Showing papers on "Epileptogenesis published in 1997"
TL;DR: The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons, and it is hypothesized that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
Abstract: Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-d-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
788 citations
TL;DR: Findings from the dentate gyrus of epileptic kainate‐treated rats are strikingly similar to those reported for human temporal lobe epilepsy, and they suggest that neuron loss and axon reorganization in the temporal hippocampus may be important in epileptogenesis.
Abstract: We sought to describe quantitatively the morphological and functional changes that occur in the dentate gyrus of kainate-treated rats, an experimental model of temporal lobe epilepsy. Adult rats were treated systemically with kainic acid, and, months later, after displaying spontaneous recurrent motor seizures, their dentate gyri were examined. Histological, immunocytochemical, and quantitative stereological techniques were used to estimate numbers of neurons per dentate gyrus of various classes and to estimate the extent of granule cell axon reorganization along the septotemporal axis of the hippocampus in control rats and epileptic kainate-treated rats. Compared with control rats, epileptic kainate-treated rats had fewer Nissl-stained hilar neurons and fewer somatostatin-immunoreactive neurons. There was a correlation between the extent of hilar neuron loss and the extent of somatostatin-immunoreactive neuron loss. However, functional inhibition in the dentate gyrus, assessed with paired-pulse responses to perforant-pathway stimulation, revealed enhanced, and not the expected reduced, inhibition in epileptic kainate-treated rats. Numbers of parvalbumin- and cholecystokinin-immunoreactive neurons were similar in control rats and in most kainate-treated rats. A minority (36%) of the epileptic kainate-treated rats had fewer parvalbumin- and cholecystokinin-immunoreactive neurons than control rats, and those few (8%) with extreme loss in these interneuron classes showed markedly hyperexcitable dentate gyrus field-potential responses to orthodromic stimulation. Compared with control rats, epileptic kainate-treated rats had larger proportions of their granule cell and molecular layers infiltrated with Timm stain. There was a correlation between the extent of abnormal Timm staining and the extent of hilar neuron loss. Granule cell axon reorganization and dentate gyrus neuron loss were more severe in temporal vs. septal hippocampus. These findings from the dentate gyrus of epileptic kainate-treated rats are strikingly similar to those reported for human temporal lobe epilepsy, and they suggest that neuron loss and axon reorganization in the temporal hippocampus may be important in epileptogenesis.
502 citations
TL;DR: Age‐related differences in response to GABAergic agents provide further evidence that the pathophysiology of seizures in the immature brain differs from that in the mature brain.
Abstract: Summary: Children with epilepsy present unique challenges to the clinician In addition to having differences in clinical and EEG phenomena, children differ from adults in regard to etiological factors, response to antiepileptic drugs (AEDs), and outcome It is now recognized that the immature brain also differs from the mature brain in the basic mechanisms of epileptogenesis and propagation of seizures The immature brain is more prone to seizures due to an imbalance between excitation and inhibition γ-Aminobutyric acid (GABA), the major CNS inhibitory neurotransmitter in the mature brain, can lead to depolarization in the hippocampal CA3 region in very young rats There are also age-related differences in response to GABA agonists and antagonists in the substantia nigra, a structure important in the propagation of seizures These age-related differences in response to GABAergic agents provide further evidence that the pathophysiology of seizures in the immature brain differs from that in the mature brain Although prolonged seizures can cause brain damage at any age, the extent of brain damage after prolonged seizures is highly age dependent Far less histological damage and fewer disturbances in cognition result from prolonged seizures in the immature brain than from seizures of similar duration and intensity in mature animals However, detrimental effects of AEDs may be greater in the immature brain, than in the mature brain These lessons from the animal laboratory raise questions about the appropriateness of current therapeutic approaches to childhood seizure disorders
274 citations
TL;DR: This article summarizes recent observations, conclusions, and hypotheses regarding the possible role of GABA in epileptogenesis based on presentations made at the International Symposium “Focus on Epilepsy 111: GABA and Epileptogenesis” held in Whistler, B.C., in May 1995.
