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)

In vivo gene transfer of glutamate decarboxylase (GAD) has been explored as a means of inducing or increasing the production of the inhibitory amino-acid neurotransmitter, GABA. This strategy has been applied to neuroprotection, seizure prevention, and neuromodulation. In the present experiment, AAV2 was used to transfer the genes for green fluorescence protein (GFP) and GAD65 into the lateral nucleus of the rat hypothalamus. Microinjection of 500 nl of AAV2 resulted in transduction of a 0.25+/-0.04 mm(3) with targeting errors of X=0.48 mm, Y=0.18 mm, Z=0.37 mm using standard stereotactic technique. Pre- and postinjection food and water consumption, urine and feces production, and weight were recorded. In comparison with rAAVCAGGFP- and PBS-injected animals, rats treated with rAAVCAGGAD65 demonstrated reduced weight gain (P<0.014) and transiently reduced daily food consumption (P<0.007) during the postoperative period. No changes in water consumption or waste production were recorded. Effective GAD65 gene transfer was confirmed with in situ hybridization using a probe to the woodchuck post-transcriptional regulatory element sequence included in the vector. These findings suggest that increased GABA production in lateral nucleus of the hypothalamus induced by GAD65 gene transfer may reduce weight gain through reduced feeding.
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PMID:Adeno-associated viral glutamate decarboxylase expression in the lateral nucleus of the rat hypothalamus reduces feeding behavior. 1496 Oct 66

The ketogenic diet is a very low-carbohydrate, high-fat diet used to treat refractory epilepsy. We hypothesized that this diet may act by increasing expression of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis. Thus, we evaluated brain GAD levels in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest ( approximately 10%) calorie restriction, we studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). We found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.
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PMID:Caloric restriction augments brain glutamic acid decarboxylase-65 and -67 expression. 1521 93

GABAergic inhibition of the substantia nigra pars reticulata (SNR) has been shown to suppress seizures in most models of epilepsy, including the amygdala-kindling model of temporal lobe epilepsy (TLE). A dysfunction of this seizure gating mechanism of the SNR may lead to facilitation of seizure propagation in such models. In post-status epilepticus models of TLE, GABAergic neurons in the SNR are damaged, but it is not known whether such damage also occurs in kindling. By using stereological techniques for cell counting in amygdala-kindled rats, we determined the density of SNR neurons that were labeled for GABA by immunohistochemistry or for the two isoforms of the GABA-synthesizing enzyme glutamate decarboxylase (GAD), GAD65 and GAD67, by in situ hybridization (ISH). In addition, GABA neurons in the basolateral amygdala (BLA) were counted. While there was a significant reduction of GAD65 mRNA expressing neurons in the BLA of kindled rats, no alteration in the density of neurons was observed in the anterior or posterior SNR when cells were counted 6 weeks after the last kindled seizure. Our previous finding of reduced GAD and GABA levels in synaptosomes isolated from the SN of kindled rats together with the present observation of unchanged density of SNR neurons in such rats suggest that kindling affects the GABAergic projections from the striatum or globus pallidus to the SNR rather than directly affecting GABA neurons in the SNR.
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PMID:Amygdala-kindling does not induce a persistent loss of GABA neurons in the substantia nigra pars reticulata of rats. 1546 61

Diazepam (DZ) and phenobarbital (PH) are commonly used to treat early-life seizures and act on GABAA receptors (GABAR). The developing GABAergic system is highly plastic, and the long-term effects of postnatal treatment with these drugs on the GABAergic system has not been extensively examined. In the present study, we investigated the effects of prolonged DZ and PH treatment during postnatal development and then discontinuation on expression of a variety of genes involved in GABAergic neurotransmission during adulthood. Rat pups were treated with DZ, PH or vehicle from postnatal day (P) 10-P40 and then the dose was tapered for 2 weeks and terminated at P55. Expression of GABAR subunits, GABAB receptor subunits, GABA transporters (GAT) and GABA synthesizing enzymes (glutamic acid decarboxylase: GAD) mRNAs in hippocampal dentate granule neurons (DGNs) were analyzed using antisense RNA amplification at P90. Protein levels for the alpha1 subunit of GABAR, GAD67, GAT1 and 3 were also assessed using Western blotting. At P90, mRNA expression for GAT-1, 3, 4, GABAR subunits alpha4, alpha6, beta3, delta and theta and GABAB receptor subunit R1 was increased and mRNA expression for GAD65, GAD67 and GABAR subunits alpha1 and alpha3 were decreased in DGNs of rats treated with DZ and PH. The current data suggest that prolonged DZ and PH treatment during postnatal development causes permanent alterations in the expression of hippocampal GABA receptor subunits, GATs and GAD long after therapy has ended.
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PMID:Long-term effects of diazepam and phenobarbital treatment during development on GABA receptors, transporters and glutamic acid decarboxylase. 1580 92

