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 gene encoding of the 65 kDa isoform of the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), GAD65, was targeted in mice by homologous recombination. Viable GAD65 -/- mice were obtained with the expected mendelian frequency and displayed no gross morphological defects. Despite the complete loss of GAD65 mRNA and protein in a homozygous mutant, there was no difference in GABA content in the brains of GAD65 +/+, +/-, and -/- mice. As for the other 67 kDa isoform (GAD67), the levels of mRNA and protein were largely unchanged by the GAD65 mutation. General behavior, including locomotor activity and performance in the Morris water maze task, appeared normal, but seizures were more easily induced by picrotoxin and pentylenetetrazol: the latencies to seizures induced by picrotoxin were shorter and the dose of pentylenetetrazol required for induction of seizures was lower.
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PMID:Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures. 895 91

A recently-developed method of gene mapping is reviewed. Several responses to EtOH were studied with the purpose of identifying genes with modest effects (Quantitative Trait Loci, or QTLs). As an example, results from a study of acute ethanol withdrawal severity are discussed. Mice from inbred strains C57BL/6J and DBA/2J, and 19 of their Recombinant Inbred (BXD RI) strains, were given 4 g/kg EtOH and their acute withdrawal severity assessed with the handling-induced convulsion (HIC). HIC scores varied markedly among strains. Comparison of the pattern of strain means for withdrawal with a database comprising genotype of each BXD RI strain for almost 800 mapped polymorphic genetic markers revealed associations with several potential QTLs appearing on several mouse chromosomes. To verify the presence of a gene affecting withdrawal, we then withdrawal-tested individual F2 mice bred from the F1 cross of the parental C57 and DBA strains. These mice were then genotyped for several polymorphic markers close to a putative QTL on chromosome 2. Possession of the DBA allele in severely withdrawing F2 animals was significantly associated with one such marker, D2Mit9, confirming the presence of a gene nearby affecting withdrawal. As a further test, mice of the replicated Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) lines, selected for severity of EtOH withdrawal HIC, were also genotyped. Alleles at the D2Mit9 locus assorted disproportionately (and consistently) between the two pairs of WSP and WSR lines, while alleles at other loci did not. Thus, three tests consistently suggest the influence of a gene, tentatively termed Aw1, 37 cM from the centromere on chromosome 2, that appears to control as much as 40% of the genetic variance in withdrawal. The provisional locus is located very near to two candidate genes. Gad1 codes for the synthesis of glutamic acid decarboxylase, the rate-limiting enzyme for synthesis of GABA. A cluster of genes (Scn1, Scn2, Scn3) code for voltage-sensitive sodium channel proteins. These genes are plausible candidates for affecting withdrawal HIC.
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PMID:Use of recombinant inbred strains for studying genetic determinants of responses to alcohol. 897 18

Several similarities exist between the alterations observed in the chronic pilocarpine model of recurrent seizures in the rat and those found in human temporal lobe epilepsy. The present studies are focused on changes in the GABA system in this model. Following the initial pilocarpine-induced seizures, a substantial loss of glutamic acid decarboxylase (GAD) mRNA-containing neurons has been found in the hilus of the dentate gyrus (Obenaus et al., J. Neurosci., 13 (1993) 4470-4485), and, recently, a loss of GAD mRNA-labeled neurons has also been found in stratum oriens of CA1. Yet numerous other GABA neurons remain within the hippocampal formation, and there appear to be multiple compensatory changes in these neurons. Labeling for GAD65 mRNA and associated protein is substantially increased in the remaining GABA neurons at 2-4 months after the initial seizure episode. Such increased labeling suggests that the remaining GABA neurons are part of a functional circuit and may be responding to the need for increased activity. Alterations also occur in at least one subunit of the GABA-A receptor. Labeling for the alpha(5) subunit mRNA is substantially decreased in CA1 and CA2 of pilocarpine-treated rats during the chronic, seizure-prone period. These findings emphasize the complexity of changes in the GABA system and indicate a need for evaluating the functional consequences of each of the changes. The initial loss of specific groups of GABA neurons could be a critical first step in the gradual development of epileptiform activity. While many of the subsequent changes in the GABA system may be considered to be compensatory, significant deficits of GABAergic function could remain.
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PMID:Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures. 898 1