Abstract: y-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. It exerts an inhibitory action in all forebrain structures, and it may play a role in the physiopathogenesis of certain neurological conditions, including epilepsy. Impairment of GABA functions produces seizures, whereas enhancement results in an anticonvulsant effect. Accordingly, several anticonvulsant drugs, including some antiepileptic drugs (AEDs), act by enhancing the efficacy of GABAmediated mechanisms (1,2). Numerous steps in GABA synaptic function are relevant to epileptogenesis: (a) GABA synthesis; (b) GABA release; (c) GABA transport; and (d) activation of receptors, subtypes A and B. Therefore several potential targets exist for epilepsy medications that are related to GABA. GABAA receptors apparently are particularly important in epileptogenesis and therapeutics. Several reviews have described the molecular and functional aspects of GABAA receptors (3-6). In this article, we summarize recent observations, conclusions, and hypotheses regarding the possible role of GABA in epileptogenesis. Much of the information is based on presentations made at the International Symposium “Focus on Epilepsy 111: GABA and Epileptogenesis” held in Whistler, B.C., in May 1995. A list of the faculty that participated in this conference is included in the Notes section.
273 citations
TL;DR: It is demonstrated that cycloheximide, a protein synthesis inhibitor, blocked pilocarpine- and kainate-induced mossy fiber sprouting in rats, but did not prevent the subsequent development of spontaneous seizures or affect their frequency.
159 citations
TL;DR: Hypothalamic hamartomas are rare malformations containing neurons that can be associated with a remark- able epileptic syndrome, characterized by laughing (gelastic) seizures beginning in early child- hood, often in the neonatal period.
Abstract: Hypothalamic hamartomas are rare malformations containing neurons that can be associated with a remark- able epileptic syndrome. This syndrome is characterized by laughing (gelastic) seizures beginning in early child- hood, often in the neonatal period. Usually there is later development of both focal seizures including complex partial seizures (CPS) and a pattern of symptomatic gen- eralized epilepsy with tonic, atonic and other seizure types in association with slow spike-and-wave discharge
150 citations
TL;DR: It is found that in response to muscarinic activation, pools of EC interneurons discharge synchronously by a mechanism not necessarily involving principal cell activation, and their robust epileptogenic character may be of major importance in temporal lobe epilepsy.
Abstract: Oscillation and synchronization of neural activity is important in normal brain function but is also relevant to epileptogenesis. One of the most frequent forms of epilepsy originates in temporal lobe circuitry of which the entorhinal cortex (EC) is crucial. Because muscarinic receptor activation promotes oscillatory dynamics in EC neurons, we investigated in a brain slice preparation the effects of carbachol (CCh) on oscillatory population activity in the EC. We found that CCh produced epileptiform activity in EC, which according to field profile and current source density analysis was usually driven by layer V. In addition, localized CCh application and surgical isolation experiments demonstrated that EC layer II, but not layer III, can also independently generate synchronous population activity. Intracellular recordings from EC principal cells during epileptiform activity demonstrated large-amplitude, synaptically driven depolarizing events and bursts of action potentials synchronized to the field spikes. In layer II neurons, the depolarizing events had a multiphasic reversal potential that suggested concurrent glutamatergic and GABAergic synaptic input. Interestingly, although the epileptiform activity required activation of AMPA but not NMDA receptors, small-amplitude field spikes persisted during block of fast excitatory neurotransmission. These field spikes were correlated to large-amplitude IPSPs in layer II neurons, and both activities were abolished by GABAA-receptor antagonism. Thus, in response to muscarinic activation, pools of EC interneurons discharge synchronously by a mechanism not necessarily involving principal cell activation. Given the differential projection pattern of EC layers V and II toward the neocortex and hippocampus, respectively, their robust epileptogenic character may be of major importance in temporal lobe epilepsy.
