NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

Cover of Jasper's Basic Mechanisms of the Epilepsies

Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

Show details

The Time Course and Circuit Mechanisms of Acquired Epileptogenesis

and .

Author Information

Identification of the critical molecular and cellular mechanisms that lead to acquired epilepsy depends on an understanding of the time course of the development of spontaneous recurrent seizures after a brain injury. Here, the temporal characteristics of acquired epilepsy were studied using nearly-continuous video-electrographic (EEG) recordings in (1) kainate-treated rats, a model of temporal lobe epilepsy, and (2) rats subjected to unilateral carotid occlusion with superimposed hypoxia at postnatal day 7, a model of perinatal stroke. The data do not support the hypothesis that epileptogenesis is a step function of time after injury; rather, epileptogenesis appears to be a continuous process that starts at the time of the brain injury and extends well past the first spontaneous clinical seizure. Histopathological and electrophysiological data strongly support two hypothetical mechanisms that are probably important for acquired epileptogenesis: (1) the selective loss of specific, vulnerable, GABAergic interneurons, and (2) axon sprouting and the progressive formation of new recurrent excitatory circuits. These circuit mechanisms may contribute to the latent period and the progressive increase in the frequency and severity of spontaneous recurrent seizures characteristic of acquired epilepsy, which may be an important consideration in the development of strategies to suppress epileptogenesis after brain injury.

In order to develop and test possible therapeutic strategies for preventing or suppressing epileptogenesis, the temporal features of acquired epilepsy and its underlying mechanisms must be understood. These temporal features include the frequency, duration, and cortical extent of spontaneous seizures; this review focuses primarily on seizure frequency. Traumatic brain injury, stroke, status epilepticus, and infection/inflammation are some of the major causes of acquired epilepsy. The spontaneous recurrent epileptic seizures of acquired epilepsy usually occur after a latent period following the injury, and in at least some patients, the epilepsy is progressive (i.e., the seizures become more frequent and severe). Nearly all patients receive antiepileptic drugs (AEDs) after one or a few clinical seizures. Therefore, quantitative analyses of the temporal features of acquired epileptogenesis, independent of the effects of AEDs, cannot be studied in humans. Animal models of acquired epilepsy can circumvent this problem. The research summarized here analyzed the development of spontaneous recurrent seizures (1) in kainate-treated rats,1 an animal model of temporal lobe epilepsy, and (2) in rats subjected to hypoxic-ischemic brain damage at postnatal day 7, a model of perinatal stroke.2–4

Many mechanisms have been hypothesized to account for epileptogenesis after brain injury. Numerous studies have focused on molecular and cellular changes during the latent period (the time from brain injury to the first clinical seizure), which has been thought to mark the duration of epileptogenesis; however, whether the first clinical seizure actually signals the completion of epileptogenesis, or whether epileptogenesis continues well beyond the first seizure is unknown. The frequency and pattern of spontaneous recurrent seizures as a function of time after the brain injury defines the time course of epileptogenesis, and this information is fundamental to an understanding of the mechanisms of acquired epilepsy. This time course, which is essentially the natural history of acquired epilepsy, places constraints on the hypothetical mechanisms that contribute to epileptogenesis after brain injury. The present chapter uses information on the time course of acquired epileptogenesis to evaluate hypotheses regarding the underlying mechanisms of epilepsy. Our focus is primarily at the level of neuronal circuits and synaptic reorganization: selective loss of specific, vulnerable, GABAergic interneurons and the progressive formation of new recurrent excitatory circuits after axonal sprouting. We propose that these two mechanisms may account for – or at least contribute to - the time course of injury-induced epileptogenesis.

TWO MODELS OF ACQUIRED EPILEPSY

Most research using animal models of temporal lobe epilepsy that have spontaneous recurrent seizures are based on status epilepticus; some of the studies described in this chapter used an animal model where status epilepticus was induced with repeated low-dose injections of kainate.5–8 In the second animal model of acquired epilepsy, hypoxic-ischemic brain injury was induced in immature rats2,3,9 as an animal model of perinatal stroke, which is an important cause of intractable epilepsy in children.10,11 Use of this model allowed determination of the time course of the development of spontaneous recurrent seizures after perinatal brain injury.4 These two animal models are quite different, but both of them show clear brain damage with neuronal death, and they both unequivocally develop epilepsy, which is manifest as readily documentable electrographic and behavioral seizures. Finally, a reduced in vitro preparation, the organotypic slice preparation, has been used to model post-traumatic epileptogenesis.12,13 Advantages of this model are the compressed two-week time scale over which epileptogenesis occurs, and the isolation from other brain centers and systems, such as the blood brain barrier and immune system, which might influence epileptogenesis.

