Showing papers on "Epileptogenesis published in 1998"
TL;DR: Combining patch-clamp recording and single-cell mRNA amplification (aRNA) techniques in single dentate granule cells, it is demonstrated that expression of GABAA receptor subunit mRNAs is substantially altered in neurons from epileptic rats, indicating that aberrant GAB AA receptor expression and function has an essential role in the process of epileptogenesis.
Abstract: Temporal lobe epilepsy is the most prevalent seizure disorder in adults. Compromised inhibitory neurotransmitter function in the hippocampus contributes to the hyperexcitability generating this condition, but the underlying molecular mechanisms are unknown. Combining patch-clamp recording and single-cell mRNA amplification (aRNA) techniques in single dentate granule cells, we demonstrate that expression of GABAA receptor subunit mRNAs is substantially altered in neurons from epileptic rats. These changes in gene expression precede epilepsy onset by weeks and correlate with profound alterations in receptor function, indicating that aberrant GABAA re- ceptor expression and function has an essential role in the process of epileptogenesis.
738 citations
TL;DR: The observation that seizure frequency initially increased as a function of time after kainate treatment supports the hypothesis that temporal lobe epilepsy can be a progressive syndrome.
361 citations
TL;DR: The lack of increased DGC neurogenesis after fewer kindled seizures or at early timepoints following kindling suggests that this process is not involved in kindling development, and newly generated DGCs may be important for maintenance of the kindled state or the increased susceptibility to spontaneous recurrent seizures.
238 citations
TL;DR: It is indicated that NMDA receptor activation is required for epileptogenesis following SE in this model of limbic epilepsy, and inhibition by MK-801 prevented the development of epilepsy and interictal activity following SE.
170 citations
TL;DR: The immunoreactivity of the highly polysialylated neural cell adhesion molecule (PSA‐NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug‐refractory temporal lobe epilepsy is investigated to provide evidence that synaptic reorganization is an active process in human drug‐ refractory TLE.
Abstract: Neuronal loss and axonal sprouting are the most typical histopathological findings in the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE). It is under dispute, however, whether remodeling of neuronal circuits is a continuous process or whether it occurs only during epileptogenesis. Also, little is known about the plasticity outside of the hippocampus. We investigated the immunoreactivity of the highly polysialylated neural cell adhesion molecule (PSA-NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug-refractory TLE (n=25) and autopsy controls (n=7). Previous studies have shown that the expression of PSA-NCAM is associated with the induction of synaptic plasticity, neurite outgrowth, neuronal migration, and events requiring remodeling or repair of tissue. In patients with TLE, the optical density (OD) of punctate PSA-NCAM immunoreactivity was increased both in the inner and outer molecular layers of the dentate gyrus, compared with controls. The intensity of PSA-NCAM immunoreactivity in the inner molecular layer correlated with the duration of epilepsy, severity of hippocampal neuronal loss, density of mossy fiber sprouting, and astrogliosis. In TLE patients with only mild neuronal loss in the hippocampus, the density of infragranular immunopositive neurons was increased twofold compared with controls, whereas in TLE patients with severe neuronal loss, the infragranular PSA-NCAM-positive cells were not present. In the hilus, the somata and tortuous dendrites of some surviving neurons were intensely stained in TLE. PSA-NCAM immunoreactivity was also increased in CA1 and in layer II of the rostral entorhinal cortex, where immunopositive neurons were surrounded by PSA-NCAM-positive fibers and puncta. Our data provide evidence that synaptic reorganization is an active process in human drug-refractory TLE. Moreover, remodeling is not limited to the dentate gyrus, but also occurs in the CA1 subfield and the entorhinal cortex.
168 citations
TL;DR: Recent data continue to suggest that gap junctions and electrotonic coupling play an important role in neural integration, although additional studies using new techniques will be needed to address some of the controversial issues that have arisen over the last several decades.
149 citations
TL;DR: There is clear evidence for altered NMDA receptor function in acquired epilepsy in animal models and in man, and changes in metabotropic receptor function may also play a key role in epileptogenesis.