Alcohol dependence (alcoholism) is accompanied by evidence of tolerance, withdrawal (physiological dependence), or compulsive behavior related to alcohol use. Studies of strain and individual differences using animal models for acute physiological dependence liability are useful means to identify potential genetic determinants of liability in humans. Behavioral and quantitative trait analyses were conducted using animal models for high risk versus resistance to acute physiological dependence. Using a two-step genetic mapping strategy, loci on mouse chromosomes 1, 4, and 11 were mapped that contain genes that influence alcohol withdrawal severity. In the aggregate, these three risk markers accounted for 68% of the genetic variability in alcohol withdrawal. Candidate genes in proximity to the chromosome 11 locus include genes encoding the alpha1, alpha6, and gamma2 subunits of type-A receptors for the inhibitory neurotransmitter, GABA. In addition, suggestive linkage is indicated for two loci on mouse chromosome 2, one near Gad1 encoding glutamic acid decarboxylase, and the other near the El2 locus which influences the seizure phenotype in the neurological mutant strain El. The present analyses detect and map some of the loci that increase risk to develop physiological dependence and may facilitate identification of genes related to the development of alcoholism. Syntenic conservation between human and mouse chromosomes suggests that human homologs of genes that increase risk for physiological dependence may localize to 1q21-q32, 2q24-q37/11p13, 9p21-p23/1p32-p22.1, and 5q32-q35.
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PMID:Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. 913 12

Levetiracetam is a novel antiepileptic agent with a wide spectrum of activity against experimental and clinical seizures. The mechanism of its anticonvulsant action remains to be determined. We have investigated the effects of levetiracetam on several gamma-aminobutyric acid (GABA)-related neurochemical parameters in mouse brain. Adult male mice were randomised into two groups and administered levetiracetam (0-300 mg/kg) intraperitoneally either as a single dose or twice daily for 5 days. Four hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of GABA, glutamate and glutamine and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single dose and repeated levetiracetam treatments were without effect on all of the parameters investigated. The anticonvulsant action of levetiracetam is unlikely to be mediated via an action on the GABAergic system.
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PMID:Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. 915 36

Chronic administration of ethanol to rats on an intermittent regimen, for 60 repeated intoxicating doses and repeated withdrawal episodes, results in a long-lasting kindling phenomenon. This involves an increasing severity of withdrawal, including a reduced threshold to seizures produced by the GABA(A) antagonist, pentylenetetrazol. We have shown previously that muscimol-evoked 36Cl- efflux and paired-pulse inhibition (involving GABA(A)-mediated recurrent inhibition) were decreased persistently in the CA1 region of hippocampal slices from chronic intermittent ethanol (CIE)-treated rats. We now report elevated levels of mRNA in forebrain for the alpha4 subunit of the GABA(A) receptor (GABAR), considered to be a constituent of pharmacologically and physiologically novel subtypes of GABARs. Using in situ hybridization with digoxigenin-labeled RNA probes, we show that at 2 days withdrawal, 60-dose CIE leads to a significant 30% increase in alpha4 subunit mRNA levels in the dentate gyrus, 46% increase in the CA3, and 26% increase in the CA1 regions. In contrast, there was no significant change in the mRNAs for the alpha5 subunit or glutamic acid decarboxylase 67 in the same regions. This study suggests that GABAR subunit-selective alterations occur after CIE treatment, possibly resulting in the alteration of the subunit composition of GABARs, with presumably altered physiological functions. This plasticity of GABARs may contribute to the increased withdrawal severity, reduced hippocampal inhibition, and increased seizure susceptibility of this animal model of human alcohol dependence.
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PMID:Chronic intermittent ethanol treatment in rats increases GABA(A) receptor alpha4-subunit expression: possible relevance to alcohol dependence. 916 43

In addition to its role as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system. GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined. The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues. Recently we have produced GAD65 -/- mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures. Here we report the production of GAD67 -/- mice. These mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 -/- mice. Their brain, however, did not show any discernible defects. Previous pharmacological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.
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PMID:Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. 917 46