THE TIME COURSE OF ACQUIRED EPILEPTOGENESIS

The Progressive Nature of Acquired Epilepsy

The question of whether acquired epilepsy is progressive is important and longstanding. One view, as introduced above, is that acquired epilepsy (e.g., temporal lobe epilepsy) starts after a latent period, and subsequent seizure frequency and severity are variable but not necessarily progressive over time (i.e., the step-function hypothesis, Figure 1A1). Another perspective is that acquired epilepsy is progressive; however, technical difficulties in measuring seizure frequency and severity (e.g., long-term, continuous recordings to account for seizure clusters) make it difficult to assess whether acquired epilepsy is progressive (i.e., the continuous-function hypothesis, Figure 1A2). This issue is virtually impossible to evaluate directly in humans, because patient-reporting of seizures is inaccurate and human patients are routinely treated with AEDs.14 Human temporal lobe epilepsy often seems to be progressive, based on clinical15–18 and MRI data.19–21 Evidence of ongoing neuronal death in tissue resected for intractable epilepsy also supports this hypothesis.22,23 In animal models, prolonged and virtually continuous EEG recordings are required to determine whether the frequency and severity of spontaneous recurrent seizures increases in every animal. Bertram and Cornett,24,25 who obtained extensive chronic recordings from rats with electrically-evoked status epilepticus, found that subsequent spontaneous recurrent seizures occurred with variable frequency; however, seizure frequency generally increased over time and appeared to plateau after several months. When averaged across many kainate-treated rats, Hellier and collaborators6 found that behavioral seizure frequency clearly increased as a function of time for nearly a year. After electrically induced status epilepticus (i.e., stimulation of the amygdala), video-EEG recordings every other day showed increased seizure frequency when assessed in 2-week epochs for 6 months.26 With a similar model, but involving electrical stimulation of the angular bundle, Gorter and colleagues27 observed a progressive increase in seizure frequency in most rats, although some rats appeared non-progressive. After kainate-induced status epilepticus,1 nearly continuous radiotelemetric recordings showed a progressive increase in seizure frequency (Figure 1B1). The temporal pattern was highly variable across animals, but all animals (n=9) showed a progressive increase in seizure frequency over the duration of the study (i.e., about 100 days) and the group data could be fit with a sigmoid curve. Based on examination of the data from individual rats in the study of Williams and coworkers,1 the animals from the report by Gorter and coworkers27 that appeared non-progressive might have had a progressive increase in seizure frequency if more prolonged seizure monitoring had been undertaken; on the other hand, it is possible that some animals may not show a progressive worsening of the epilepsy after brain injury. In an animal model of perinatal stroke, however, every animal with a lesion developed progressive epilepsy where seizure frequency increased over time (Figure 1B1).3,4 Notably, without virtually continuous recording for many months, seizure clusters and a low overall seizure rate would have obscured the consistent increase in seizure frequency. Thus, rats with either epilepsy after kainate-induced status epilepticus during adulthood or after a hypoxic-ischemic insult at postnatal day 7 showed a progressive increase in seizure frequency when recorded continuously over study durations lasting at least a few months.

Figure 1. Time course of acquired epileptogenesis after brain injury.

Figure 1

Time course of acquired epileptogenesis after brain injury. (A) Schematic diagrams of the step-function and continuous-function hypotheses of the time course of acquired epileptogenesis. (A1) The step-function hypothesis proposes a seizure-free period (more...)