143 citations
135 citations
TL;DR: It is demonstrated that intraventricular administration of NGF itself accelerates the progression of kindling epileptogenesis, increases mossy fiber sprouting in the CA3 region and in the inner molecular layer (IML), but reduces seizure-induced decreases in hilar cell density.
Abstract: Recurrent seizure activity induced during kindling has been reported to produce a functional synaptic reorganization of the mossy fibers in the hippocampus. To date, it is unclear whether this kindling-induced growth is secondary to decreases in hilar neuron density, which are presumed to reflect hilar neuronal cell loss, or whether it is related specifically to an activation-dependent plasticity. We recently demonstrated that blocking nerve growth factor (NGF) biological activity retards seizure development and inhibits the sprouting of mossy fibers. We now demonstrate that intraventricular administration of NGF itself accelerates the progression of kindling epileptogenesis, increases mossy fiber sprouting in the CA3 region and in the inner molecular layer (IML), but reduces seizure-induced decreases in hilar cell density. These findings provide support for a role of NGF in kindling and kindling-induced mossy fiber sprouting. In addition, the results dissociate this form of epileptogenesis from hilar cell loss or decreases in hilar cell density attributable to increases in hilar area, thereby supporting seizure-induced mossy fiber sprouting as being primarily attributable to the combined effects of neuronal activation and the activation-induced upregulation of growth factors.
120 citations
TL;DR: Recent data support the hypothesis that local inhibitory circuits mask the multisynaptic excitatory interactions that are associated with mossy fiber sprouting in the dentate gyrus and that physiological mechanisms that reduce inhibition or increase excitability unmask the new recurrent excited circuits responsible for seizures.
Abstract: This review article evaluates the hypothetical cellular mechanisms responsible for chronic lesion-induced epilepsy. Emphasis is given to particular clinical characteristics of secondary epileptogenesis: (a) a temporal latency, (b) the involvement of distant but related sites, and (c) irreversibility. Although loss of GABAergic inhibitory interneurons or increased excitatory input to these interneurons may contribute to epileptogenesis, several studies have provided evidence that inhibition is not depressed in epileptogenic regions and may actually be enhanced. Axonal sprouting, synaptic reorganization, and formation of new recurrent excitatory circuits have been proposed to account for the increased seizure susceptibility of temporal lobe epilepsy. Recent data support the hypothesis that local inhibitory circuits mask the multisynaptic excitatory interactions that are associated with mossy fiber sprouting in the dentate gyrus and that physiological mechanisms that reduce inhibition or increase excitability unmask the new recurrent excitatory circuits responsible for seizures. A hypothesis based on axonal sprouting and synaptic reorganization can account for the essential clinical characteristics of secondary epileptogenesis and may have widespread applicability to the general phenomenon of lesion-induced epilepsy.
112 citations
TL;DR: The exquisite sensitivity of agonists in the kindling model of epilepsy and the lack of evidence for endogenous receptor activation suggest that presynaptic group II- and group III-like mGluRs might be useful targets for suppression of excessive synaptic activation in neurological disorders such as epilepsy.
Abstract: Modulation of excitatory synaptic transmission by presynaptic metabotropic glutamate receptors (mGluRs) was examined in brain slices from control rats and rats with amygdala-kindled seizures. Using whole-cell voltage-clamp and current-clamp recordings, this study shows for the first time that in control and kindled basolateral amygdala neurons, two pharmacologically distinct presynaptic mGluRs mediate depression of synaptic transmission. Moreover, in kindled neurons, agonists at either group II- or group III-like mGluRs exhibit a 28- to 30-fold increase in potency and suppress synaptically evoked bursting. The group II mGluR agonist (2S,3S,4S)-2-(carboxycyclopropyl)glycine (L-CCG) dose-dependently depressed monosynaptic EPSCs evoked by stimulation in the lateral amygdala with EC50 values of 36 nM (control) and 1.2 nM (kindled neurons). The group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) was less potent, with EC50 values of 297 nM (control) and 10.8 nM (kindled neurons). The effects of L-CCG and L-AP4 were fully reversible. Neither L-CCG (0.0001-10 microM) nor L-AP4 (0.001-50 microM) caused membrane currents or changes in the current-voltage relationship. The novel mGluR antagonists (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)-glycine (MCCG; 100 microM) and (S)-2-methyl-2-amino-4-phosphonobutyrate (MAP4; 100 microM) selectively reversed the inhibition by L-CCG and L-AP4 to 81.3 +/- 12% and 65.3 +/- 6.6% of predrug, respectively. MCCG and MAP4 (100-300 microM) themselves did not significantly affect synaptic transmission. The exquisite sensitivity of agonists in the kindling model of epilepsy and the lack of evidence for endogenous receptor activation suggest that presynaptic group II- and group III-like mGluRs might be useful targets for suppression of excessive synaptic activation in neurological disorders such as epilepsy.
