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Biomedical subjects

F E Dudek

Publications and source records attributed to F E Dudek.

At least 37 records · Page 2Linked to original sources
PubMed1999

Spontaneous motor seizures of rats with kainate-induced epilepsy: effect of time of day and activity state.

Kainate treatment in rats can result in a chronic behavioral state that is similar to human temporal lobe epilepsy. We tested the hypothesis that, like some humans with epilepsy, rat with kainate-induced epilepsy have more spontaneous motor seizures during inactivity (i.e. little to no volitional movement, including apparent sleep) than during activity (i.e. apparent volitional movement, as in walking, grooming, eating, etc.). Rats were given intraperitoneal (i.p.) injections of kainate (5 mg/kg) every hour so that class III/IV/V seizures were elicited for > or = 3 h. Seizure behavior was video-monitored (24 h for 5-6 days, n = 32 rats at 3 months and n = 23 rats at 4 months after treatment) to examine the occurrence of seizures as a function of light versus dark (12-12-h light-dark cycle) and inactivity versus activity. Significantly more spontaneous motor seizures occurred during inactive versus active states (82% vs. 18%, P = 0.0001). Although more seizures occurred during the light period than the dark, the difference was not significant (62% vs. 38%, P > 0. 1). These data suggest that the frequency of spontaneous motor seizures in the rat with kainate-induced epilepsy depends primarily on activity state rather than time of day (i.e. time during the light-dark cycle). The effect of inactivity on the occurrence of seizures in the rat with kainate-induced epilepsy appears similar to some forms of human epilepsy.

Animals↗
PubMed1999

Abnormal responses to perforant path stimulation in the dentate gyrus of slices from rats with kainate-induced epilepsy and mossy fiber reorganization.

Previous electrophysiological studies have demonstrated that in a subset of hippocampal slices from tissue resected from patients with mesial temporal lobe epilepsy, perforant path stimulation can elicit prolonged negative field-potential shifts in the dentate granule cell layer (Masukawa et al., 1989. Brain Res. 493, 168-174; Isokawa and Fried, 1996. Neuroscience 72, 31-37). In this investigation, hippocampal slices were prepared from rats: (1) 2-4 days following kainate treatment, when little or no reorganization of the mossy fibers would be present and (2) 3-13 months after kainate treatment, when mossy fiber reorganization would have occurred. In saline-treated controls, perforant path stimulation typically evoked a single population spike. In contrast, perforant path stimulation could evoke 3-12 population spikes in nearly all slices from kainate-injected rats 2-4 days and 3-13 months after treatment. The majority of slices from kainate-injected rats 3-13 months after treatment had qualitatively similar responses to perforant path stimulation as that observed in slices from kainate-injected rats 2-4 days after treatment. However, in 17% of the slices from kainate-treated rats 3-13 months after treatment (29% of rats), the multiple population spikes were followed by a prolonged negative field-potential shift (duration: 140 ms-1.5 s) with variable superimposed population spike activity. This type of epileptiform activity was only observed in slices with robust Timm's staining in the inner molecular layer and similar responses could also be evoked in these slices with hilar stimulation. Furthermore, pharmacological depression of inhibition by adding the GABA(A) receptor antagonist bicuculline unmasked hilar-evoked prolonged negative field-potential shifts in most slices from kainate-treated rats 3-13 months following treatment, and these slices had robust Timm's staining in the inner molecular layer. Such events were not observed in slices from saline-treated controls or kainate-injected rats 2-4 days after treatment. In conclusion, the prolonged negative field-potential shifts evoked to perforant path stimulation in normal ACSF were associated with mossy fiber reorganization, but the relative contribution of altered inhibition, increased synaptic excitation, or even non-synaptic mechanisms is unknown.

Action Potentials↗
PubMed1999

Zinc and flunitrazepam modulation of GABA-mediated currents in rat suprachiasmatic neurons.

The suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for generating circadian rhythms in mammals, and GABA is the predominant neurotransmitter in the SCN. Properties of gamma-aminobutyric acid-A (GABAA) responses in SCN neurons were examined in acutely prepared hypothalamic slices from 3- to 8-wk-old rats with the use of whole cell voltage-clamp techniques. Zn2+ reduced the amplitude of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration-dependent manner ranging from a reduction of control amplitude to 88% at 10 microM to 27% at 1,000 microM. Zn2+ reduced IPSC amplitude to a similar degree in the presence of tetrodotoxin and also significantly reduced the amplitude of currents evoked by application of exogenous GABA (100 microM, pressure applied). Zn2+ increased the frequency of IPSCs at lower concentrations and decreased it at higher ones. Flunitrazepam (100 nM) usually failed to potentiate the amplitude of sIPSCs, but prolonged sIPSC kinetics. Two exponential components were normally resolved in the sIPSC decay constants, and flunitrazepam significantly increased those two components. Thus flunitrazepam increased the duration of sIPSCs and potentiated the amplitude of currents evoked by pressure application of GABA. Zn2+ and benzodiazepine each modulated the effect of GABA in nearly all cells, suggesting that most SCN neurons have a similar GABAA receptor subunit composition in this respect. Zn2+ also affected sIPSC frequency, which suggests that Zn2+ increased neuronal firing rate at lower concentrations. These results begin to define the cellular roles that these GABAA receptor modulators might play in circadian regulation.

Animals↗
PubMed1999

In vivo intracellular analysis of granule cell axon reorganization in epileptic rats.

In vivo intracellular recording and labeling in kainate-induced epileptic rats was used to address questions about granule cell axon reorganization in temporal lobe epilepsy. Individually labeled granule cells were reconstructed three dimensionally and in their entirety. Compared with controls, granule cells in epileptic rats had longer average axon length per cell; the difference was significant in all strata of the dentate gyrus including the hilus. In epileptic rats, at least one-third of the granule cells extended an aberrant axon collateral into the molecular layer. Axon projections into the molecular layer had an average summed length of 1 mm per cell and spanned 600 microm of the septotemporal axis of the hippocampus-a distance within the normal span of granule cell axon collaterals. These findings in vivo confirm results from previous in vitro studies. Surprisingly, 12% of the granule cells in epileptic rats, and none in controls, extended a basal dendrite into the hilus, providing another route for recurrent excitation. Consistent with recurrent excitation, many granule cells (56%) in epileptic rats displayed a long-latency depolarization superimposed on a normal inhibitory postsynaptic potential. These findings demonstrate changes, occurring at the single-cell level after an epileptogenic hippocampal injury, that could result in novel, local, recurrent circuits.

Action Potentials↗
PubMed1999

Synaptic responses of neurons in heterotopic gray matter in an animal model of cortical dysgenesis.

Neuronal heterotopia is a malformation of cortical development that is closely associated with epilepsy in humans. Despite emerging interest in the structure and function of the heterotopic cortex, little is known about the membrane properties and synaptic connections of these displaced neurons. We used whole-cell patch-clamp and extracellular field potential recordings from heterotopic neurons in slices from young adult rats with experimentally induced cortical dysgenesis to determine if local synaptic connections were present in nodular heterotopia. Complex synaptic responses were observed after electrical stimulation of adjacent white matter. The results suggest that neurons in nodular heterotopic gray matter can form local excitatory and inhibitory synaptic connections and may participate in epileptiform events.

Animals↗
PubMed1999

Electrophysiological responses in vivo of hippocampal CA1 pyramidal neurons in an animal model of neuronal migration disorders.

Cortical dysgenesis arising from neuronal migration disorders is closely associated with intractable epilepsy in humans. We used extracellular field potential and conventional intracellular recordings from the dorsal hippocampus of intact adult rats to determine if the excitability of CA1 pyramidal cells was enhanced in rats with experimentally induced hippocampal dysplasia. Electrical stimulation of afferent fibers resulted in more robust population responses in the CA1 region of irradiated rats versus controls. Synaptic inhibition of pyramidal cells was also reduced in these animals. These results suggest that the excitability of the CA1 region in rats with hippocampal dysplasia is greater than in control animals.

Animals↗
PubMed1999

A reexamination of the role of GABA in the mammalian suprachiasmatic nucleus.

Three independent electrophysiological approaches in hypothalamic slices were used to test the hypothesis that gamma-amino butyric acid (GABA)A receptor activation excites suprachiasmatic nucleus (SCN) neurons during the subjective day, consistent with a recent report. First, multiple-unit recordings during either the subjective day or night showed that GABA or muscimol inhibited firing activity of the SCN population in a dose-dependent manner. Second, cell-attached recordings during the subjective day demonstrated an inhibitory effect of bath- or microapplied GABA on action currents of single SCN neurons. Third, gramicidin perforated-patch recordings showed that bicuculline increased the spontaneous firing rate during the subjective day. Therefore, electrophysiological data obtained by three different experimental methods provide evidence that GABA is inhibitory rather than excitatory during the subjective day.