The Latent Period and the Duration of Epileptogenesis

The latent period, which is generally defined as the time from a brain insult to the first clinical seizure (Figure 1A), is clearly one of the most intriguing concepts in epilepsy research. In humans, it has been reported to range from a few weeks to many years.28 Bertram and Cornett24,25 reported that non-convulsive seizures always preceded the first convulsive seizure; the data in the report of Williams and coworkers1 support this conclusion. Although the first convulsive seizures were detected at roughly 2 weeks after kainate-induced status epilepticus, non-convulsive EEG seizures first occurred at about 7 days. Furthermore, several non-convulsive EEG seizures usually preceded the first convulsive seizure in this study.1 The studies from these two research groups (and others) raise the possibility that in humans thought to have had latent periods of many years, unrecognized subclinical seizures may have preceded the first convulsive seizures. When examined in more quantitative detail, the longest inter-seizure intervals for the first 20 seizures in the work of Williams and coworkers1 were only slightly less than the latent periods for the first electrographic non-convulsive seizures. This result, and other data, suggest that the latent period can be viewed as the first of many long inter-seizure intervals (i.e., inter-cluster intervals), and that epileptogenesis per se involves a smooth and continuous increase in seizure probability over time after the brain injury (Figure 1A2 and 1B). Measurements of the latent period are actually quite difficult; first, because the latent period is the time of an asymptotic departure from a baseline; and, second, because determination of the latent period requires continuous recording from the brain insult to the first convulsive seizure. Thus, although the latent period is a genuine phenomenon, it may be best viewed as the initial phase of a continuous process. The continuous nature of epileptogenesis is often obscured by variable seizure frequency and the occurrence of seizure clusters. Therefore, quantitative assessments of acquired epileptogenesis may be accomplished more accurately by long-term measures of seizure frequency than by measurement of the latent period.

CIRCUIT MECHANISMS AND SYNAPTIC REORGANIZATION

Synaptic Reorganization

Acquired epilepsy may involve a wide range of mechanisms, including alterations in neurotransmitter receptors (e.g., GABAA receptors) and/or voltage-dependent currents (e.g., sodium channels). Although other systems may contribute to the time course of epileptogenesis, the progressive nature of this process in reduced preparations12,13 supports the idea that local circuit alterations are sufficient to induce epilepsy. While local alterations in ligand- and voltage-gated channels may well be important, this chapter focuses on alterations in local synaptic circuits (i.e., synaptic reorganization). Two hypothetical mechanisms (also see review by Ben-Ari and Dudek29) that have been studied extensively are: 1) death of GABAergic interneurons and consequent decreases in GABA-mediated inhibition (Figure 2A); and 2) axon sprouting with subsequent increases in recurrent excitation (Figure 2B). The first mechanism involves a rapid loss of GABAergic interneurons after status epilepticus or other injuries, but interneurons may also continue to die during epileptogenesis. A mechanism that has gained considerable attention because it would be expected to require time to occur is axonal sprouting and subsequent formation of new excitatory (and inhibitory?) synaptic circuits; this time-dependence could thus account for or contribute to the initial latent period and subsequent progression of epilepsy.

Figure 2. Hypothetical changes in local synaptic circuits during epileptogenesis.

Figure 2

Hypothetical changes in local synaptic circuits during epileptogenesis. (A) Loss of specific interneurons and decreased GABAergic inhibition in the hippocampus during epileptogenesis. Schematic diagram showing hippocampal pyramidal cells and interneurons (more...)

Loss of GABAergic Interneurons

Experiments based on several independent morphological and physiological techniques in human tissue and animal models of acquired epilepsy support the hypothesis that a modest loss of specific GABAergic interneurons is associated with epileptogenesis (Figure 2A). Immunohistochemical and in situ hybridization techniques have shown that a relatively small number of specific types of GABAergic interneurons are lost in both hippocampal and cortical areas5,27,30–32. Several laboratories have used whole-cell recordings of miniature inhibitory postsynaptic currents (mIPSCs) to test more specifically the hypothesis of a loss of interneuron input to granule cells33,34 and CA1 pyramidal cells;35 these studies have generally found that the frequency of mIPSCs is reduced (Figures 3 and 4), which supports the hypothesis of a reduction of inhibitory GABAergic synaptic terminals (i.e., loss of GABAergic interneurons). Other interpretations of these data, such as reduced release probability, are possible but not congruent with the anatomical findings. Notably, these studies have not found reductions in the amplitude of mIPSCs (Figures 3 and 4), thus suggesting that alterations in GABAA receptors do not contribute substantially to decreases in GABAergic inhibition during epileptogenesis, at least under these conditions. This approach has its limitations, but it uses tetrodotoxin to block action potential-mediated activity and is independent of the problems of extracellular stimulation (e.g., activation of fibers-of-passage; changes in action potential threshold between control and experimental groups, etc.); thus, the number of confounding variables is reduced. Therefore, the evidence from experiments on several animal models from multiple laboratories suggests that epileptogenesis is associated with a modest but significant loss of specific types of vulnerable interneurons in the dentate gyrus and CA1 area of the hippocampus and in other areas, which in turn is manifest as a reduction of GABAergic inhibition. The reduction in GABAergic inhibition may be more robust early in the course of epileptogenesis, and at least partially resolve by the time of the first seizure.33 For example, sprouting of GABAergic interneurons may at least partially restore inhibition.36 Other mechanisms of disinhibition, such as reductions in the transport systems that maintain an inhibitory gradient for GABA-mediated chloride currents, may also contribute to epileptogenesis.37–39

