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 effect of priming for audiogenic seizures (AGS) on the development of epileptiform activity in the hippocampus was studied using in vitro kindling (IVK) in Long-Evans rats. AGS priming consists of intense auditory stimulation during a critical period of auditory development, resulting in sound-induced clonic convulsions upon subsequent testing. Between postnatal day (PND) 28 and 50, slices from subjects primed and sham-primed for AGS on PND 18 were used for recording responses in area CA1 of hippocampus following Schaffer collateral stimulation from stratum radiatum of area CA2/CA3. The developmental priming procedure, which enhances auditory brainstem excitability, resulted in fewer afterdischarges in slices from primed subjects across initial IVK stimulation sequences. These results suggest that changes in excitability that occur with acoustic priming can initially diminish selective epileptiform response characteristics in forebrain areas such as the hippocampus.
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PMID:Anti-epileptiform effects of audiogenic seizure priming on in vitro kindling in rat hippocampus. 1116 78

The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Na(v)1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24.
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PMID:A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. 1116 17

Exposure to an enriched environment, a procedure that induces plasticity in the cerebral cortex, is associated with pronounced morphological changes, including higher density of dendritic spines, enlargement of synaptic boutons, and other putative correlates of altered neurotransmission. Recently, it has been demonstrated that animals reared in an enriched environment setting for 3 weeks have less neuronal damage as a result of seizures and have decreased rates of spontaneous apoptosis. Even though clear morphological modifications are observed in the cerebral cortex of animals exposed to heightened environmental complexity, the molecular mechanisms that underlie such modifications are yet to be described. In the present work, we investigated the expression of the immediate early gene arc in the cortex of animals exposed to an enriched environment. Animals were exposed daily, for 1 h, to an enriched environment, for a total period of 3 weeks. Brains were processed for in-situ hybridization against arc mRNA. We found a marked upregulation of arc mRNA in the cerebral cortex of animals exposed to the enriched environment, when compared to undisturbed controls, an effect that was most pronounced in cortical layers III and V. Animals in an additional control group that were handled for 5 min daily, displayed intermediate levels of arc mRNA. Furthermore, arc expression was upregulated in the CA1, CA2 and CA3 hippocampal subfields and in the striatum, but to a lesser extent in the dentate gyrus of animals exposed to an enriched environment, as compared to the two control groups. Our results support the association between the upregulation of the immediate early gene arc and plasticity-associated anatomical changes in the cerebral cortex of the adult mammal.
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PMID:Upregulation of the immediate early gene arc in the brains of rats exposed to environmental enrichment: implications for molecular plasticity. 1145 92

Kainic acid induces seizures with consecutive degeneration of highly vulnerable hippocampal CA3 neurons in adult rats. An abnormal influx of calcium through newly synthesized alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors lacking the GluR2 subunit, which normally renders AMPA receptors calcium impermeable, is thought to play a pivotal role for postictal neuronal death (GluR2 hypothesis). Using a specific GluR2 antiserum, postictal hippocampal GluR2 protein expression was investigated and compared to GluR1 between 6 and 96 h after seizure induction. In addition, postictal protein expression of a recently cloned AMPA receptor binding protein (ABP), which anchors AMPA receptors in the plasma membrane was also analyzed, to address the question of whether its protein expression is associated with neuronal death or survival. At 6 h after seizure induction, GluR2 immunoreactivity (IR) in CA3 was more markedly reduced compared to GluR1, but at 24 h GluR2 IR reattained control levels. More importantly, GluR2 IR was also markedly, but transiently decreased between 6 and 48 h in hippocampal CA1 neurons, but no significant cell loss was observed. These findings modify the GluR2 hypothesis in so far as only a subset of, but not all, hippocampal CA1 and CA3 pyramidal neurons may die due to reduced GluR2 levels with consecutive calcium overload through calcium-permeable AMPA receptors. ABP was induced postictally in presumed CA2 and a subpopulation of CA3 neurons and seems not to be involved in mechanisms of delayed neuronal death.
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PMID:Kainate-induced epilepsy alters protein expression of AMPA receptor subunits GluR1, GluR2 and AMPA receptor binding protein in the rat hippocampus. 1148 17