Action Potentials↗
PubMed1998

Vagally evoked synaptic currents in the immature rat nucleus tractus solitarii in an intact in vitro preparation.

1. Whole-cell voltage-clamp recordings in an in vitro brainstem-cranial nerve explant preparation were used to assess the local circuitry activated by vagal input to nucleus tractus solitarii (NTS) neurones in immature rats. 2. All neurones that responded to vagal stimulation displayed EPSCs of relatively constant latency. Approximately 50 % of these also demonstrated variable-latency IPSCs, and approximately 31 % also displayed variable-latency EPSCs to vagal stimulation. All neurones also had spontaneous EPSCs and IPSCs. 3. Evoked and spontaneous EPSCs reversed near 0 mV and were blocked by the glutamate AMPA/kainate receptor antagonists 6,7-nitroquinoxaline-2,3-dione (DNQX) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) at rest. Evoked EPSCs had rapid rise times (< 1 s) and decayed monoexponentially (tau = 2. 04 +/- 0.03 ms) at potentials near rest. 4. At holding potentials positive to approximately -50 mV, a slow EPSC could be evoked in the presence of DNQX or CNQX. This current peaked at holding potentials near -25 mV and was blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5). It was therefore probably due to activation of NMDA receptors by vagal afferent fibres. 5. Fast IPSCs reversed near -70 mV and were blocked by the GABAA receptor antagonist bicuculline. In addition, bicuculline enhanced excitatory responses to vagal stimulation and increased spontaneous EPSC frequency. Antagonists to AMPA/kainate receptors reversibly blocked stimulus-associated IPSCs and also decreased the frequency of spontaneous IPSCs. 6. These findings suggest that glutamate mediates synaptic transmission from the vagus nerve to neurones in the immature NTS by acting at non-NMDA and NMDA receptors. NTS neurones may also receive glutamatergic and GABAergic synaptic input from local neurones that can be activated by vagal input and/or regulated by amino acid inputs from other brainstem neurones.1. Whole-cell voltage-clamp recordings in an in vitro brainstem-cranial nerve explant preparation were used to assess the local circuitry activated by vagal input to nucleus tractus solitarii (NTS) neurones in immature rats.

2-Amino-5-phosphonovalerate↗
PubMed1998

Axonal sprouting in hippocampus of cats infected with feline immunodeficiency virus (FIV).

Neurologic dysfunction and neuropathology are common findings in patients infected with HIV and in cats infected with feline immunodeficiency virus (FIV). The pathogenesis of lentivirus-associated alterations in the central nervous system (CNS) is multifactorial. Because seizures, alterations in memory, and behavioral changes are clinical manifestations in adults and children infected with HIV, we explored the possibility that changes in neuronal structure may occur in the hippocampus. To do this, we examined the dentate gyrus of FIV-infected cats, an animal model of HIV infection. Neuropathologic findings included gliosis within the hilus of the dentate gyrus and granule cell axonal sprouting. Using the Timm's method, which labels axons of dentate gyrus granule cells, abnormally high amounts of staining were observed in the inner one third of the molecular layer in 45% of FIV-infected cats (n = 11) and in none of the controls (n = 19). Prominent axonal sprouting was seen in three FIV-infected cats that were infected as kittens, suggesting that younger cats may be more susceptible. Axon reorganization of the dentate granule cells has been hypothesized to underlie complex partial seizure activity in human temporal lobe epilepsy. These results suggest that FIV infection causes granule cell axon reorganization in the hippocampus of cats. A similar neuropathogenetic mechanism may contribute to neurologic dysfunction in HIV-infected patients.

Age Factors↗
PubMed1998

Ultrastructure, histological distribution, and freeze-fracture immunocytochemistry of gap junctions in rat brain and spinal cord.

The historical development of concepts of gap junctions as sites for electrical, ionic, and metabolic coupling is reviewed, from the initial discovery of gap junctions linking heart cells, to the current concepts that gap junctions represent 'electrotonic synapses' between neurons. The ultrastructure and immunocytochemistry of gap junctions in heart, brain, and spinal cord of adult rats is examined using conventional thin sections, negative staining, grid-mapped freeze-fracture replicas, and immunogold-labeled freeze-fracture replicas. We review evidence for neuronal gap junctions at 'mixed' (combined electrical and chemical) synapses throughout adult rat spinal cord. We also show immunogold labeling of connexin43 in astrocyte and ependymocyte gap junctions and of connexin32 in oligodendrocyte gap junctions. Ultrastructural and freeze-fracture immunocytochemical methods have provided for definitive determination of the number, size, histological distribution, and connexin composition of gap junctions between neurons in all regions of the central nervous systems of vertebrate species.