TL;DR: Experimental data from animal models strongly supports the hypothesis that a prolonged generalized or limbic seizure in early life damages the hippocampus and other limbic structures, facilitating an epileptogenic process that, after a latent period, gives rise to spontaneous limbic seizures.
Abstract: Alfred Meyer and his colleagues were the first to report (1954-1956) that the most frequent pathology in tissue from patients with complex partial seizures successfully treated by anterior temporal lobectomy is mesial temporal sclerosis, and that the majority of patients with this lesion give a history of a prolonged seizure early in life. These observations have been repeatedly confirmed. Experimental data from animal models strongly supports the hypothesis that a prolonged generalized or limbic seizure in early life damages the hippocampus and other limbic structures, facilitating an epileptogenic process that, after a latent period, gives rise to spontaneous limbic seizures. Some mechanisms potentially contributing to this process have been identified.
TL;DR: As researchers gain more understanding of the cellular, molecular, and genetic mechanisms underlying seizure propagation, they should be better able to develop therapeutic agents designed to suppress seizure‐provoking mechanisms and to enhance the brain's natural protective mechanisms.
Abstract: Although a wide variety of drugs are available for treatment of epilepsy, many patients with epilepsy still experience uncontrolled seizures. In addition, there is a need for new drugs that can halt epileptogenesis after brain injury. Mechanisms that underlie seizure processes constitute potential target areas for the development of new antiepileptic drugs (AEDs). An understanding of the underlying mechanisms of interictal spike discharge and seizure spread is critical for the development of AEDs for treatment of partial seizures. Suppression of specific forms of voltage-dependent calcium currents and inhibition of GABA(B) receptor-mediated inhibition are two key target areas for new AEDs to treat primary generalized seizures. As researchers gain more understanding of the cellular, molecular, and genetic mechanisms underlying seizure propagation, we should be better able to develop therapeutic agents designed to suppress seizure-provoking mechanisms and to enhance the brain's natural protective mechanisms.
TL;DR: The results suggest the mechanisms by which presynaptically active glutamate receptor agonists block the development of the chronically epileptic state induced by electrical kindling, and indicate that their anticonvulsive activity is due to inhibition of presynaptic glutamate and/or aspartate release following blockade of Presynaptic Ca2+ entry.
TL;DR: Some neuroplasticity processes known to develop during epileptogenesis (neuronal-hyperexcitability, modulation of GABA/benzodiazepine transmission) may participate in these lasting changes of behaviour, especially in structures involved in the control of fear-promoted reactions (amygdala, periaqueductal grey matter).
TL;DR: The hypothesis that mossy fibre sprouting facilitates epileptogenesis of mossy fibres from dentate granule cells is argued against.
Abstract: Sprouting of mossy fibres from dentate granule cells occurs in several animal models of epilepsy and in epileptic humans. Mossy fibre sprouting might contribute to epileptogenesis but also could be a compensatory, inhibitory response. We analysed mossy fibre sprouting in the supragranular zone of the dentate gyrus using Timm's histochemical method in genetically fast and slow kindling rats. Before the start of amygdala kindling, the slow rats showed higher Timm's staining scores than did the fast kindlers. No increase of mossy fibre density was observed when the animals were stimulated until either the fast or the slow rats had reached the fully kindled state. Our data argue against the hypothesis that mossy fibre sprouting facilitates epileptogenesis.