Figure 3. Examples of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) recorded from granule cells of the dentate gyrus in rats >3 months after saline (A) or kainate treatment (B).

Figure 3

Examples of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) recorded from granule cells of the dentate gyrus in rats >3 months after saline (A) or kainate treatment (B). The upper traces are recordings of sIPSCs (more...)

Figure 4. Changes in the amplitude and frequency of sIPSCs and mIPSCs during acquired epileptogenesis in kainate-treated rats.

Figure 4

Changes in the amplitude and frequency of sIPSCs and mIPSCs during acquired epileptogenesis in kainate-treated rats. (A) Summary of the data on mean IPSC amplitudes in rats 4–7 days versus >3 months after kainate treatment. (A1) Although (more...)

Axon Sprouting and Increased Recurrent Excitation

The concept of synaptic reorganization was initially based on the observation of “mossy fiber sprouting” and the associated hypothesis of increased recurrent excitation during acquired epileptogenesis, which has led to many studies aimed at exploring its potential role in temporal lobe epilepsy. One reason for the interest is that several laboratories had reported Timm stain in the inner molecular layer of the dentate gyrus of patients with intractable temporal lobe epilepsy.40–43 This phenomenon is present in numerous animal models, including pilocarpine- and kainate-treated rats and the kindling model (see 44,45 for review). Several types of electrophysiological and ultrastructural data strongly suggest that nearly all of the new mossy fiber connections are excitatory (see 44,45 for review). For example, hilar or perforant path stimulation can evoke long-latency EPSPs with prolonged spike bursts several months after status epilepticus, particularly when slices from rats with chronic epilepsy are bathed in GABAA receptor antagonists and/or high potassium; in similar experiments on slices from control animals, comparable electrical stimulation only evokes an EPSP and/or a single action potential.46–51 The rationale for performing these experiments during blockade of GABAA mediated inhibition is not only because of previous work showing that GABA-mediated inhibition has a “masking” effect on recurrent excitation,52–55 but also because this procedure controls at least partially for epileptogenesis-associated differences in GABA-mediated inhibition (see above). Electrical stimulation, however, activates axons-of-passage. Experiments using glutamate microdrops48,51 or focal photoactivation of caged glutamate,56,57 which does not stimulate fibers-of-passage, have provided more direct evidence for the formation of new recurrent excitatory circuits. Dual intracellular recordings have further supported the hypothesis that mossy fiber sprouting in rats with pilocarpine-induced epilepsy is associated with an increase in monosynaptic recurrent excitatory connections among dentate granule cells.58 Quantitative ultrastructural studies also indicate that new excitatory synapses connect primarily to dentate granule cells versus interneurons.59,60 Newborn granule cells from seizure-induced neurogenesis in the dentate gyrus may play an important role in synaptic reorganization, at least in the dentate gyrus.61,62

Although mossy fiber sprouting and synaptic reorganization may be particularly important in the dentate gyrus, axon sprouting and the formation of new recurrent excitatory circuits is probably a widespread response to brain damage in many areas of the hippocampus and neocortex during epileptogenesis. Numerous studies have reported morphological and electrophysiological data that axonal sprouting (Figure 5A) and enhanced recurrent excitation (Figure 5B) occur in the CA1 area during epileptogenesis.63–68 The CA1 area of the hippocampus is highly vulnerable to excitotoxic neuronal death, and loss of neurons in CA1 is a classic marker of mesial temporal sclerosis. Synaptic reorganization in the CA1 area may reflect the type of morphological and functional changes that occur in many areas of the limbic system, possibly early in the epileptogenic process in humans. Many forms of acquired epilepsy in addition to temporal lobe epilepsy, including the epilepsy that occurs after perinatal and adult stroke2,4,69 and traumatic brain injury,70 are likely to be a network phenomenon, with at least two reorganizational mechanisms - - the loss of vulnerable interneurons along with axon sprouting of principal cells followed by formation of new recurrent excitatory circuits.