Abstract: Glutamatergic synapses play a critical role in all epileptic phenomena. Broadly enhanced activation of post-synaptic glutamate receptors (ionotropic and metabotropic) is proconvulsant. Antagonists of NMDA receptors and AMPA receptors are powerful anticonvulsants in many animal models of epilepsy. A clinical application of pure specific glutamate antagonists has not yet been established. Many different alterations in glutamate receptors or transporters can potentially contribute to epileptogenesis. Several genetic alterations have been shown to be epileptogenic in animal models but no specific mutation relating to glutamatergic function has yet been linked to a human epilepsy syndrome. There is clear evidence for altered NMDA receptor function in acquired epilepsy in animal models and in man. Changes in metabotropic receptor function may also play a key role in epileptogenesis.
146 citations
TL;DR: The results suggest that the nonlinear associations plays an important role in epileptogenesis, and that the process of neuronal entrainment during seizure onset involves a transient interaction between a distributed network of neuronal aggregates, but the maintenance of this interaction is not required for sustained seizure activity.
127 citations
UCB1
TL;DR: It is demonstrated that chronic electrical stimulation with corneal electrodes in mice can rapidly yield large numbers of kindled animals with a seizure phenomenology reflecting partial seizures in man, and corneally kindled mice represents a sensitive and valid screening model for the identification of new therapies for partial epilepsy in man.
124 citations
TL;DR: The results provide direct evidence that prolonged activation of the NMDA-Ca2+ transduction pathway causes a long-lasting plasticity change in hippocampal neurons causing increased excitability leading to the occurrence of spontaneous, recurrent epileptiform discharges.
Abstract: The molecular basis for developing symptomatic epilepsy (epileptogenesis) remains ill defined. We show here in a well characterized hippocampal culture model of epilepsy that the induction of epileptogenesis is Ca2+-dependent. The concentration of intracellular free Ca2+ ([Ca2+]i) was monitored during the induction of epileptogenesis by prolonged electrographic seizure activity induced through low-Mg2+ treatment by confocal laser-scanning fluorescent microscopy to directly correlate changes in [Ca2+]i with alterations in membrane excitability measured by intracellular recording using whole-cell current–clamp techniques. The induction of long-lasting spontaneous recurrent epileptiform discharges, but not the Mg2+-induced spike discharges, was prevented in low-Ca2+ solutions and was dependent on activation of the N-methyl-d-aspartate (NMDA) receptor. The results provide direct evidence that prolonged activation of the NMDA–Ca2+ transduction pathway causes a long-lasting plasticity change in hippocampal neurons causing increased excitability leading to the occurrence of spontaneous, recurrent epileptiform discharges.
120 citations
TL;DR: Inhibition is robust in both of these chronic models of epileptogenesis, and immunocytochemical studies show that there is enhanced immunoreactivity for several proteins in GABAergic interneurons of chronic cortical isolations, and suggest that there may be sprouting of GABAergic axons in the area of injury.
TL;DR: The findings demonstrate the high potency of DCG-IV as an anticonvulsant agent and confirm a key role for group II metabotropic glutamate receptors in the control of seizure activity via their modulatory action on neuronal glutamate release.
TL;DR: The piriform cortex is a temporal lobe structure with a very high seizure susceptibility and the deep agranular insular cortex and perirhinal cortex have a very low seizure threshold, suggesting that recurrent excitation and/or ephaptic interactions play a role in discharge propagation.
Abstract: The piriform cortex is a temporal lobe structure with a very high seizure susceptibility. To investigate the spatiotemporal characteristics of epileptiform activity, slices of piriform cortex were examined by imaging electrical activity with a voltage-sensitive fluorescent dye. Discharge activity was studied for different sites of stimulation and different planes of slicing along the anterior-posterior axis. Epileptiform behavior was elicited either by disinhibition with a gamma-aminobutyric acid-A receptor antagonist or by induction with a transient period of spontaneous bursting in low-chloride medium. Control activity recorded with fluorescent dye had the same pharmacological and temporal characteristics as control activity reported previously with microelectrodes. Simultaneous optical and extracellular microelectrode recordings of epileptiform discharges showed the same duration, latency, and all-or-none character as described previously with microelectrodes. Under all conditions examined, threshold electrical stimulation applied throughout the piriform cortex evoked all-or-none epileptiform discharges originating in a site that included the endopiriform nucleus, a previously identified site of discharge onset. In induced slices, but not disinhibited slices, the site of onset also included layer VI of the adjoining agranular insular cortex and perirhinal cortex, in slices from anterior and posterior piriform cortex, respectively. These locations had not been identified previously as sites of discharge onset. Thus like the endopiriform nucleus, the deep agranular insular cortex and perirhinal cortex have a very low seizure threshold. Additional subtle differences were noted between the induced and disinhibited models of epileptogenesis. Velocity was determined for discharges after onset, as they propagated outward to the overlying piriform cortex. Propagation in other directions was examined as well. In most cases, velocities were below that for action potential conduction, suggesting that recurrent excitation and/or ephaptic interactions play a role in discharge propagation. Future investigations of the cellular and organizational properties of regions identified in this study should help clarify the neurobiological basis of high seizure susceptibility.
