotropic glutamate receptors. The position of the sugars near the subunit interface rules out their direct involvement in subunit association but leaves open the possibility of indirect modulation. Finally, we observed several tetrameric assemblies that satisfy topological constraints with respect to connection to the receptor pore, and which are therefore candidates for the native quaternary structure.

The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurones

Kainate receptors (KARs) play an important role in synaptic physiology, plasticity and pathological phenomena such as epilepsy. However, the physiological implications for single cells and neuronal networks of the distinct expression patterns of KAR subunits are unknown. One intriguing effect of KAR activation is a long-term change to intrinsic neuronal excitability and neuronal firing patterns, such as single-spike and spike-burst firing. In this study, we describe the role of kainate receptor subunits in the metabotropic regulation of the slow and medium afterhyperpolarization (AHP) currents (I(sAHP), I(mAHP)). Using whole-cell patch-clamp recordings from CA3 pyramidal cells of wild-type (WT) and KAR knockout mice, we show that the kainate-induced decrease of I(sAHP) and I(mAHP) amplitude is protein-kinase-C-dependent and absent in GluR6(-/-) but not GluR5(-/-) pyramidal neurones. Our findings suggest that activation of GluR6-containing KARs modulates AHP amplitude, and influences the firing frequency of pyramidal neurones.

Distinct Roles for the Kainate Receptor Subunits GluR5 and GluR6 in Kainate-Induced Hippocampal Gamma Oscillations

Kainate receptors (KARs) play an important role in synaptic physiology, plasticity, and pathological phenomena such as epilepsy. However, the physiological implications for neuronal networks of the distinct expression patterns of KAR subunits are unknown. Using KAR knock-out mice, we show that subunits glutamate receptor (GluR) 5 and GluR6 play distinct roles in kainate-induced gamma oscillations and epileptiform burst activity. Ablation of GluR5 leads to a higher susceptibility of the network to the oscillogenic and epileptogenic effects of kainate, whereas lack of GluR6 prevents kainate-induced gamma oscillations or epileptiform bursts. Based on experimental and simulated neuronal network data as well as the consequences of GluR5 and GluR6 expression for cellular and synaptic physiology, we propose that the functional interplay of GluR5-containing KARs on axons of interneurons and GluR6-containing KARs in the somatodendritic region of both interneurons and pyramidal cells underlie the oscillogenic and epileptogenic effects of kainate.

The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin

The postsynaptic specialisation at glutamatergic synapses is composed of a network of proteins located within the membrane and the underlying postsynaptic density. The strong interconnectivity between the protein components is mediated by a limited number of interaction modes. Particularly abundant are PDZ domain-mediated interactions. An obstacle in understanding the fidelity of postsynaptic processes involving PDZ domains is the high degree of overlap with respect to their binding specificities. Focussing on transsynaptic adhesion molecules, we used the yeast two-hybrid system to obtain an overview of the binding specificities of selected C-terminal PDZ binding motifs. Neuroligin, a postsynaptic cell surface protein that spans the synaptic cleft and interacts with β-neurexin, served as a starting point. Neuroligin binds to the PDZ domain-containing proteins PSD95, SAP102, Chapsyn110, S-SCAM, Magi1 and 3, Shank1 and 3, Pick1, GOPC, SPAR, Semcap3 and PDZ-RGS3. Next, we examined the relationship between neuroligin and synaptic cell adhesion molecules or glutamate receptor subunits with respect to PDZ-mediated interactions. We found a limited overlap in the PDZ-domain binding specificities of neuroligin with those of Sidekick2 and Ephrin-B2. In contrast, Syndecan2 and IgSF4 show no overlap with the PDZ-domain specificity of neuroligin, instead, they bind to GRIP and syntenin. The AMPA receptor subunit GluR2 interacts with Semcap3 and PDZ-RGS3, whereas the kainate receptor subunits GluR5 and GluR6 show weak interactions with PSD95. In summary, we can sketch a complex pattern of overlap in the binding specificities of synaptic cell surface proteins towards PDZ-domain proteins.

Functional Analysis of Caenorhabditis elegans Glutamate Receptor Subunits by Domain Transplantation

Glutamate receptors are not only abundant and important mediators of fast excitatory synaptic transmission in vertebrates, but they also serve a similar function in invertebrates such as Drosophila and the nematode Caenorhabditis elegans. In C. elegans, an animal with only 302 neurons, 10 different glutamate receptor subunits have been identified and cloned. To study the ion channel properties of these receptor subunits, we recorded glutamate-gated currents from Xenopus oocytes that expressed either C. elegans glutamate receptor subunits or chimeric rat/C. elegans glutamate receptor subunits. The chimeras were constructed between the C. elegans glutamate receptor pore domains and either the rat kainate receptor subunit GluR6, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunit GluR1, or the N-methyl-d-aspartate (NMDA) receptor subunit NMDAR1-1a. Although native subunits were nonfunctional, 9 of 10 ion pores were found to conduct current upon transplantation into rat receptor subunits. A provisional classification of the C. elegans glutamate receptor subunits was attempted based on functionality of the chimeras. C. elegans glutamate receptor ion pores, at a position homologous to a highly conserved site critical for ion permeation properties in vertebrate glutamate receptor pores, contain amino acids not found in vertebrate glutamate receptors. We show that the pore-constricting Q/R site, which in vertebrate receptors determines calcium permeability and rectification properties of the ion channel, in C. elegans can be occupied by other amino acids, including, surprisingly, lysine and proline, without loss of these properties.

Rapid and Differential Regulation of AMPA and Kainate Receptors at Hippocampal Mossy Fibre Synapses by PICK1 and GRIP

We identified four PDZ domain-containing proteins, syntenin, PICK1, GRIP, and PSD95, as interactors with the kainate receptor (KAR) subunits GluR5 2b, GluR5 2c, and GluR6. Of these, we show that both GRIP and PICK1 interactions are required to maintain KAR-mediated synaptic function at mossy fiber-CA3 synapses. In addition, PKCα can phosphorylate ct-GluR5 2b at residues S880 and S886, and PKC activity is required to maintain KAR-mediated synaptic responses. We propose that PICK1 targets PKCα to phosphorylate KARs, causing their stabilization at the synapse by an interaction with GRIP. Importantly, this mechanism is not involved in the constitutive recycling of AMPA receptors since blockade of PDZ interactions can simultaneously increase AMPAR- and decrease KAR-mediated synaptic transmission at the same population of synapses.

RNA Editing at the Q/R Site for the Glutamate Receptor Subunits GLUR2, GLUR5, and GLUR6 in Hippocampus and Temporal Cortex from Epileptic Patients

Posttranscriptional editing of mRNA is a phenomenon that generates molecular heterogeneity and functional variety. With the intention to test if RNA editing plays a role in pathological processes, which contribute to seizure maintenance, we examined the ratio of the unedited (Q) to edited (R) form of the AMPA receptor subunit GluR2 and kainate receptor subunits GluR5 and GluR6 in the hippocampus and temporal cerebral cortex, both excised from patients with pharmacoresistant temporal lobe epilepsies. We compared the data with samples from nonepileptic human control tissue (autopsy tissue). The ratio of Q/R editing was analyzed by means of reverse transcription-polymerase chain reaction followed by a restriction enzyme assay. We found that the editing efficiency for the kainate receptor subunits GluR5 and GluR6 was significantly higher in temporal cortex than in normal controls. The alteration in GluR5 and GluR6 mRNA editing in the neocortical tissue may reflect an adaptive reaction of ongoing seizure activity to prevent excessive Ca2+ influx.