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 molecular pharmacologic basis of epileptogenesis in cortical tubers in the tuberous sclerosis complex is unknown. Altered transcription of genes encoding glutamatergic and gamma-aminobutyric acid (GABA)-ergic receptors and uptake sites may contribute to seizure initiation and may occur selectively in dysplastic neurons and giant cells. Arrays containing GABA A (GABAAR), GluR, NMDA receptor (NR) subunits, GAD65, the vesicular GABA transporter (VGAT), and the neuronal glutamate transporter (EAAC1) cDNAs were probed with amplified poly (A) mRNA from tubers or normal neocortex to identify changes in gene expression. Increased levels of EAAC1, and NR2B and 2D subunit mRNAs and diminished levels of GAD65, VGAT, GluR1, and GABAAR alpha1 and alpha2 were observed in tubers. Ligand-binding experiments in frozen tuber homogenates demonstrated an increase in functional NR2B-containing receptors. Arrays were then probed with poly (A) mRNA from single, microdissected dysplastic neurons, giant cells, or normal neurons (n = 30 each). Enhanced expression of GluR 3, 4, and 6 and NR2B and 2C subunit mRNAs was noted in the dysplastic neurons, whereas only the NR2D mRNA was upregulated in giant cells. GABAAR alpha1 and alpha2 mRNA levels were reduced in both dysplastic neurons and giant cells compared to control neurons. Differential expression of GluR, NR, and GABAAR mRNAs in tubers reflects cell-specific changes in gene transcription that argue for a distinct molecular phenotype of dysplastic neurons and giant cells and suggests that dysplastic neurons and giant cells make differential contributions to epileptogenesis in the tuberous sclerosis complex.
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PMID:Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers. 1119 98

In the normal granule cells of the dentate gyrus, glutamate and both gamma-aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD) coexist. GAD expression is increased after seizures, and simultaneous glutamatergic and GABAergic neurotransmission from the mossy fibers to CA3 appears, supporting the hypothesis that GABA can be released from the mossy fibers. To sustain GABAergic neurotransmission, the amino acid must be transported into synaptic vesicles. To address this, using RT-PCR we looked for the presence and regulation of expression of the vesicular GABA transporter (VGAT) mRNA in the dentate gyrus and in mossy fiber synaptosomes of control and kindled rats. We found trace amounts of VGAT mRNA in the dentate gyrus and mossy fiber synaptosomes of control rats. In the dentate gyrus of kindled rats with several seizures and of control rats subject to one acute seizure, no changes were apparent either 1 or 24 h after the seizures. However, repetitive synaptic or antidromic activation of the granule cells in slices of control rats in vitro induces an activity-dependent enhancement of VGAT mRNA expression in the dentate. Surprisingly, in the mossy fiber synaptosomes of seizing rats, the levels of VGAT mRNA were significantly higher than in controls. These data show that the granule cells and their mossy fibers, besides containing machinery for the synthesis of GABA, also contain the elements that support its vesiculation. This further supports the notion that local synaptic molecular changes enable mossy fibers to release GABA in response to enhanced excitability.
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PMID:Vesicular GABA transporter mRNA expression in the dentate gyrus and in mossy fiber synaptosomes. 1158 98

GABAergic transmission in the mossy fiber (MF) projection of the hippocampus is not normally detected in the rat. However, seizures induce simultaneous glutamatergic and GABAergic transmission in this projection, which coincides with an overexpression of GAD(67) and vesicular GABA transporter (VGAT) mRNA in the dentate gyrus (DG) and MF. To test whether this plastic change could be induced in an activity-dependent fashion in the absence of seizures, I recorded intracellularly from slices/cells that served as their own control, before and after direct or synaptic kindling of the DG in vitro. As expected, synaptic responses of CA3 pyramidal cells to test pulse DG stimulation were blocked by perfusion of N-methyl-D-aspartate (NMDA) and non-NMDA receptors' antagonists. However, after kindling the perforant path (3 1-s trains of 0.1-ms pulses at 100 Hz, 1 min apart from each other every 15 min for 3 h), which potentiated synaptic responses without inducing epileptiform activity, the perfusion of glutamatergic antagonists blocked the excitatory synaptic potential and isolated a fast bicuculline-sensitive inhibitory synaptic potential. Immunohistochemical experiments confirmed the overexpression of GAD(67) in the kindled slices. If kindling stimulation was provided just for 1 h or if it was completed in the presence of the protein synthesis inhibitor, cycloheximide, the expression of the GABAergic potential was prevented. Alternatively, when control synaptic responses of a given cell were first blocked, the direct kindling stimulation over the same site during perfusion of glutamatergic antagonists resulted in the induction of fast GABAergic potentials after 16.6 +/- 0.9 kindling trials. Furthermore, a high spacial specificity of this phenomenon was evidenced by recording synaptic responses of a given pyramidal cell to two different MF inputs. After blockade of all synaptic responses with the perfusion of glutamatergic antagonists, one of the inputs was kindled, while synaptic responses between the kindling trials were monitored by applying test pulse stimulation to both inputs. After 17 +/- 1 trials, test pulse stimulation provided over the kindled site evoked GABAergic potentials, whereas test pulse stimulation delivered to the alternative nonkindled parallel MF input remained ineffective. The DG-evoked GABAergic responses were inhibited by the activation of GABA(B)R and mGluR, whereby activation of group III mGluR with L-2-amino-4-phosphonobutyric acid (L-AP4) was significantly more effective than the activation of group II mGluR with DCG-IV. These data demonstrate that GABAergic transmission from the MF projection has distinctive features in the adult rat, and that its induction is dependent on protein synthesis responding in an activity-dependent fashion.
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PMID:Activity-dependent expression of simultaneous glutamatergic and GABAergic neurotransmission from the mossy fibers in vitro. 1197 92