TL;DR: It is indicated that endogenous NT-3 levels can influence the rate of epileptogenesis, and a link betweenNT-3 and BDNF gene regulation in dentate granule cells is suggested.
TL;DR: According to the data, a few seizures of amygdaloid origin may cause more severe damage to SOM-ir neurons in the amygdala than in the hilus and, therefore, contribute to epileptogenesis.
TL;DR: Converging lines of evidence suggest that an autoimmune process is important in the pathogenesis of Rasmussen's encephalitis.
Abstract: Summary: Purpose: Rasmussen's encephalitis (RE) is a progressive childhood disease characterized by unilateral brain dysfunction, seizures, and inflammatory histopathology. Converging lines of evidence suggest that an autoimmune process is important in the pathogenesis of RE.
Methods: Two patients with pathologically confirmed RE and increased levels of circulating glutamate receptor subunit (GluR3) antibodies were studied prospectively before, during, and after trials of plasmapheresis (PEX) and other immunomodulation. Frequency, duration, and intensity of clinical seizures were directly correlated with the abundance of interictal epileptiform activity on serial EEGs.
Results: Serial EEGs in these patients suggest that early in the course of RE interictal epileptiform activity is localized to the affected hemisphere and that disease progression is associated with increasingly frequent bilaterally synchronous and contralateral epileptiform activity.
Conclusions: The clinical and EEG parameters of epileptogenesis were transiently diminished by PEX, which suggests that circulating factors induce dose-dependent, reversible epileptogenic effects in some patients with RE.
TL;DR: Data indicate that specific kindling processes are initiated during the interval of repeated seizure induction and evolve in the absence of continued seizure induction, and mechanisms of epileptogenesis were found to be manifest predominantly as a change in the seizure phenotype expressed and to proceed independent of changes in the generalized seizure threshold.
Abstract: This study examined both the acute and long-lasting changes in seizure susceptibility that occur in response to the repeated induction of generalized seizure activity. Daily flurothyl-induced generalized clonic seizures resulted in a progressive decrease in both the generalized seizure threshold and the latency to the first myoclonic jerk. The threshold reduction was significant as early as the second trial and was maximal by trial 5. However, a minimum of eight seizures was necessary for the maximal reduction to be long-lasting. The present study also examined the effects of the number of seizures and the duration of the stimulation-free interval on the type of generalized seizure expressed. During the induction phase of the experiment, only generalized clonic seizures (“forebrain seizures”) were expressed. If, however, the animal was retested after a 1, 2, 3, or 4 week stimulation-free interval, a progressive increase in both the proportion of animals expressing “brainstem seizure” behaviors and the median seizure score was observed. The progression of flurothyl-induced generalized seizure behaviors was significantly altered if (1) a minimum of eight generalized clonic seizures had been expressed, and (2) a minimum of a 2 week stimulation-free interval followed. Fewer generalized clonic seizures failed to reliably produce changes in seizure phenotype, even after extended stimulus-free intervals. These data indicate that specific kindling processes are initiated during the interval of repeated seizure induction and evolve in the absence of continued seizure induction. Furthermore, these mechanisms of epileptogenesis were found to be manifest predominantly as a change in the seizure phenotype expressed and to proceed independent of changes in the generalized seizure threshold.
TL;DR: The mechanism of mesial temporal spike generation was investigated to determine whether amygdalohippocampotomy by radiofrequency lesions altered spike rates in patients with medically intractable temporal lobe epilepsy.