Specific ligand binding to rat hippocampal adenosine A1 receptor after administration of the convulsant drug 3-mercaptopropionic acid (MP) was studied by means of a quantitative autoradiographic method. 2-Chloro-N6-[cyclopentyl-2,3,4,5-3H adenosine] ([3H]CCPA), a potent and selective A1 receptor ligand, was selected for binding studies. MP administration (150 mg/kg, i.p.), at seizure, caused significant increases in the following CA1 layers: pyramidal (45%), radiatum (18%) and lacunosum molecular (35%); in CA2 area, a significant decrease in stratum oriens (36%) and an increase in stratum radiatum (14%) and lacunosum molecular (33%) layers was observed. In CA3 area a rise in pyramidal (40%) and radiatum layers (26%), as well as in hillus (97%) was found. At postseizure, changes were restricted to CA1, CA2 and CA3 pyramidal layers and to CA1 lacunosum molecular layer, with increases ranging from 22 to 50%. These results show that [3H]CCPA binding is modified diversely in intrahippocampal layers and areas, thus indicating their dissimilar role in seizure activity.
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PMID:Seizure activity produces differential changes in adenosine A1 receptors within rat hippocampus. 1149 45

Studies with animal seizure models have indicated that changes in temporal and spatial expression of voltage-gated sodium channels may be important in the pathology of epilepsy. Here, by using in situ hybridisation with previously characterised subtype-selective oligonucleotide probes [Whitaker et al. (2000) J. Comp. Neurol. 422, 123-139], we have compared the cellular expression of all four brain alpha-subunit sodium channel mRNAs in "normal" and epileptic hippocampi from humans. Neuronal cell loss was observed in all regions of the hippocampus of diseased patients, indicating that sclerosis had occurred. Losses of up to 40% compared to post-mortem controls were observed which were statistically significant in all regions studied (dentate gyrus, hilus, and CA1-3). To assess mRNA levels of the different alpha-subtypes in specific subregions, control and diseased tissue sections were hybridised to subtype-specific probes. To quantify any changes in expression while allowing for cell loss, the sections were processed for liquid emulsion autoradiography and grain counts were performed on populations of individual neurones in different subregions. No significant differences were found in the expression of type I and VI mRNAs. In contrast, a significant down-regulation of type II mRNA was observed in the epileptic tissue in the remaining pyramidal cells of CA3 (71+/-7% of control, P<0.01), CA2 (81+/-8% of control, P<0.05) and CA1 (72+/-6% of control, P<0.05) compared with control tissue. Additionally, a significant up-regulation in type III mRNA in epileptic CA4 pyramidal cells (145+/-7% of control, P<0.05) was observed. It is not clear whether these changes play a causal role in human epilepsy or whether they are secondary to seizures or drug treatment; further studies are necessary to investigate these alternatives. However, it is likely that such changes would affect the intrinsic excitability of hippocampal neurones.
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PMID:Changes in the mRNAs encoding voltage-gated sodium channel types II and III in human epileptic hippocampus. 1156

By immunocytochemical study by both light and electron microscopy of the hippocampus of patients with mesial temporal lobe epilepsy, we have shown that mGluR2/3 and mGluR4alpha immunoreaction product was mainly localised in the molecular layer of the dentate gyrus and CA2 area. Electron microscopy showed that most of the immunoreaction product due to mGluR2/3, 4a and 8 was deposited in the postsynaptic elements of the CA2 pyramidal layer and the inner molecular layer of the dentate gyrus. Only mGluR8 immunoreaction product in the CA2 area and mGluR2/3 in the inner molecular layer of the dentate gyrus were demonstrated in presynaptic elements, suggesting that mGluR2/3 and 8 may be involved in presynaptic inhibition of glutamate release in these areas. The demonstration of some degenerating axon terminals in the inner molecular layer of the dentate gyrus suggests that degeneration of interneurons caused by repeated seizures was still in progress. The finding of mGluR2/3, 4 and 8 immunoreactive astrocytes in patient hippocampus suggests that mGluR2/3, 4 and 8 receptors may be involved in gliosis.
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PMID:Expression of the group II and III metabotropic glutamate receptors in the hippocampus of patients with mesial temporal lobe epilepsy. 1157 52