Figure 5. Axon sprouting and increased recurrent excitation of CA1 pyramidal cells in kainate-induced epilepsy.

Figure 5

Axon sprouting and increased recurrent excitation of CA1 pyramidal cells in kainate-induced epilepsy. (A) Examples of biocytin-filled axons from CA1 pyramidal cells during whole-cell recordings in isolated CA1 slices. (A1) Axon from a saline-treated control (more...)

POSSIBLE CONCLUSIONS

The spontaneous recurrent seizures after a brain injury, which define acquired epilepsy, typically worsen in terms of seizure frequency and severity. Although this result has not always been seen in previous work, quantitative analyses of long-term continuous recordings are often required to detect progression. Studies of this type in the kainate model1 and in a model of perinatal stroke4 have provided clear evidence of progressive epilepsy in virtually all of the animals that were studied. Axonal sprouting and formation of new recurrent excitatory circuits is well-known to be a progressive process, and this mechanism could be the basis for the progressive changes that occur in these and other models. Selective interneuron loss may also be progressive and an important part of the changes that lead to progressive epileptogenesis. Considerable research has targeted the dentate gyrus, but similar mechanisms have been identified in many temporal structures and even in neocortical areas after brain injury (e.g., status epilepticus and perinatal stroke). Acquired epileptogenesis therefore appears to be a slow, time-dependent process (Figure 1A2 and B), rather than a simple step-function (Figure 1A1) with a discrete latent period defining the boundaries of epileptogenesis;1,4 synaptic reorganization defined by interneuron loss and the formation of sprouting-induced recurrent excitation may be an important component of acquired epilepsy that contributes to its natural history and progressive characteristics.

Acknowledgements

Supported by the NINDS and the American Heart Association.