Abstract: Purpose To investigate the mechanism of mesial temporal spike generation, we sought to determine whether amygdalohippocampotomy by radiofrequency lesions altered spike rates in patients with medically intractable temporal lobe epilepsy. Methods The subjects were 14 patients whose ictal semiology, ictal and interictal EEGs, and neuropsychological profile were compatible with seizure origin from MRI-demonstrated unilateral mesial temporal sclerosis. Mesial temporal spikes were recorded by a multicontact electrode line stereotactically placed in the temporal horn of the lateral ventricle. A recording and lesioning electrode was also stereotactically advanced to multiple amygdala and hippocampal targets. Several confluent (9 patients) or discrete (5 patients) radiofrequency lesions were made in the amygdala and anterior hippocampus. Scalp and invasive recordings were performed before lesioning, between each lesioning process, and for 48 postoperative h. Results As compared to prelesion recordings, no consistent change in anterior and total mesial temporal spike rates occurred intraoperatively or postoperatively. Postlesion: prelesion spike ratios failed to correlate with effectiveness of lesionectomy for seizure control. In contrast, complex partial seizures improved in 13 of 14 patients. Conclusions Amygdala and hippocampal destructive lesions had no consistent effect on meisal temporal spike quantity, but reduced temporal lobe CPS in 13 of 14 patients. This dichotomy suggests that CPS may result from concerted epileptogenesis of the hippocampus, entorhinal cortex, and possibly the amygdala, while the entorhinal cortex alone can produce interictal spikes.
TL;DR: It is demonstrated that the amygdaloid body is severely altered in most patients with temporal lobe epilepsy and that these changes are independent of those in the hippocampus.
Abstract: Although clinical and electrophysiological evidence indicates that the amygdaloid body plays an important role in the pathogenesis of temporal lobe epilepsy, there are very few detailed data on histopathological changes in this nucleus in epilepsy patients. In the present study we have examined the lateral nucleus of the amygdaloid body in 70 surgical specimens from patients with temporal lobe epilepsy and in 10 control specimens with respect to neuronal density and gliosis. The results were compared to the neuronal loss in the hippocampal formation. Our goal was to examine the pathological alterations of the amygdaloid body and their correlation with other morphological changes in temporal lobe epilepsy. In epilepsy patients with Ammon's horn sclerosis or focal lesions of the temporal lobe, the neuronal density of the lateral amygdaloid nucleus was significantly decreased as compared to normal controls (P < 0.001). Overall, the mean volumetric density in epilepsy patients was reduced to 59% of that in normal individuals. There was no correlation between the neuronal density in the lateral amygdaloid nucleus and that in the different segments of the hippocampal formation or to the age at onset or the duration of epilepsy. The neuronal loss of the amygdaloid nucleus correlated well with the presence of fibrillary gliosis. Our findings demonstrate that the amygdaloid body is severely altered in most patients with temporal lobe epilepsy and that these changes are independent of those in the hippocampus. The presence of neuronal loss and gliosis in the amygdaloid nucleus of patients with focal lesions but no Ammon's horn sclerosis is compatible with an involvement of the amygdala in secondary epileptogenesis.
TL;DR: The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively.
Abstract: Kindling involves repeated administration of brief high-frequency electrophysiological stimulation of the brain at initially subthreshold intensities that eventually evoke full-blown seizures. It has thus been used not only as a model of epileptogenesis, but of long-term neuronal memory. Quenching is a phenomenon that utilizes low-frequency stimulation for much longer periods of time (eg, 1 Hz for 15 minutes), and appears to exert preventive effects on the development of kindling and inhibit the manifestation of full-blown kindled seizures by markedly increasing the amygdala afterdischarge and seizure threshold. (See also “Kindling and Quenching: Conceptual Implications for rTMS,” by Weiss and Post, page 32). The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively. These neuroplastic changes are relatively long lasting and appear reversible at the level of synaptic function with either LTD or LTP capable of countering the effects of the other.
TL;DR: Results demonstrate that the seizure-like activity developing in deep dendrotomized cortical segments resulted from two sources of GABAergic disinhibition: the physical removal of important superficial inhibitory circuits and glutamate-triggered increases in intracellular calcium.