Although the granule cells of the dentate gyrus are glutamatergic, they contain the machinery for the synthesis and vesiculation of GABA. Furthermore, glutamic acid decarboxylase and the vesicular GABA transporter mRNA are expressed in the granule cells and mossy fibers in an activity-dependent manner, suggesting that these cells release GABA in addition to glutamate. Supporting this hypothesis, we found that seizures induce simultaneous glutamatergic and GABAergic transmission in the mossy fiber projection. To further explore this expression of inhibition, we looked for the presence and expression of endogenous GABA in a synaptosomal preparation enriched with mossy fiber nerve endings of kindled rats. We also studied the capacity of this preparation to capture and release [(3)H]GABA under control conditions and after kindling epilepsy. In accordance with our hypothesis we show that the mossy fiber synaptosomal preparation of the kindled rats has a significantly higher content of endogenous GABA than controls. We also found that the protein content in the mossy fiber synaptosomal preparation of kindled rats was significantly augmented, which is consistent with mossy fiber sprouting. Due to this, the total [(3)H]GABA incorporated in the synaptosomal preparation was also augmented. However, [(3)H]GABA uptake (expressed in % radioactivity/mg protein) and its evoked release were similar in both groups. With the present results, we provide further support for the hypothesis of the emergence of GABAergic transmission in the mossy fiber synapse that can constitute a protective mechanism in response to seizures.
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PMID:The expression of GABA in mossy fiber synaptosomes coincides with the seizure-induced expression of GABAergic transmission in the mossy fiber synapse. 1242 29

To identify the roles of vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) in epileptogenesis and the recovery mechanisms in spontaneous seizure, we conducted a chronological and comparative analysis of VGAT expression. VGAT immunoreactivity was stronger in the seizure resistant group than that in the pre-seizure group of seizure sensitive (SS) gerbils. In 3 h postictal group, the density of VGAT immunoreactivity was significantly increased in the hippocampus, as compared to pre-seizure group. In 24 h postictal group, VGAT immunodensity had recovered to its pre-seizure level. In addition, VGAT immunoreactivity in the hippocampus was also increased by vigabatrin (GVG) administration. These results suggest that decreased VGAT expression in the SS gerbil hippocampus may affect epileptogenesis in this animal, and that the subsequent alteration in its expression induced by seizure and the administration of GVG may reflect a modulation of GABA release to alleviate seizure activity.
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PMID:Changed vesicular GABA transporter immunoreactivity in the gerbil hippocampus following spontaneous seizure and vigabatrin administration. 1253 68

The granule cells of the dentate gyrus (DG) are considered to be glutamatergic, but they contain glutamic acid decarboxylase, gamma-amino butyric acid (GABA), and the vesicular GABA transporter mRNA. Their expression is regulated in an activity-dependent manner and coincides with the appearance of GABAergic transmission from the mossy fibers (MF) to pyramidal cells in area CA3. These data support the hypothesis that MF are able to release glutamate and GABA. Following the principle that a given neuron releases the same neurotransmitter(s) onto all its targets, we here demonstrate the emergence, after a generalized convulsive seizure, of MF GABAergic signaling sensitive to activation mGluR-III onto pyramidal cells and interneurons of CA3. Despite this, excitation overrides inhibition in interneurons, preventing disinhibition. Furthermore, on blockade of GABA and glutamate ionotropic receptors, an M1-cholinergic depolarizing signal is also revealed in both targets, which postsynaptically modulates the glutamatergic and GABAergic fast neurotransmission. The emergence of these nonglutamatergic signals depends on protein synthesis. In contrast to cholinergic responses evoked by associational/commissural fibers activation, cholinergic transmission evoked by DG stimulation is only observed after seizures and is strongly depressed by the activation of mGluR-II, whereas both are depressed by M2-AChR activation. With immunohistological experiments, we show that this cholinergic pathway runs parallel to the MF. Thus seizures compromise a delicate balance of excitation and inhibition, on which a complex interaction of different neurotransmitters emerges to counteract excitation at pre- and postsynaptic sites. Particularly, MF GABAergic inhibition emerges to exert an overall inhibitory action on CA3.
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PMID:Activity-dependent induction of multitransmitter signaling onto pyramidal cells and interneurons of hippocampal area CA3. 1261 45