REFERENCES

1.
Williams PA, White AM, Clark S, Ferraro DJ, Swiercz W, Staley KJ, Dudek FE. Development of spontaneous recurrent seizures after kainate-induced status epilepticus. J Neurosci. 2009;29:2103–2112. [PMC free article: PMC2897752] [PubMed: 19228963]
2.
Williams PA, Dou P, Dudek FE. Epilepsy and synaptic reorganization in a perinatal rat model of hypoxia-ischemia. Epilepsia. 2004;45:1210–1218. [PubMed: 15461675]
3.
Kadam S, Dudek F. Neuropathological features of a rat model for perinatal hypoxic-ischemic encephalopathy with associated epilepsy. J Comp Neurol. 2007;505:716–737. [PMC free article: PMC4607042] [PubMed: 17948865]
4.
Kadam SD, White AM, Staley KJ, Dudek FE. Continuous electroencephalographic monitoring with radio-telemetry in a rat model of perinatal hypoxia-ischemia reveals progressive post-stroke epilepsy. J Neurosci. 2010;30:404–415. [PMC free article: PMC2903060] [PubMed: 20053921]
5.
Buckmaster PS, Dudek FE. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J Comp Neurol. 1997;385:385–404. [PubMed: 9300766]
6.
Hellier JL, Patrylo PR, Buckmaster PS, Dudek FE. Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy. Epilepsy Res. 1998;31:73–84. [PubMed: 9696302]
7.
Dudek FE, Hellier JL, Williams PA, Ferraro DJ, Staley KJ. The course of cellular alterations associated with the development of spontaneous seizures after status epilepticus. Prog Brain Res. 2002;135:53–65. [PubMed: 12143370]
8.
Dudek FE, Clark S, Williams PA, Grabenstatter HL. Kainate-induced status epilepticus: A chronic model of acquired epilepsy. In: Pitkanen A, Schwartzkroin PA, Moshe SL, editors. Models of Seizures and Epilepsy. Elsevier Academic Press; 2006. pp. 415–432.
9.
Rice JE III, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol. 1981;9:131–141. [PubMed: 7235629]
10.
Bergamasco B, Benna P, Ferrero P, Gavinelli R. Neonatal hypoxia and epileptic risk: a clinical prospective study. Epilepsia. 1984;25:131–136. [PubMed: 6538479]
11.
Marin-Padilla M. Neuropathologic correlates of perinatal asphyxia. Int Pediatrics. 2000;15:221–228.
12.
McBain CJ, Boden P, Hill RG. Rat hippocampal slices ‘in vitro’ display spontaneous epileptiform activity following long-term organotypic culture. J Neurosci Methods. 1989;27:35–49. [PubMed: 2563782]
13.
Dyhrfjeld-Johnsen J, Berdichevsky Y, Swiercz W, Sabolek H, Staley KJ. Interictal spikes precede ictal discharges in an organotypic hippocampal slice culture model of epileptogenesis. J Clin Neurophysiol. 2010;27:418–424. [PMC free article: PMC4167405] [PubMed: 21076333]
14.
Hoppe C, Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch Neurol. 2007;64:1595–1599. [PubMed: 17998441]
15.
Engel J Jr. Clinical evidence for the progressive nature of epilepsy. Epilepsy Res Suppl. 1996;12:9–20. [PubMed: 9302499]
16.
Engel J. Natural history of mesial temporal lobe epilepsy with hippocampal sclerosis: How does kindling compare with other commonly used animal models? In: Corcoran ME, Moshé SL, editors. Kindling. Vol. 6. Springer Science + Business Media, Inc.; New York: 2005. pp. 371–384.
17.
Engel J Jr. Surgical treatment for epilepsy: too little, too late. JAMA. 2008;300:2548–2550. [PubMed: 19050199]
18.
Engel J, Berg AT. From prediction of medical intractability to early surgical treatment. In: Ryvlin P, Beghi E, Camfield P, Hesdorffer D, editors. From First Unprovoked Seizure to Newly Diagosed Epilepsy: Progress in Epileptic Disorders. John Libbey Eurotext; London: 2007. pp. 209–220.
19.
Fuerst D, Shah J, Shah A, Watson C. Hippocampal sclerosis is a progressive disorder: a longitudinal volumetric MRI study. Ann Neurol. 2003;53:413–416. [PubMed: 12601713]
20.
Cascino GD. Temporal lobe epilepsy is a progressive neurologic disorder: Time means neurons! Neurology. 2009;72:1718–1719. [PubMed: 19321843]
21.
Bernhardt BC, Worsley KJ, Kim H, Evans AC, Bernasconi A, Bernasconi N. Longitudinal and cross-sectional analysis of atrophy in pharmacoresistant temporal lobe epilepsy. Neurology. 2009;72:1747–1754. [PMC free article: PMC2827310] [PubMed: 19246420]
22.
Henshall DC, Schindler CK, So NK, Lan JQ, Meller R, Simon RP. Death-associated protein kinase expression in human temporal lobe epilepsy. Ann Neurol. 2004;55:485–494. [PubMed: 15048887]
23.
Schindler CK, Pearson EG, Bonner HP, So NK, Simon RP, Prehn JH, Henshall DC. Caspase-3 cleavage and nuclear localization of caspase-activated DNase in human temporal lobe epilepsy. J Cereb Blood Flow Metab. 2006;26:583–589. [PubMed: 16121124]