Abstract: Yang, Lie and Larry S. Benardo. Epileptogenesis following neocortical trauma from two sources of disinhibition. J. Neurophysiol. 78: 2804–2810, 1997. Intracellular and field potential recordings we...
TL;DR: The VDCC alpha1-subunit gene expression is altered in a subclass-specific manner during the early stages of kindling and may play a role in the establishment of a kindled focus, possibly caused by an alteration of the population of VD CCs involved in neurotransmitter release.
TL;DR: Results presented here indicate that a transient focal disinhibition promotes persistent intrinsic and synaptic excitability changes in piriform cortex neurons, which may be responsible for the propagation of epileptiform activity and for the induction of secondary epileptogenesis.
Abstract: The development of long-lasting excitability changes after a single intracerebral injection of bicuculline (1 mM) in a restricted region of the anterior piriform cortex was studied by means of simultaneous intra- and extracellular recordings in the isolated guinea-pig brain preparation maintained in vitro by arterial perfusion. The transitory disinhibition induced by bicuculline revealed transient afterdischarges that were followed by the activation of a synaptic potential mediated by the recurrent propagation of the focal epileptiform activity along cortico-cortical associative fibres. The epileptiform associative potential persisted for the duration of the experiment. Both the induction and the long-term expression of the epileptiform associative potential were dependent on the activation of glutamatergic receptors of the NMDA type, as demonstrated by perfusion with the NMDA receptor antagonist 2-aminopentanoic acid (AP5) (100 microM). After bicuculline washout, piriform cortex neurons responded to afferent stimulation with a burst discharge superimposed on a paroxysmal depolarizing potential. The early component of the burst was mediated by a Ca(2+)-dependent, non-synaptic potential located at the proximal apical dendrites and soma of layer II-III cells, since (i) it was abolished by membrane hyperpolarization, (ii) it was not affected by AP5, (iii) it was correlated with a current sink in layer II, as demonstrated by current source density analysis of field potential laminar profiles, and (iv) it was abolished by cadmium (2-5 mM) applied locally in layer II. The late component of the burst response (i) coincided in time with the extracellular epileptiform associative potential, (ii) increased linearly in amplitude during membrane hyperpolarization, (iii) was blocked by AP5, and (iv) was correlated with an extracellular sink in layer Ib, where the associative fibres contact the distal apical dendrites of piriform cortex neurons. The results presented here indicate that a transient focal disinhibition promotes persistent intrinsic and synaptic excitability changes in piriform cortex neurons. These changes may be responsible for the propagation of epileptiform activity and for the induction of secondary epileptogenesis.
TL;DR: Molecular genetic study of these disorders is likely to lead to discovery of other epilepsy genes, which will lead to an improved understanding of human epileptogenesis, with implications for clinical diagnosis, genetic counselling, pharmacological therapy and possibly prevention of epilepsy.
Abstract: Single gene disorders offer the best opportunity for identification of genetic linkage and of abnormal genes. Epilepsies with single gene inheritance include symptomatic epilepsies where there is associated diffuse brain dysfunction, and idiopathic epilepsies where seizures are the major neurological abnormality. There are over 200 single gene symptomatic epilepsies; most are rare. Gene identification has been achieved in a number of these conditions but these important advances have not yet led to a better understanding of epileptogenesis, because of the associated brain disease. Idiopathic single gene epilepsies include benign familial neonatal convulsions, where genetic linkage to chromosomes 20q and 8q has been found in different families, and benign familial infantile convulsions where linkage is presently unknown. Recently, four autosomal dominant partial epilepsies have been described. In autosomal dominant nocturnal frontal lobe epilepsy a genetic defect in the a4 subunit of the nicotinic acetylcholine receptor was found in one family. This is the first genetic defect described in an idiopathic epilepsy. The other three syndromes are autosomal dominant partial epilepsy with variable foci, autosomal dominant rolandic epilepsy with speech dyspraxia, and familial temporal lobe epilepsy. In the latter condition, linkage to chromosome 10q has been reported in one family, but the genetic defect is unknown. It is likely that other idiopathic single gene epilepsies will be identified. Molecular genetic study of these disorders is likely to lead to discovery of other epilepsy genes. This will lead to an improved understanding of human epileptogenesis with implications for clinical diagnosis, genetic counselling, pharmacological therapy and possibly prevention of epilepsy.