Although of clinical importance, little is known about the mechanism of seizure in neuronal ceroid lipofuscinosis (NCL). In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin D-deficient (CD-/-) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL. In hippocampal slices prepared from CD-/- mice at post-natal day (P)24, spontaneous burst discharges were recorded from CA3 pyramidal cells. At P24, the mean amplitude of IPSPs after stimulation of the mossy fibres was significantly smaller than that of wild-type mice, which was substantiated by the decreased level of gamma-aminobutyric acid (GABA) contents in the hippocampus measured by high-performance liquid chromatography (HPLC). At this stage, activated microglia were found to accumulate in the pyramidal cell layer of the hippocampal CA3 subfield of CD-/- mice. However, there was no significant change in the numerical density of GABAergic interneurons in the CA3 subfield of CD-/- mice at P24, estimated by counting the number of glutamate decarboxylase (GAD) 67-immunoreactive somata. In the hippocampus and the cortex of CD-/- mice at P24, some GABAergic interneurons displayed extremely high somatic granular immunoreactivites for GAD67, suggesting the lysosomal accumulation of GAD67. GAD67 levels in axon terminals abutting on to perisomatic regions of hippocampal CA3 pyramidal cells was not significantly changed in CD-/- mice even at P24, whereas the total protein levels of GAD67 in both the hippocampus and the cortex of CD-/- mice after P24 were significantly decreased as a result of degradation. Furthermore, the recombinant human GAD65/67 was rapidly digested by the lysosomal fraction prepared from the whole brain of wild-type and CD-/- mice. These observations strongly suggest that the reduction of GABA contents, presumably because of lysosomal degradation of GAD67 and lysosomal accumulation of its degraded forms, are responsible for the dysfunction of GABAergic interneurons in the hippocampal CA3 subfield of CD-/- mice.
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PMID:Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice. 1599 79

The piriform cortex (PC) is the largest region of the mammalian olfactory cortex with strong connections to other limbic structures, including the amygdala, hippocampus, and entorhinal cortex. In addition to its functional importance in the classification of olfactory stimuli, the PC has been implicated in the study of memory processing, spread of excitatory information, and the facilitation and propagation of seizures within the limbic system. Previous data from the kindling model of epilepsy indicated that alterations in GABAergic inhibition in the transition zone between the anterior and posterior PC, termed here central PC, are particularly involved in the processes underlying seizure propagation. In the present study we studied alterations in GABAergic neurons in different parts of the PC following seizures induced by kainate or pilocarpine in rats. GABA neurons were labeled either immunohistochemically for GABA or its synthesizing enzyme glutamate decarboxylase (GAD) or by in situ hybridization using antisense probes for GAD65 and GAD67 mRNAs. For comparison with the PC, labeled neurons were examined in the basolateral amygdala, substantia nigra pars reticulata, and the hippocampal formation. In the PC of controls, immunohistochemical labeling for GABA and GAD yielded consistently higher neuronal densities in most cell layers than labeling for GAD65 or GAD67 mRNAs, indicating a low basal activity of these neurons. Eight hours following kainate- or pilocarpine-induced seizures, severe neuronal damage was observed in the PC. Counting of GABA neurons in the PC demonstrated significant decreases in densities of neurons labeled for GABA or GAD proteins. However, a significantly increased density of neurons labeled for GAD65 and GAD67 mRNAs was determined in layer II of the central PC, indicating that a subpopulation of remaining neurons up-regulated the mRNAs for the GAD isoenzymes. One likely explanation for this finding is that remaining GABA neurons in layer II of the central PC maintain high levels of activity to control the increased excitability of the region. In line with previous studies, an up-regulation of GAD67 mRNA, but not GAD65 mRNA, was observed in dentate granule cells following seizures, whereas no indication of such up-regulation was determined for the other brain regions examined. The data substantiate the particular susceptibility of the central PC to seizure-induced plasticity and indicate that this brain region provides an interesting tool to study the regulation of GAD isoenzymes.
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PMID:Acute changes in the neuronal expression of GABA and glutamate decarboxylase isoforms in the rat piriform cortex following status epilepticus. 1679 50

