Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The level of the mRNAs encoding the AMPA-selective glutamate receptors-A and -B, alternatively splice variants, Flip and Flop, was studied by in situ hybridization in the brains of rats kindled by Schaffer collateral/commissural-fiber stimulation. In comparison to control animals, the expression level of the Flip variant of both GluR-A and GluR-B mRNAs was bilaterally enhanced in the dentate granule neurons of kindled animals 24 h after last-generalized seizure, whereas no obvious alterations were observed in the GluR-A Flop and GluR-B Flop mRNA variants. In kindled animals, studied 1 month after the last seizure, GluR-A Flip and GluR-B Flip mRNA had returned to control levels. We suggest that these changes may result in an enhanced glutamate receptor sensitivity in the fascia dentata during kindling.
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PMID:Hippocampal kindling increases the expression of glutamate receptor-A Flip and -B Flip mRNA in dentate granule cells. 130 May 3

The arginine residue at position 586 of the GluR-B subunit renders heteromeric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptor channels impermeable to calcium. The codon for this arginine is introduced at the precursor messenger RNA (pre-mRNA) stage by site-selective adenosine editing of a glutamine codon. Heterozygous mice engineered by gene targeting to harbor an editing-incompetent GluR-B allele synthesized unedited GluR-B subunits and, in principal neurons and interneurons, expressed AMPA receptors with increased calcium permeability. These mice developed seizures and died by 3 weeks of age, showing that GluR-B pre-mRNA editing is essential for brain function.
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PMID:Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. 750 80

The editing status of mRNA at the Q/R site of the glutamate receptor subtypes -A, -B, -5 and -6 modulates channel conductivity and ion selectivity of glutamate operated ion channels [4,15,26,30]. In order to investigate whether a modification of this editing process may be involved in kindling epileptogenesis, the percentage of edited variant was determined in the hippocampus of kindled rats and compared to the percentage in control animals. In the latter, GluR-A mRNA was detected only in the unedited form (with detection threshold for edited form < 0.7%), whereas GluR-B was completely edited (> 99%). For percentages were not significantly changed in Schaffer collateral/commissural pathway kindled animals that were sacrificed 24 h after the last generalized seizure. It is concluded that the increased sensitivity for the induction of seizures characteristic for Schaffer collateral kindled animals is not related to a less selective or less efficient mRNA editing process of the different glutamate receptor subunits in the hippocampus.
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PMID:Editing status at the Q/R site of glutamate receptor-A, -B, -5 and -6 subunit mRNA in the hippocampal kindling model of epilepsy. 776 99

In the hippocampus, glutamatergic pathways are altered following seizure activity or transient global ischemia, both pathological conditions leading to selective neuronal degeneration. Glutamatergic receptors, and notably alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionate (AMPA) receptors, a family of glutamate receptors involved in fast synaptic transmission and in the maintenance of synaptic potentiation may play an important role in the pathological outcome. AMPA receptors are assembled from GluR-A, GluR-B, GluR-C and GluR-D polypeptides which exist in flop and flip variants, the latter allowing larger glutamate responses. Using in situ hybridization techniques, we show that kainate-induced epilepsy provokes a rapid but transient increase (50%) of GluR-B flip mRNA levels in all subregions of the hippocampus (CA1, CA3, dentate gyrus). This early phase is followed by a second, persistent GluR-B flip increase in regions in which neurons are known to be seizure-resistant (i.e. CA1 an dentate gyrus) while a 35% decrease is observed in the vulnerable CA3 area. Following global ischemia, the levels of GluR-B flip and flop variants are dramatically reduced (90-100%), well before any morphological signs of cell death, in the subiculum and CA1, two areas known to be particularly sensitive to ischemic insult. In keeping with the properties of GluR flip variants, it is suggested that altered subunit stoichiometry may lead to long-lasting enhanced efficiency of fast synaptic transmission in the epileptic hippocampus. Since GluR-B containing receptors are Ca2+ impermeable, our results also suggest altered Ca2+ permeability in the vulnerable pyramidal neurons of areas CA3 and CA1 in the epileptic and ischemic hippocampi, respectively.
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PMID:Alterations of the GluR-B AMPA receptor subunit flip/flop expression in kainate-induced epilepsy and ischemia. 830 23