Animals↗
PubMed1998

'Non-synaptic' mechanisms in seizures and epileptogenesis.

The role of 'non-synaptic' mechanisms (i.e. those mechanisms that are independent of active chemical synpases) in the synchronization of neuronal activity during seizures and their possible contribution to chronic epileptogenesis are summarized. These 'non-synaptic' mechanisms include electrotonic coupling through gap junctions, electrical field effects (i.e. ephaptic transmission), and ionic interactions (e.g. increases in the extracellular concentration of K(+)). Several lines of evidence indicate that granule cells and pyramidal cells of the hippocampus, and probably other cortical neurons, can generate synchronized electrical activity after active chemical synaptic transmission has been blocked. This synchronized activity is sensitive to alterations in the size of the extracellular space, thus suggesting that electrical field effects and ionic mechanisms contribute to this synchronized activity. Recent studies also indicate that 'non-synaptic' synchronization is quite prominent early in development. Electrophysiological data from hippocampal and neocortical slices have led to a re-interpretation of the fast prepotentials (i.e. partial spikes) recorded in cortical pyramidal cells, suggesting that they may not be due to dendritic spike generation. Improvement in freeze-fracture ultrastructural techniques have led to a re-assessment of previous data on gap junctions in the nervous system and opened new approaches to the quantitative analysis and characterization of gap junctions on glia and neurons. Finally, new methods of dye/tracer coupling have the potential to provide a more rigorous basis for evaluating gap junctions and electrotonic communication between neurons in the mammalian central nervous system. Therefore, 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.

Animals↗
PubMed1998

Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy.

Human temporal lobe epilepsy is associated with complex partial seizures that can produce secondarily generalized seizures and motor convulsions. In some patients with temporal lobe epilepsy, the seizures and convulsions occur following a latent period after an initial injury and may progressively increase in frequency for much of the patient's life. Available animal models of temporal lobe epilepsy are produced by acute treatments that often have high mortality rates and/or are associated with a low proportion of animals developing spontaneous chronic motor seizures. In this study, rats were given multiple low-dose intraperitoneal (i.p.) injections of kainate in order to minimize the mortality rate usually associated with single high-dose injections. We tested the hypothesis that these kainate-treated rats consistently develop a chronic epileptic state (i.e. long-term occurrence of spontaneous, generalized seizures and motor convulsions) following a latent period after the initial treatment. Kainate (5 mg/kg per h, i.p.) was administered to rats every hour for several hours so that class III-V seizures were elicited for > or = 3 h, while control rats were treated similarly with saline. This treatment protocol had a relatively low mortality rate (15%). After acute treatment, rats were observed for the occurrence of motor seizures for 6-8 h/week. Nearly all of the kainate-treated rats (97%) had two or more spontaneous motor seizures months after treatment. With this observation protocol, the average latency for the first spontaneous motor seizure was 77+/-38 (+/-S.D.) days after treatment. Although variability was observed between rats, seizure frequency initially increased with time after treatment, and nearly all of the kainate-treated rats (91%) had spontaneous motor seizures until the time of euthanasia (i.e. 5-22 months after treatment). Therefore, multiple low-dose injections of kainate, which cause recurrent motor seizures for > or = 3 h, lead to the development of a chronic epileptic state that is characterized by (i) a latent period before the onset of chronic motor seizures, and (ii) a high but variable seizure frequency that initially increases with time after the first chronic seizure. This modification of the kainate-treatment protocol is efficient and relatively simple, and the properties of the chronic epileptic state appear similar to severe human temporal lobe epilepsy. Furthermore, 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.

Animals↗
PubMed1998

Physiological unmasking of new glutamatergic pathways in the dentate gyrus of hippocampal slices from kainate-induced epileptic rats.