Following kainate (KA)-induced epilepsy, rat hippocampal neurons strongly express immediate early gene (IEG) products, i.e., c-FOS and c-JUN, and neural stress protein, HSP72. Prolonged expression of c-JUN and c-FOS 48 hr after cerebral ischemia has been underwent delayed neuronal death. However, it is not yet clear whether IEGs actually assume the essential roles in the cell death process or simply as a by-product due to external stimuli because of the prolonged expression of c-FOS, more than one week, on intact CA2 neurons of the hippocampus in a KA-induced epilepsy model. This study investigated the relationships between prolonged expression of c-JUN and hippocampal neuronal apoptosis in a KA-induced epilepsy model. Epileptic seizure was induced in rats by a single microinjection of KA (1 microgram/microL) into the left amygdala. Characteristic seizures and hippocampal neuronal injury were developed. The expression of c-JUN was evaluated by immunohistochemistry, and neuronal apoptosis by in situ end labeling. The seizures were associated with c-JUN expression in the hippocampal neurons, of which the level showed a positive correlation with that of apoptosis. Losses of hippocampal neurons, especially in the CA3 region, were partly caused by apoptotic cell death via a c-JUN-mediated signaling pathway. This is thought to be an important component in the pathogenesis of hippocampal neuronal injury via KA-induced epilepsy.
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PMID:c-JUN expression and apoptotic cell death in kainate-induced temporal lobe epilepsy. 1164 38

In patients suffering from temporal lobe epilepsy (TLE), increased extracellular glutamate levels in the epileptogenic hippocampus both during and after clinical seizures have been reported. These increased glutamate levels could be the result of malfunctioning and/or downregulation of glutamate transporters (also known as EAATs; excitatory amino acid transporters). In this study, the distribution of protein and mRNA of EAAT subtypes was examined in the hippocampus of TLE patients with hippocampal sclerosis (HS group) and without hippocampal sclerosis (non-HS group), and in autopsy controls without neurological disorders. EAAT protein localization was studied by immunohistochemistry on paraffin sections using specific poly- and monoclonal antibodies against the glial glutamate transporters EAAT1 and EAAT2 and the neuronal glutamate transporter EAAT3. Antibody specificity was shown by immunoblotting. In the HS group, a small decrease in EAAT1-immunoreactivity (IR) was observed in CA4 and in the polymorphic and supragranular layer of the dentate gyrus, compared with the control group. The strongest changes were found for EAAT2 levels. In the non-HS group, increased EAAT2-IR was detected in the CA1 and CA2 field, compared with non-epileptic controls. EAAT2-IR was decreased in the HS compared with the non-HS group. Fewer EAAT3-positive cells were found in the HS group than in the non-HS and control group. In both TLE groups, increased EAAT3 levels were observed in individual neurones. In the HS group, the percentage of EAAT3-IR neurones was increased in CA2 and in the granule cell layer of the dentate gyrus. Radioactive in situ hybridization for EAAT1-3 confirmed our immunohistochemical results. Non-radioactive in situ hybridization showed that not only astrocytes, but also neurones express EAAT2 mRNA. Taken together, differences in both mRNA and protein levels of glutamate transporter subtypes were found in specific regions in the TLE hippocampus, with most severe changes found for EAAT2 and EAAT3 levels. The results indicate an upregulation of EAAT2 protein expression in CA1 and CA2 in neurones in the non-HS group. This is in line with decreased EAAT2 protein levels in the HS group, since these hippocampi are characterized by severe neuronal cell loss. The functional consequences (glutamate transport capacity) of the reported changes in EAAT2 and EAAT3 remain to be determined.
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PMID:Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. 1183 91

The immunoreactivity of Na(+)-K(+)-Cl(-) cotransporter (NKCC) in the gerbil hippocampus associated with various sequelae of spontaneous seizures were investigated in order to identify the roles of NKCC in the epileptogenesis and the recovery mechanisms in these animals. The NKCC immunoreactivities in the CA2-3 regions, the subiculum and the entorhinal cortex, were significantly more intensified in the pre-seizure group of seizure sensitive (SS) gerbils than in the seizure resistant (SR) gerbils. Following the on-set of seizure, the immunoreactivity of NKCC was significantly changed. In the hippocampal complex except the CA1 region, NKCC immunoreactivity in GABAergic neurons was significantly decreased 30 min after seizure on-set, versus the pre-seizure group. On the other hand, NKCC immunoreactivity was dramatically elevated in the CA1 regions, and 3 h postictal NKCC immunoreactivity increased significantly in the dentate gyrus and the dendrites of the pyramidal cells in the CA2-3 regions. These findings suggest that altered NKCC expression may be associated with seizure activity, and have an important role in the postictal recovery by regulating GABA-mediated inhibitory circuit in the hippocampal complex of the gerbil.
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PMID:Changes in Na(+)-K(+)-Cl(-) cotransporter immunoreactivity in the gerbil hippocampus following spontaneous seizure. 1241 57


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