Changes in vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) expression in the gerbil hippocampus after treatment with baclofen (GABA(B) receptor agonist) or phaclofen (GABA(B) receptor antagonist) were investigated to identify the GABA(B) receptor-mediated regulation of VGAT expression. In the baclofen-treated seizure-resistant gerbils, VGAT expression was significantly reduced, as compared with the control animals, thus the VGAT immunoreactive pattern in these gerbils was similar to that in control seizure-sensitive (SS) gerbils. In the phaclofen-treated SS gerbils, VGAT expression was dramatically elevated, compared to SS gerbil controls. Our findings demonstrated that GABA(B) receptor-mediated regulation of VGAT expression may be another mechanisms for presynaptic GABA release, which is accompanied by a reduction in Ca(2+) conductance by the inhibition of voltage-gated Ca(2+) channels.
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PMID:Presynaptic gamma-aminobutyric acid type B receptor-mediated regulation of vesicular gamma-aminobutyric acid transporter expression in the gerbil hippocampus. 1285 May 45

Kainic acid-induced seizures cause a marked increase in the expression of glutamate decarboxylase 67 (GAD67) in granule cells of the dentate gyrus. To determine the possible modes of sequestration of newly formed gamma-aminobutyric acid (GABA), we used in situ hybridization and immunocytochemistry to investigate the expression of several proteins related to GABA in dentate granule cells of rats 4 h to 60 days after kainic acid-induced status epilepticus and in controls. GAD67 and GAD65 mRNA levels were increased by up to 300% and 800%, respectively, in the granule cell layer 6-24 h after kainate injection. Subsequently, increased GAD and GABA immunoreactivity was observed in the terminal field of mossy fibers and in presumed dendrites of granule cells. mRNA of both known plasma membrane GABA transporters (GAT-1 and GAT-3) was expressed in granule cells of control rats. GAT-1 mRNA levels increased (by 30%) 9 h after kainate injection but were reduced by about 25% at later intervals. GAT-3 mRNA was reduced (by 35-75%) in granule cells 4 h to 30 days after kainic acid injection. In contrast, no expression of the mRNA or immunoreactivity of the vesicular GABA transporter was detected in granule cells or in mossy fibers, respectively. GABA transaminase mRNA was only faintly expressed in granule cells, and its levels were reduced (by 60-65%) 12 h to 30 days after kainate treatment. The results indicate that GABA can be taken up and synthesized in granule cells. No evidence for the expression of the vesicular GABA transporter (VGAT) in granule cells was obtained. After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells. It is suggested that, during epileptic seizures, elevated intracellular GABA and sodium concentration could then result in nonvesicular release of GABA from granule cell dendrites. GABA could then act on GABA-A receptors, protecting granule cells from overexcitation.
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PMID:Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures. 1462 Aug 76

Epileptiform discharges and behavioral seizures may be the consequences of excess excitation from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). GABA is taken up and accumulated in synaptic vesicles by the action of vesicular GABA transporter (VGAT) before its release into the synaptic cleft, and removed from synaptic regions by the action of transporter proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, the effects of diazoxide (DIZ) on the VGAT, GAT-1 and GAT-3 mRNA and protein levels in hippocampus, and on the seizure activities of picrotoxin (PTX)-induced kindling rats were observed. DIZ caused increase in the quantity of VGAT mRNAs and proteins, and down regulation of GABA transporters GAT-1 and GAT-3 mRNAs and proteins after the PTX re-kindling. Furthermore, DIZ produced not only a prompt but also a later suppression of PTX-induced seizures. Although DIZ has effects on ATP-sensitive potassium (K(ATP)) channels when measured in vitro, our study suggests that additional mechanisms of action may involve the regulation of GABA transporters, which may aid in understanding epileptogenesis and inform investigators about future design and development of K(ATP) channel openers to treat epilepsy.
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PMID:Effect of diazoxide on regulation of vesicular and plasma membrane GABA transporter genes and proteins in hippocampus of rats subjected to picrotoxin-induced kindling. 1548 95

AP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking mu3B, a subunit of AP-3B. mu3B-/- mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of gamma-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in mu3B-/- mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.
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PMID:Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor. 1549 41


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