The peritumoural neocortex removed from epileptic patients represents an important region for research because of its possible relationship to the generation, maintenance, and propagation of seizures. The peritumoural neocortex removed from an epileptic patient showing a regrowth of an anaplastic astrocytoma was examined in detail using immunocytochemistry for gamma-aminobutyric acid, glutamic acid decarboxylase, parvalbumin, nonphosphorylated neurofilament protein, glial fibrillary acidic protein, and histocompatibility antigen HLA-DR. The patterns of immunostaining were compared with the cytoarchitecture and myeloarchitecture in adjacent sections, and with the patterns of immunostaining observed in normal control neocortex. Furthermore, quantitative electron microscopy was used to compare the synaptic densities of presumptive excitatory and inhibitory synapses between regions showing different grades of cytoarchitectural and neurochemical alterations in the peritumoural neocortex, and to compare these regions with normal neocortex. A variety of changes in synaptic circuits in the peritumoural neocortex was found, but it appears that neurons within the less abnormal-looking regions were involved in altered synaptic circuits that might contribute to epileptic activity. In these regions, the most prominent change was the loss of inhibitory synapses on the soma and axon initial segment of pyramidal cells, but numerous excitatory synapses were present on their dendrites that would make these neurons hyperexcitable. However, the most abnormal regions histologically were likely a primary zone for progression of the tumour, with many surviving neurones, but which received and formed very few synapses; thus, they were probably unrelated to the initiation, maintenance, or propagation of seizures.
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PMID:Loss of inhibitory synapses on the soma and axon initial segment of pyramidal cells in human epileptic peritumoural neocortex: implications for epilepsy. 928 31

There is accumulating evidence of anterior-posterior differences in the susceptibility of the piriform cortex to seizure induction and to functional alterations in response to seizures elicited from other limbic brain regions, but the reasons for such differences along the anterior-posterior axis of the piriform cortex are not clear. In the present study, GABAergic neurons have been identified in the piriform cortex of the rat at light microscopic level by immunocytochemical localization of GABA and the GABA-synthesizing enzyme glutamic acid decarboxylase. A monoclonal antibody to GABA and, for comparison, polyclonal antibodies to GABA and glutamic acid decarboxylase were used for this purpose. In both anterior and posterior piriform cortex, the highest number and density of GABA-immunoreactive cells was found in layer II. Lower density of GABAergic cells was found in layers I and III and the subjacent endopiriform cortex. When cells were quantified in 19 corresponding sections of the piriform cortex, covering most of anterior-posterior extension of this region, there appeared to be an increased density of GABAergic neurons in sections near to or within the transition zone between anterior and posterior piriform cortex. A more detailed analysis at 4 section levels in the anterior and posterior piriform cortex and the transition zone between the 2 parts substantiated a significantly higher density of GABAergic neurons in the transition zone, which was predominantly due to increased numbers of cells in layers II and III. We propose that the transition zone between anterior and posterior piriform cortex is a location where numerous GABAergic interneurons regulate the activity of neighbouring deep pyramidal cells which receive dense excitatory input from both the olfactory bulb and distant pyramidal cells in the more anterior and posterior parts of the piriform cortex at the same time, thus increasing the risk of paroxysmal activation within this restricted area. This proposal is in line with recent observations of increased susceptibility to epileptiform activation and to kindling-induced neurochemical alterations within the transition zone between anterior and posterior piriform cortex.
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PMID:Differences in the distribution of GABA- and GAD-immunoreactive neurons in the anterior and posterior piriform cortex of rats. 968 74

For the evaluation of glutamatergic and GABAergic transmission during seizures, rat hippocampal CA1 and CA3 areas were separately assessed by brain microdialysis, and extracelluar glutamate and GABA were measured through the course of the seizures after a systemic administration of kainic acid (KA). The generalized convulsion started at about 1.5 h and was suppressed by diazepam at 2 h after the KA treatment. In the CA3 area, extracellular glutamate started to increase soon after the KA injection and returned to the control level at about 1.5 h. A decrease and then slight increase of the extracellular glutamate level in CA3 followed the diazepam injection. In the CA1 area, in contrast, a long-lasting decrease of extracellular glutamate was observed. The extracellular GABA concentration in the CA3 area increased immediately after the systemic administration of KA and returned to the normal level at about 3.5 h. A second increase in the extracellular GABA in this area began at about 4.5 h after the KA treatment. In the CA1 area, an increase of extracellular GABA began at about 3.5 h after KA administration (much later than that observed in the CA3 area) and was maintained throughout the observation. In situ hybridization showed a transient expression of glutamic acid decarboxylase (GAD)-67 mRNA in the granule cell layer of the dentate gyrus at 4 and 6 h, whereas GAD65 mRNA was unaffected. GABA immunoreactivity in the same area and mossy fibers in the CA3 were increased most significantly at 8 h after administration of KA. The possible relation of GABA induction in mossy fibers with the delayed increase in extracellular GABA in CA3 was discussed.
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PMID:Changes in extracellular glutamate and GABA levels in the hippocampal CA3 and CA1 areas and the induction of glutamic acid decarboxylase-67 in dentate granule cells of rats treated with kainic acid. 968


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