To investigate whether lasting changes in excitatory amino acid (EAA) receptor subtypes occurred at their mRNA levels as a result of kindling, we carried out in situ hybridization of rat brain sections using synthetic oligonucleotide probes, which were complementary to cloned EAA receptor subunits, namely NMDAR1 for N-methyl-D-aspartate (NMDA), GluR-2 for alpha-amino-3-hydroxy-5-methylisoxazole 4-propionic acid (AMPA), KA-1 for kainate (KA) and mGluR1 for metabotropic EAA receptors. Rats in which left-amygdala-kindling had been established were decapitated 28 days after the last kindled seizure along with the matched controls, which had been subjected to electrode implantation but not to kindling, and the brain sections were hybridized with the probes. The amount of KA receptor mRNA detected with the KA-1 probe increased (25%) on both the left and right sides of the hippocampal CA3 region in the kindled rats, but in no other brain areas (hippocampal CA1, dentate gyrus, amygdala nuclei and pyriform cortex). There was no significant modification of NMDAR1, GluR-2 or mGluR1 receptor mRNAs in any brain area examined. The increase of KA receptor mRNA in the CA3 of amygdala-kindled rats may indicate that the excitability of the neural circuits mediated by KA receptors increased in the hippocampus as a consequence of kindling.
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PMID:Increase of kainate receptor mRNA in the hippocampal CA3 of amygdala-kindled rats detected by in situ hybridization. 839 66

We generated mouse mutants with targeted AMPA receptor (AMPAR) GluR-B subunit alleles, functionally expressed at different levels and deficient in Q/R-site editing. All mutant lines had increased AMPAR calcium permeabilities in pyramidal neurons, and one showed elevated macroscopic conductances of these channels. The AMPAR-mediated calcium influx induced NMDA-receptor-independent long-term potentiation (LTP) in hippocampal pyramidal cell connections. Calcium-triggered neuronal death was not observed, but mutants had mild to severe neurological dysfunctions, including epilepsy and deficits in dendritic architecture. The seizure-prone phenotype correlated with an increase in the macroscopic conductance, as independently revealed by the effect of a transgene for a Q/R-site-altered GluR-B subunit. Thus, changes in GluR-B gene expression and Q/R site editing can affect critical architectural and functional aspects of excitatory principal neurons.
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PMID:Neurological dysfunctions in mice expressing different levels of the Q/R site-unedited AMPAR subunit GluR-B. 1019 81

This manuscript summarizes mouse mutants for ionotropic glutamate receptors that were generated by different laboratories to analyze the function of the NMDA and AMPA receptors in the mouse. Thus, NMDA receptor mutant mice that were generated by the "knock-in" technology demonstrate that the NR1 and the NR2B subunits participate in the formation of NMDA receptors that are involved in vital functions like breathing and suckling of a newborn mouse. Mice that lack NR2A, -2C, and -2D subunits were described to be viable and have been used to study the role of NMDA receptors in adult mice. The depletion of the GluR-B subunit revealed an NMDA receptor-independent form of long-term potentiation (LTP). This AMPA receptor-mediated LTP at CA3/CA1 synapses was also observed in mice that carry an editing-deficient GluR-B allele even though these mice die prematurely after heavy epileptic seizures. In other mutants, the intracellular COOH-terminal domain of the NMDA receptor was truncated; and when compared to NMDA receptor "knock-out" mice, a functional knock-out of the NMDA receptor was observed. However, in the synapses of NR2AC/AC mutants, gatable NMDA receptors were synaptically activated, indicating that the knock-out phenotypes mediated by the COOH-terminally truncated NMDA receptors appear to reflect defective intracellular signaling.
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PMID:Mice with genetically modified NMDA and AMPA receptors. 1041 26