Active behavior, such as exploring a novel environment, induces the expression of the immediate-early gene Arc (activity-regulated cytoskeletal associated protein, or Arg 3.1) in many brain regions, including the hippocampus, neocortex, and striatum. Arc messenger ribonucleic acid and protein are localized in activated dendrites, and Arc protein is required for the maintenance of long-term potentiation and memory consolidation. Although previous evidence suggests that Arc is expressed in neurons, there is no direct demonstration that only neurons can express Arc. Furthermore, there is no characterization of the main neuronal types that express Arc. The data reported here show that behavior- or seizure-induced Arc expression in the hippocampus, primary somatosensory cortex, and dorsal striatum of rats colocalizes only with neuronal (NeuN-positive) and not with glial (GFAP-positive) cells. Furthermore, Arc was found exclusively in non-GABAergic alpha-CaMKII-positive hippocampal and neocortical neurons of rats that had explored a novel environment. Some GAD65/67-positive neurons in these regions were observed to express Arc, but only after a very strong stimulus (electroconvulsive seizure). In the dorsal striatum, spatial exploration induced Arc only in GABAergic and alpha-CaMKII-positive neurons. Combined, these results show that although a very strong stimulus (seizure) can induce Arc in a variety of neurons, behavior induces Arc in the CaMKII-positive principal neurons of the hippocampus, neocortex, and dorsal striatum. These results, coupled with recent in vitro findings of interactions between Arc and CaMKII, are consistent with the hypothesis that Arc and CaMKII act as plasticity partners to promote functional and/or structural synaptic modifications that accompany learning.
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PMID:Spatial exploration induces ARC, a plasticity-related immediate-early gene, only in calcium/calmodulin-dependent protein kinase II-positive principal excitatory and inhibitory neurons of the rat forebrain. 1687 37

Exposure to hyperbaric oxygen (HBO) can lead to seizures, the etiology of which is not completely understood. Glutamic acid decarboxylase (GAD) plays a very important role in maintaining excitatory-inhibitory balance of the central nervous system (CNS). In the present study we investigated the effects of HBO on the activity and content of GAD in vivo and in primarily cultured neurons to probe in detail its effect on the formation of convulsion induced by HBO exposure. The results obtained from in vivo and in vitro experiments were identical. In the latent period before the onset of seizure, the GAD activity followed a rise-and-fall pattern with the prolongation of HBO exposure. At the time of the onset of seizure, GAD activity descended to the normal level. Besides, in the latent period, GAD content also reduced. Such reduction came from a GAD subtype, GAD67, while the content of another GAD subtype, GAD65, remained almost unchanged. Our investigations indicated that GAD is indeed an enzyme highly sensitive to the effect of HBO exposure. The rapid reduction in GAD67 content may be very closely related to seizures induced by HBO exposure.
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PMID:Rapid decrease of GAD 67 content before the convulsion induced by hyperbaric oxygen exposure. 1771 32

In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABA(A) receptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABA(A) receptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5alpha][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the alpha4 subunit. Expression of the alpha4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the alpha4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The alpha4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and alpha4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.
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PMID:Diminished neurosteroid sensitivity of synaptic inhibition and altered location of the alpha4 subunit of GABA(A) receptors in an animal model of epilepsy. 1800 43

Prenatal choline supplementation (SUP) protects adult rats against spatial memory deficits observed after excitotoxin-induced status epilepticus (SE). To examine the mechanism underlying this neuroprotection, we determined the effects of SUP on a variety of hippocampal markers known to change in response to SE and thought to underlie ensuing cognitive deficits. Adult offspring from rat dams that received either a control or SUP diet on embryonic days 12-17 were administered saline or kainic acid (i.p.) to induce SE and were euthanized 16 days later. SUP markedly attenuated seizure-induced hippocampal neurodegeneration, dentate cell proliferation, and hippocampal GFAP mRNA expression levels, prevented the loss of hippocampal GAD65 protein and mRNA expression, and altered growth factor expression patterns. SUP also enhanced pre-seizure hippocampal levels of BDNF, NGF, and IGF-1, which may confer a neuroprotective hippocampal microenvironment that dampens the neuropathological response to and/or helps facilitate recovery from SE to protect cognitive function.
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PMID:Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus. 1835 63


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