TL;DR: It is concluded that pharmaco-resistance in these patients is not associated with a changed modulation of the sodium current by VPA, and a reduced sodium current modulation by carbamazepine in CA1 neurons of patients with hippocampal sclerosis is discussed.
TL;DR: There was a tendency for a reduced expression of EAAC-1 messenger RNA in most regions of the genetically epileptic-prone rat brain although this reached statistical significance only in the striatum, and differences in messenger RNA levels are not reflected or are only partially reflected in the expression of the corresponding proteins.
TL;DR: The in vivo activation of group I mGluRs with the selective agonist 3,5‐DHPG produces hyperexcitatory effects that lead to seizures and neuronal damage, these effects being more severe than those observed after infusion of the non‐selective agonist 1S,3R‐ACPD.
Abstract: While it is well documented that the overactivation of ionotropic glutamate receptors leads to seizures and excitotoxic injury, little is known about the role of metabotropic glutamate receptors (mGluRs) in epileptogenesis and neuronal injury. Intracerebroventricular (i.c.v.) infusion of the group I mGluR specific agonist (R,S)-3,5-dihydroxyphenylglycine (3,5-DHPG) (1.5 micromol) to conscious rats produced severe and delayed seizures (onset at 4 hr) in 70% of the animals. The i.c.v. infusion of the group I mGluR non-selective agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (2 micromol) produced a similar rate of severe seizures, but with an early onset (0.6 hr). The analysis of motor activity showed that 3,5-DHPG elicited higher central stimulatory action than did 1S,3R-ACPD. Histopathological analysis of the hippocampus showed that 3,5-DHPG produced severe neuronal damage mainly in the CA1 pyramidal neurons and, to a lesser extent, in the CA3. Although 1S,3R-ACPD infusion also induced a slight injury of the CA1 and CA3 pyramidal neurons, damage was greater in the CA4 and dentate gyrus cells. In conclusion, the in vivo activation of group I mGluRs with the selective agonist 3,5-DHPG produces hyperexcitatory effects that lead to seizures and neuronal damage, these effects being more severe than those observed after infusion of the non-selective agonist 1S,3R-ACPD.
TL;DR: Findings are consistent with a spatial and time-dependent MAPK expression in selected limbic structures, and its activation could represent an initial trigger for neuronal modifications that may take part in the mechanism underlying acute epileptogenesis and in long-lasting neuropathological changes of the PILO model of epilepsy.
TL;DR: The hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit stoichiometry; this may contribute to limbic epileptogenesis is supported.