24.
Bertram EH, Cornett JF. The ontogeny of seizures in a rat model of limbic epilepsy: evidence for a kindling process in the development of chronic spontaneous seizures. Brain Res. 1993;625:295–300. [PubMed: 8275310]
25.
Bertram EH, Cornett JF. The evolution of a rat model of chronic spontaneous limbic seizures. Brain Res. 1994;661:157–162. [PubMed: 7834366]
26.
Nissinen J, Halonen T, Koivisto E, Pitkanen A. A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res. 2000;38:177–205. [PubMed: 10642046]
27.
Gorter JA, van Vliet EA, Aronica E, Lopes da Silva FH. Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons. Eur J Neurosci. 2001;13:657–669. [PubMed: 11207801]
28.
Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med. 1998;338:20–24. [PubMed: 9414327]
29.
Ben-Ari Y, Dudek FE. Primary and secondary mechanisms of epileptogenesis in the temporal lobe: there is a before and an after. Epilepsy Curr. 2010;10:118–125. [PMC free article: PMC2951692] [PubMed: 20944823]
30.
Ribak CE, Bradurne RM, Harris AB. A preferential loss of GABAergic, symmetric synapses in epileptic foci: a quantitative ultrastructural analysis of monkey neocortex. J Neurosci. 1982;2:1725–1735. [PubMed: 6815309]
31.
Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science. 1987;235:73–76. [PubMed: 2879352]
32.
Obenaus A, Esclapez M, Houser CR. Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures. J Neurosci. 1993;13:4470–4485. [PubMed: 8410199]
33.
Kobayashi M, Buckmaster PS. Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy. J Neurosci. 2003;23:2440–2452. [PubMed: 12657704]
34.
Shao L-R, Dudek FE. Changes in mIPSCs and sIPSCs after kainate treatment: evidence for loss of inhibitory input to dentate granule cells and possible compensatory responses. J Neurophysiol. 2005;94:952–960. [PubMed: 15772233]
35.
Wierenga CJ, Wadman WJ. Miniature inhibitory postsynaptic currents in CA1 pyramidal neurons after kindling epileptogenesis. J Neurophysiol. 1999;82:1352–1362. [PubMed: 10482754]
36.
Zhang W, Yamawaki R, Wen X, Uhl J, Diaz J, Prince DA, Buckmaster PS. Surviving hilar somatostatin interneurons enlarge, sprout axons, and form new synapses with granule cells in a mouse model of temporal lobe epilepsy. J Neurosci. 2009;29:14247–14256. [PMC free article: PMC2802278] [PubMed: 19906972]
37.
Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002;291:1418–1421. [PubMed: 12434059]
38.
Jin X, Huguenard JR, Prince DA. Impaired Cl- extrusion in layer V pyramidal neurons of chronically injured epileptogenic neocortex. J Neurophysiol. 2005;93:2117–2126. [PubMed: 15774713]
39.
Pathak HR, Weissinger F, Terunuma M, Carlson GC, Hsu FC, Moss SJ, Coulter DA. Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy. J Neurosci. 2007;27:14012–14022. [PMC free article: PMC2211568] [PubMed: 18094240]
40.
Babb TL, Kupfer WR, Pretorius JK, Crandall PH, Levesque MF. Synaptic reorganization by mossy fibers in human epileptic fascia dentata. Neuroscience. 1991;42:351–363. [PubMed: 1716744]
41.
de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 1989;495:387–395. [PubMed: 2569920]
42.
Houser CR, Miyashiro JE, Swartz BE, Walsh GO, Rich JR, Delgado-Escueta AV. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy. J Neurosci. 1990;10:267–282. [PubMed: 1688934]
43.
Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol. 1989;26:321–330. [PubMed: 2508534]
44.
Dudek FE, Sutula TP. Epileptogenesis in the dentate gyrus: a critical perspective. Prog Brain Res. 2007;163:755–773. [PubMed: 17765749]
45.
Sutula TP, Dudek FE. Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system. Prog Brain Res. 2007;163:541–563. [PubMed: 17765737]
46.
Tauck DL, Nadler JV. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci. 1985;5:1016–1022. [PubMed: 3981241]
47.
Cronin J, Obenaus A, Houser CR, Dudek FE. Electrophysiology of dentate granule cells after kainate-induced synaptic reorganization of the mossy fibers. Brain Res. 1992;573:305–310. [PubMed: 1504768]
48.
Wuarin JP, Dudek FE. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats. J Neurosci. 1996;16:4438–4448. [PubMed: 8699254]
49.
Patrylo PR, Dudek FE. Physiological unmasking of new glutamatergic pathways in the dentate gyrus of hippocampal slices from kainate-induced epileptic rats. J Neurophysiol. 1998;79:418–429. [PubMed: 9425210]
50.