RNA editing by site-selective deamination of adenosine to inosine alters codons and splicing in nuclear transcripts, and therefore protein function. ADAR2 (refs 7, 8) is a candidate mammalian editing enzyme that is widely expressed in brain and other tissues, but its RNA substrates are unknown. Here we have studied ADAR2-mediated RNA editing by generating mice that are homozygous for a targeted functional null allele. Editing in ADAR2-/- mice was substantially reduced at most of 25 positions in diverse transcripts; the mutant mice became prone to seizures and died young. The impaired phenotype appeared to result entirely from a single underedited position, as it reverted to normal when both alleles for the underedited transcript were substituted with alleles encoding the edited version exonically. The critical position specifies an ion channel determinant, the Q/R site, in AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor GluR-B pre-messenger RNA. We conclude that this transcript is the physiologically most important substrate of ADAR2.
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PMID:Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. 1089 45

Dysembryoplastic neuroepithelial tumour (DNT) is a rare low-grade, mixed neuronal and glial tumour, usually associated with pharmacologically intractable, complex partial or generalised seizures which date from childhood. The prognosis after surgery is favourable. We present a classic case of DNT occurring in an 18-year-old male, who presented simple partial seizures without signs of raised intracranial pressure. CT and MR demonstrated focal mass located in the right temporal lobe. Histologically there were found the features of a typical DNT architecture with mixed cellular composition. The response to surgery was excellent. The tumour has not recurred, and the control of seizures remained good. Immunostaining for glutamate receptor GluR-2 showed stronger immunopositivity in neurones dispersed within the tumour and especially in margins of lesion as compared with apparently normal cerebral cortex. The expression of both excitatoryamino acid transporterproteins EAAT1 and EAAT2 was weaker then in normal cortex and uneven. This perhaps may explain the mechanism of seizures (elevated glutaminergic stimulation), and may suggest the excitotoxic damage of neurones.
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PMID:Dysembryoplastic neuroepithelial tumour (DNT). Is the mechanism of seizures related to glutamate? An immunohistochemical study. 1168 Jun 32

'Kindling' is a phenomenon of epileptogenesis, which has been widely used as an experimental model of temporal lobe epilepsy. In the present study, we have examined the contribution of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors and their subunits (GluR-A, -B, -C and -D) to the acquisition and maintenance of the kindled state in the pentylenetetrazole (PTZ)-induced 'kindling' mouse model, by using quantitative autoradiography and in situ hybridization. Region-specific increases in [3H]AMPA binding were seen in kindled animals in the CA3 region of hippocampus and in the temporal cortex 1 week after the last PTZ injection. At the same time, a significant decrease in the level of transcripts encoding the GluR-B and -C subunits was detected in the hippocampal CA1 region and dentate gyrus, suggestive of a higher proportion of Ca(2+)-permeable AMPA receptors in these neurons. These changes did not persist 1 month after establishment of kindling, indicating a transient role of AMPA receptors in the acquisition of the kindled state. At 1 month after the last PTZ injection, an upregulation in [3H]AMPA binding appeared in the motor cortex and the basal ganglia of kindled animals, which is consistent with electrophysiological data showing hyperexcitability in the cortex of the PTZ-kindled animals at that time. Interestingly, an increase in mRNA for the GluR-B subunit appeared in the outer layers of motor and somatosensory cortices of the kindled animals 1 month after acquisition of the kindled state, possibly as part of a gene-regulated, compensatory mechanism against seizure susceptibility, since this change should give rise to a higher proportion of Ca(2+)-impermeable AMPA receptors. These results support the evidence of a transient role of hippocampal AMPA receptors in the acquisition of the 'kindling' phenomenon and they also suggest an involvement of AMPA receptors in the maintenance of kindled state at least in two brain areas, cortex and basal ganglia.
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PMID:Changes in AMPA receptor binding and subunit messenger RNA expression in hippocampus and cortex in the pentylenetetrazole-induced 'kindling' model of epilepsy. 1168 74


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