Abstract: There is considerable controversy whether aberrant fascia dentata (FD) mossy fiber sprouting is an epiphenomena related to neuronal loss or a pathologic abnormality responsible for spontaneous limbic seizures. If mossy fiber sprouting contributes to seizures, then reorganized axon circuits should alter postsynaptic glutamate receptor properties. In the pilocarpine-status rat model, this study determined if changes in alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and n-methyl-D-aspartic acid (NMDA) receptor subunit mRNA levels correlated with mossy fiber sprouting. Sprague-Dawley rats were injected with pilocarpine (320 mg/kg; i.p.) and maintained in status epilepticus for 6 to 8 hours (pilocarpine-status). Rats were killed during the: (1) latent phase after neuronal loss but before spontaneous limbic seizures (day 11 poststatus; n = 7); (2) early seizure phase after their first seizures (day 25; n = 7); and (3) chronic seizure phase after many seizures (day 85; n = 9). Hippocampi were studied for neuron counts, inner molecular layer (IML) neo-Timm's staining, and GluR1–3 and NMDAR1–2b mRNA levels. Compared with controls, pilocarpine-status rats in the: (1) latent phase showed increased FD GluR3, NMDAR1, and NMDAR2b; greater CA4 and CA1 NMDAR1; and decreased subiculum GluR1 hybridization densities; (2) early seizure phase showed increased FD GluR3, increased CA1 NMDAR1, and decreased subiculum NMDAR2b densities; and (3) chronic seizure phase showed increased FD GluR2; increased FD and CA4 GluR3; decreased CA1 GluR2; and decreased subiculum GluR1, GluR2, NMDAR1, and NMDAR2b levels. In multivariate analyses, greater IML neo-Timm's staining: (1) positively correlated with FD GluR3 and NMDAR1 and (2) negatively correlated with CA1 and subiculum GluR1 and GluR2 mRNA levels. These results indicate that: (1) hippocampal AMPA and NMDA receptor subunit mRNA levels changed as rats progressed from the latent to chronic seizure phase and (2) certain subunit alterations correlated with mossy fiber sprouting. Our findings support the hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit stoichiometry; this may contribute to limbic epileptogenesis. J. Neurosci. Res. 54:734–753, 1998. © 1998 Wiley-Liss, Inc.
TL;DR: The findings likely indicate enhanced interictal inhibitory mechanisms in patients with partial epilepsy involving the primary motor cortex and could be greater in the intact hemisphere rather than in the affected one, in which the hyperexcitability of the epileptic focus had to be counterbalanced.
TL;DR: It is suggested that the selective activation of the group II metabotropic glutamate receptors by agonists such as 2R,4R-APDC may be of therapeutic potential in the treatment of seizure disorders.
TL;DR: It is confirmed that the piriform cortex is not a homogeneous structure but that there are differences along the anterior‐posterior axis of this region in neurochemical (and most certainly also functional) consequences in response to kindling stimulation from other limbic brain regions.
Abstract: Several lines of evidence indicate a critical role of the piriform cortex (PC) in the kindling model of temporal lobe epilepsy, suggesting that the PC is part of an epileptic network that is pivotal in the genesis of kindling, facilitating, and intensifying the spread of seizures from a focus in amygdala, hippocampus, or other limbic brain regions to cortical and subcortical regions. Kindling of the amygdala has been shown to induce long-lasting changes in synaptic efficacy in the ipsilateral PC comparable to abnormalities seen in epileptic foci, but the neurochemical alterations possibly underlying these functional changes are not known. The possibility that the enhanced excitability of the PC in response to kindling is related to a reduction of GABAergic neurotransmission prompted us to examine if a lasting reduction in GABA-immunoreactive PC neurons is detectable after kindling of the basolateral amygdala (BLA) in rats. Furthermore, GABA immunoreactivity was determined in the BLA in order to investigate whether GABAergic neurons decrease in focal tissue, as previously suggested by neurochemical and immunocytochemical studies in amygdala-kindled rats. Three groups of age-matched rats were used: (1) a group of rats that was kindled via electrical stimulation by a bipolar electrode implanted in the right BLA, (2) a group of BLA-implanted but nonstimulated rats, and (3) a group of non-implanted, naive control rats. The kindled rats were sacrificed 40 days after the last fully kindled seizure. The two other groups of rats were sacrificed together with the kindled rats on the same days, and tissues from kindled and control rats were treated concurrently throughout the immunohistochemical analysis. GABA neurons were stained by a monoclonal antibody to GABA. Kindling of the BLA led to a pronounced decrease in the number of GABA immunoreactive neurons in the ipsi- and contralateral BLA at all section levels examined. In the PC, no significant differences between groups were seen in the contralateral hemisphere, while a significant reduction in GABA immunoreactive cells was observed in the transition zone between anterior and posterior PC in the hemisphere ipsilateral to the BLA electrode. The present findings add to the accumulating evidence that the PC is critically involved in kindling-induced epileptogenesis. The data furthermore substantiate that the PC is not a homogeneous structure but that there are differences along the anterior-posterior axis of this region in neurochemical (and most certainly also functional) consequences in response to kindling stimulation from other limbic brain regions.