Hardison JL, Okazaki MM, Nadler JV. Modest increase in extracellular potassium unmasks effect of recurrent mossy fiber growth. J Neurophysiol. 2000;84:2380–2389. [PubMed: 11067980]
51.
Lynch M, Sutula T. Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats. J Neurophysiol. 2000;83:693–704. [PubMed: 10669485]
52.
Christian EP, Dudek FE. Characteristics of local excitatory circuits studied with glutamate microapplication in the CA3 area of rat hippocampal slices. J Neurophysiol. 1988;59:90–109. [PubMed: 2893832]
53.
Traub RD, Wong RK. Cellular mechanism of neuronal synchronization in epilepsy. Science. 1982;216:745–747. [PubMed: 7079735]
54.
Traub RD, Wong RK. Synchronized burst discharge in disinhibited hippocampal slice. II. Model of cellular mechanism. J Neurophysiol. 1983;49:459–471. [PubMed: 6300344]
55.
Miles R, Wong RK. Inhibitory control of local excitatory circuits in the guinea-pig hippocampus. J Physiol. 1987;388:611–629. [PMC free article: PMC1192568] [PubMed: 3656200]
56.
Molnar P, Nadler JV. Mossy fiber-granule cell synapses in the normal and epileptic rat dentate gyrus studied with minimal laser photostimulation. J Neurophysiol. 1999;82:1883–1894. [PubMed: 10515977]
57.
Wuarin JP, Dudek FE. Excitatory synaptic input to granule cells increases with time after kainate treatment. J Neurophysiol. 2001;85:1067–1077. [PubMed: 11247977]
58.
Scharfman HE, Sollas AL, Berger RE, Goodman JH. Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting. J Neurophysiol. 2003;90:2536–2547. [PubMed: 14534276]
59.
Zhang N, Houser CR. Ultrastructural localization of dynorphin in the dentate gyrus in human temporal lobe epilepsy: a study of reorganized mossy fiber synapses. J Comp Neurol. 1999;405:472–490. [PubMed: 10098940]
60.
Buckmaster PS, Zhang GF, Yamawaki R. Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit. J Neurosci. 2002;22:6650–6658. [PubMed: 12151544]
61.
Kron MM, Zhang H, Parent JM. The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. J Neurosci. 2010;30:2051–2059. [PubMed: 20147533]
62.
Pierce JP, McCloskey DP, Scharfman HE. Morphometry of hilar ectopic granule cells in the rat. J Comp Neurol. 2011;519:1196–1218. [PMC free article: PMC3984463] [PubMed: 21344409]
63.
Perez Y, Morin F, Beaulieu C, Lacaille JC. Axonal sprouting of CA1 pyramidal cells in hyperexcitable hippocampal slices of kainate-treated rats. Eur J Neurosci. 1996;8:736–748. [PubMed: 9081625]
64.
Meier CL, Dudek FE. Spontaneous and stimulation-induced synchronized burst afterdischarges in the isolated CA1 of kainate-treated rats. J Neurophysiol. 1996;76:2231–2239. [PubMed: 8899598]
65.
Esclapez M, Hirsch JC, Ben Ari Y, Bernard C. Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy. J Comp Neurol. 1999;408:449–460. [PubMed: 10340497]
66.
Smith BN, Dudek FE. Short- and long-term changes in CA1 network excitability after kainate treatment in rats. J Neurophysiol. 2001;85:1–9. [PubMed: 11152700]
67.
Smith BN, Dudek FE. Network interactions mediated by new excitatory connections between CA1 pyramidal cells in rats with kainate-induced epilepsy. J Neurophysiol. 2002;87:1655–1658. [PubMed: 11877537]
68.
Shao LR, Dudek FE. Increased excitatory synaptic activity and local connectivity of hippocampal CA1 pyramidal cells in rats with kainate-induced epilepsy. J Neurophysiol. 2004;92:1366–1373. [PubMed: 15084640]
69.
Williams PA, Dudek FE. A chronic histopathological and electrophysiological analysis of a rodent hypoxic-ischemic brain injury model and its use as a model of epilepsy. Neuroscience. 2007;149:943–961. [PMC free article: PMC2897748] [PubMed: 17935893]
70.
Prince DA, Parada I, Huifang L, McDonald W, Graber K. Neocortical posttraumatic epileptogenesis. Epilepsia. 2010;51:30. [PubMed: 21158780]

Conflict of Interest Disclosures

FED has received financial support from Johnson Pharmaceutical Research Institute, Johnson-Ethicon, and Neurotherapeutics Pharma, and he has equity interest in Epitel, Inc. KJS has no potential conflicts of interest.

Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

All Jasper's Basic Mechanisms of the Epilepsies content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license, which permits copying, distribution and transmission of the work, provided the original work is properly cited, not used for commercial purposes, nor is altered or transformed.

Bookshelf ID: NBK98152PMID: 22787656

Views

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...