TL;DR: The relationship between the site of ictal onset with the presence of segmental atrophy in patients with non-lesional MTLE using magnetic resonance imaging (MRI) and depth EEG and the location of the depth electrode contacts was correlated with anatomical landmarks.
TL;DR: The results suggest that TT-induced seizure activity initially spread to a variable extent but was gradually restricted 2–3 d after seizure onset, and lateral inhibition between neighboring cortical regions will be affected and contribute to a neurochemical segregation of an epileptic focus from surrounding cortex.
Abstract: To study potential molecular mechanisms of epileptogenesis in the neocortex, the motor cortex of rats was injected with tetanus toxin (TT), and gene expression for 67 kDa glutamic acid decarboxylase (GAD-67), type II calcium/calmodulin-dependent protein kinase (CaMKII), NMDA receptor subunit 1 (NR1), and AMPA receptor subunit 2 (GluR2) was investigated by in situ hybridization histochemistry. Injections of 20-35 ng TT induced recurrent seizures after a postoperative period ranging from 4 to 13 d. A majority of rats perfused 5-7 d after TT injection showed altered gene expression, but the changes varied in their areal extent, ranging from most neocortical areas on the injected side in some rats to mainly the frontoparietal cortex or the motor cortex in others. Epileptic rats perfused 14 d after TT injection showed a focus of increased GAD-67 and NR1, and of decreased alpha-CaMKII and GluR2 mRNA levels at the injection site. A zone of cortex surrounding the focus showed changes in alpha-CaMKII, GAD-67, and NR1 mRNA levels that were reciprocal to those in the focus. The results suggest that TT-induced seizure activity initially spread to a variable extent but was gradually restricted 2-3 d after seizure onset. The focus and the surround showing reciprocal changes in gene expression are thought to correspond to the electrophysiologically identified epileptic focus and inhibitory surround, respectively. The findings suggest that lateral inhibition between neighboring cortical regions will be affected and contribute to a neurochemical segregation of an epileptic focus from surrounding cortex.
TL;DR: A novel model of epileptogenesis based on the convulsive actions of flurothyl in mice is developed and characterized, with a reliable change in the type of seizure expressed in response to flurohyl from generalized clonic to generalized tonic seizures.
Abstract: Summary: Purpose: We have developed and characterized a novel model of epileptogenesis based on the convulsive actions of flurothyl in mice. The hallmark feature of this model is a reliable change in the type of seizure expressed in response to flurothyl from generalized clonic to generalized tonic seizures. The purpose of our study was to evaluate the effects of chronic administration of valproate (VPA), phenytoin (PHT), and MK-801 on the change in seizure phenotype observed in our model system.
Methods: Male C57BL/6J mice received flurothyl seizures on 8 consecutive days. Two hours after the last generalized seizure, chronic drug or vehicle was administered twice daily at 12-h intervals for 28 days. The drugs evaluated were VPA (250 mg/kg), PHT (30 mg/kg), and MK-801 (0.5 mg/kg). After a 7-day drug washout period, mice were retested with flurothyl.
Results: Among uninjected or vehicle-injected control mice, there was a significant increase in the proportion of animals expressing tonic seizures after the 28-day stimulation-free interval. Chronic administration of VPA or MK-801, but not PHT, blocked the characteristic change in seizure type from clonic to tonic.
Conclusions: The change in seizure phenotype observed after exposure to our paradigm indicates a fundamental reorganization in the propagation of flurothyl-initiated seizures. As in electrical kindling, VPA and MK-801 are effective at blocking or retarding the reorganization, whereas PHT is not. The concordance in pharmacologic profiles between kindling and our model suggests that the processes underlying changes in seizure susceptibility in these two models share mechanisms in common.