TL;DR: The progression of subclinical neuronal excitatory activity to a clinical seizure may relate directly to the phenomenon of cortical plasticity, a disorder of recurrent seizures that are neural in origin.
TL;DR: It is suggested that epileptogenesis followed by chronic, spontaneous seizures could be initiated by deposition of iron-containing compounds into limbic structures of the rat.
Patent•
12 Mar 1998TL;DR: In this paper, the methods and compounds useful for the inhibition of convulsive disorders, including epilepsy, are disclosed, and methods for preparing the compounds of the invention are also described.
Abstract: Methods and compounds useful for the inhibition of convulsive disorders, including epilepsy, are disclosed. The methods and compounds of the invention inhibit or prevent ictogenesis and epileptogenesis. Methods for preparing the compounds of the invention are also described.
TL;DR: The recent occurrence of seizures in amygdala-kindled rats compromised sensorimotor gating in a way compatible with psychotic states in humans, as measured as prepulse inhibition of the acoustic startle response (PPI).
TL;DR: The results suggest that different NTFs can be recruited at different stages of kindling epileptogenesis and, accordingly, may play different parts in the adaptive changes taking place in this experimental paradigm.
Abstract: Neurotrophic factors (NTF) play important roles in the developing and in the adult brain. NTF involvement in neuronal plasticity is suggested by the modulation of NTF expression patterns in different physiological and pathological situations and by the effects they produce in the adult brain (e.g. axonal sprouting induction and neuroprotection). We used the RNAase protection assay to investigate the expression patterns of some NTFs during amygdala kindling, an animal model of epilepsy in which ‘pathological’ neuronal plasticity appears to occur. After a single kindling stimulation, fibroblast growth factor-2 (FGF-2) mRNA levels were increased in the hippocampus, the cortex and the hypothalamus, whereas they were not significantly altered in the thalamus and the striatum. A single stimulation did not alter fibroblast growth factor-1 (FGF-1) and brain-derived neurotrophic factor (BDNF) gene expression. Fully kindled animals, left unstimulated for a week, did not exhibit any alteration in the mRNA levels for any of the NTFs examined. However, in contrast with the effect of a single stimulation, amygdala stimulation of kindled animals (evoking a generalized tonic-clonic seizure) produced a great increase in hippocampal and cortical BDNF mRNA levels, but FGF-1 mRNA levels were not altered, and FGF-2 mRNA levels were significantly increased only in the cortex. These results suggest that different NTFs can be recruited at different stages of kindling epileptogenesis and, accordingly, may play different parts in the adaptive changes taking place in this experimental paradigm.
TL;DR: Results suggest that there is a significant progressive lowering of the brainstem seizure threshold, during the incubation phase of the flurothyl paradigm, which is coincident with the previously reported time course of change in the behavioral seizure phenotype observed using this flurothy model.
TL;DR: The data indicate that the long-lasting stimulus-evoked seizures are mainly responsible for inducing delayed kindling, whereas the number of seizure events or generalized convulsions, and the total duration of epileptiform activity are less important.
01 Jan 1998
TL;DR: It is of interest, then, that anterior temporal lobectomy in human epileptics resecting the amygdala and the anterior hippocampus reduces a preexisting anxiety disorder.
Abstract: Kindling of the mammalian limbic system has been suggested as a model of epileptogenesis in complex partial seizure disorder2 (CPS). The most commonly agreed upon problems of an affective nature associated with epilepsy are anxiety and depression2,42,87. An extensive literature implicates the amygdala in the production of fearful and anxiety related states in animals and humans. It is of interest, then, that anterior temporal lobectomy in human epileptics resecting the amygdala and the anterior hippocampus reduces a preexisting anxiety disorder43. Data like these, and a great deal of other data1, implicate alteration of amygdala functioning in affective disturbance in epilepsy.
TL;DR: Data support the concept that separate anatomical systems mediate the expression of the two generalized seizure phenotypes and the ventromedial nucleus of the hypothalamus may be a point of interaction between the systems and may play a role in seizure-induced neural reorganization.