In humans with temporal lobe epilepsy and kainate-treated rats, the mossy fibers of the dentate granule cells send collateral axons into the inner molecular layer. Prior investigations on kainate-treated rats demonstrated that abnormal hilar-evoked events can occasionally be observed in slices with mossy fiber sprouting when gamma-aminobutyric acid-A (GABAA)-mediated inhibition is blocked with bicuculline. However, these abnormalities were observed infrequently, and it was unknown whether these rats were epileptic. Wuarin and Dudek reported that in slices from kainate-induced epileptic rats (3-13 mo after treatment), hilar stimulation evoked abnormal events in most slices with mossy fiber sprouting exposed simultaneously to bicuculline and elevated extracellular potassium concentration [K+]o. Using the same rats, extracellular recordings were obtained from granule cells in hippocampal slices to determine whether 1) hilar stimulation could evoke abnormal events in slices with sprouting in normal artificial cerebrospinal fluid (ACSF), 2) adding only bicuculline could unmask hilar-evoked abnormalities and glutamate-receptor antagonists could block these events, and 3) increasing only [K+]o could unmask these abnormalities. In normal ACSF, hilar stimulation evoked abnormal field potentials in 27% of slices with sprouting versus controls without sprouting (i.e., saline-treated or only 2-4 days after kainate treatment). In bicuculline (10 microM) alone, hilar stimulation triggered prolonged field potentials in 84% of slices with sprouting, but not in slices from the two control groups. Addition of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5), either blocked the bursts or reduced their probability of occurrence. The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), always eliminated the epileptiform bursts. In kainate-treated rats with sprouting, but not in saline-treated controls, abnormal hilar-evoked responses were also revealed in 6-9 mM [K+]o. Additionally, 63% of slices with sprouting generated spontaneous bursts lasting 1-40 s in ACSF containing 9 mm [K+]o; similar bursts were not observed in controls. These results indicate that 1) mossy fiber sprouting is associated with new glutamatergic pathways, and although NMDA receptors are important for propagation through these circuits, AMPA receptor activation is crucial, 2) modest elevations of [K+]o, in a range that would have relatively little effect on granule cells, can unmask these new excitatory circuits and generate epileptiform bursts, and 3) this new circuitry underlies an increased electrographic seizure susceptibility when inhibition is depressed or membrane excitability is increased.

2-Amino-5-phosphonovalerate↗
PubMed1997

Grid-mapped freeze-fracture analysis of gap junctions in gray and white matter of adult rat central nervous system, with evidence for a "panglial syncytium" that is not coupled to neurons.

In white matter regions of the brain and spinal cord of adult mammals, gap junctions previously were observed linking astrocytes to astrocytes, as well as to oligodendrocytes and ependymacytes. The resulting "functional syncytium" was proposed to modulate the ion fluxes that occur during electrical activity of the associated axons. Gap junctions also have been reported linking neurons with glia, and functional neuronal-glial coupling has been postulated. To investigate the glial syncytium and the neuron-to-glial coupling hypotheses, we used "grid-mapped freeze fracture," conventional thin-section electron microscopy, and light microscope immunocytochemistry to examine and characterize neurons and glia in gray and white matter of adult rat brain and spinal cord. We have obtained quantitative evidence for the abundance and widespread distribution of gap junctions interlinking the three primary types of macroglia throughout both gray and white matter of the mammalian central nervous system (CNS), thereby extending the concept to that of a functional panglial syncytium. In contrast to previous reports, we show that of more than 400 gap junctions in which both participating cells were identified, none were between neurons and glia. Thus, neuronal coupling and glial coupling involved separate and distinct pathways. Finally, putative water channels (i.e., "square arrays") were confirmed to be abundant and in close association with gap junctions in astrocytes and ependymacytes. Because the astrocyte "intermediaries" extend cytoplasmic conduits throughout gray and white matter of brain and spinal cord, from the ependymal layer to the pia-glial limitans, and from oligodendrocytes surrounding axons to astrocyte endfeet surrounding capillaries, the proposed panglial syncytium, with its abundance of water channels and intercellular ion channels, is optimally positioned and equipped to modulate water and ion fluxes across broad regions of the CNS.

Animals↗
PubMed1997

Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats.

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.

Action Potentials↗
PubMed1997

Enhanced population responses in the basolateral amygdala of kainate-treated, epileptic rats in vitro.

Several lines of evidence suggest that the amygdala is altered functionally in humans with temporal lobe epilepsy, but little is known about neuronal interactions in the amygdala of humans or animals with chronic epilepsy. Using extracellular and intracellular recordings in horizontal slices, we tested the hypothesis that changes in local circuitry in the basolateral amygdala (BLA) permanently enhance neuronal responsiveness in kainate-treated, epileptic rats. Population responses in the BLA to orthodromic stimulation were significantly enhanced, which was at least partly due to a decrease in local inhibition. In the presence of GABA receptor antagonists, population responses were about twice as robust in epileptic versus control rats. We conclude that the enhanced neuronal responsiveness of the BLA in this model of temporal lobe epilepsy involves decreased inhibition, but may also include increased excitation.

Amygdala↗
PubMed1997

Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis: proposed role of synaptic reorganization.

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.

Animals↗