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1.  Chronic Cellular Hyperexcitability in Elderly Epileptic Rats with Spontaneous Seizures Induced by Kainic Acid Status Epilepticus while Young Adults 
Aging and Disease  2011;2(4):332-338.
Emerging data indicate that age-related brain changes alter seizure susceptibility, seizure-associated neurodegeneration, and responsiveness to AEDs. The present study assessed long-term animal survival in the Kainic Acid (KA) model along with in-vivo spontaneous seizure frequency, cellular hyperexcitability in CA1 in-vitro and in-vivo in subiculum, and responsiveness of in-vitro CA1 hyperexcitability to topiramate. Sprague-Dawley male rats were given KA to induce convulsive status epilepticus (KA-SE) at 2–3 months of age. The one-month mortality after KA-SE was 27%. One-month survivor rats had 37% sudden unexplained late mortality after KA-SE as compared to none in saline controls during their second year of life. In-vivo seizure frequency was examined prior to terminal experiments. The diurnal average seizure frequency in the KA-SE group at age 2 years was 1.06 ± 0.24 seizures/hour while no seizures were observed in the saline age-matched controls (p<0.001). In-vitro recordings of CA1 pyramidal neurons revealed that depolarizing current injection from −60 mV evoked an increased number of action potentials in the aged KA-SE group compared to controls (p<0.002). Topiramate exhibited dose-dependent inhibition of action potential firing evoked by current injections into CA1 pyramidal neurons of KA-SE rats. In subiculum, KA-SE rats had frequent interictal spikes associated with high frequency oscillations while only rare spontaneous EPSPs were recorded in saline controls. Our experiments revealed that the hippocampal formation of aged epileptic rats shares features of hyperexcitability previously described in young adult epileptic rats using the KA model.
PMCID: PMC3295074  PMID: 22396885
Topiramate; Aged; Epilepsy; Bursting; Hippocampal slice; SUDEP
2.  Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex 
Neuropharmacology  2012;63(5):806-817.
Injection of the seaweed toxin kainic acid (KA) in rats induces a severe status epilepticus initiating complex neuropathological changes in limbic brain areas and subsequently spontaneous recurrent seizures. Although neuropathological changes have been intensively investigated in the hippocampus proper and the dentate gyrus in various seizure models, much less is known about changes in parahippocampal areas. We now established telemetric EEG recordings combined with continuous video monitoring to characterize the development of spontaneous seizures after KA-induced status epilepticus, and investigated associated neurodegenerative changes, astrocyte and microglia proliferation in the subiculum and other parahippocampal brain areas. The onset of spontaneous seizures was heterogeneous, with an average latency of 15 ± 1.4 days (range 3–36 days) to the initial status epilepticus. The frequency of late spontaneous seizures was higher in rats in which the initial status epilepticus was recurrent after its interruption with diazepam compared to rats in which this treatment was more efficient. Seizure-induced neuropathological changes were assessed in the subiculum by losses in NeuN-positive neurons and by Fluoro-Jade C staining of degenerating neurons. Neuronal loss was already prominent 24 h after KA injection and only modestly progressed at the later intervals. It was most severe in the proximal subiculum and in layer III of the medial entorhinal cortex and distinct Fluoro-Jade C labeling was observed there in 75% of rats even after 3 months. Glutamatergic neurons, labeled by in situ hybridization for the vesicular glutamate transporter 1 followed a similar pattern of cell losses, except for the medial entorhinal cortex and the proximal subiculum that appeared more vulnerable. Glutamate decarboxylase65 (GAD65) mRNA expressing neurons were generally less vulnerable than glutamate neurons. Reactive astrocytes and microglia were present after 24 h, however, became prominent only after 8 days and remained high after 30 days. In the proximal subiculum, parasubiculum and entorhinal cortex the number of microglia cells was highest after 30 days. Although numbers of reactive astrocytes and microglia were reduced again after 3 months, they were still present in most rats. The time course of astrocyte and microglia proliferation parallels that of epileptogenesis.
Highlights
► The onset of spontaneous seizures was highly variable (3–36 days) with an average latency of 15 days. ► Massive neurodegeneration was already present 24 h after KA-induced seizures. ► Neurons of the proximal subiculum and EC layer III preferentially degenerate. ► Distribution of reactive gliosis roughly matches the pattern of neurodegeneration. ► Time course of reactive gliosis parallels that of epileptogenesis.
doi:10.1016/j.neuropharm.2012.06.009
PMCID: PMC3409872  PMID: 22722023
Temporal lobe epilepsy; Subiculum; Entorhinal cortex; Animal epilepsy model; EEG; Epileptogenesis; DG, dentate gyrus; FJ-C, Fluoro Jade C; GAD65 and GAD67, glutamate decarboxylase 65 and 67; GFAP, glial fibrillary acidic protein; KA, kainic acid; NeuN, neuron-specific nuclear protein; SE, status epilepticus; Sub, subiculum; TLE, temporal lobe epilepsy; VGLUT1, vesicular glutamate transporter 1
3.  Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex 
Neuropharmacology  2012;63(5):806-817.
Injection of the seaweed toxin kainic acid (KA) in rats induces a severe status epilepticus initiating complex neuropathological changes in limbic brain areas and subsequently spontaneous recurrent seizures. Although neuropathological changes have been intensively investigated in the hippocampus proper and the dentate gyrus in various seizure models, much less is known about changes in parahippocampal areas. We now established telemetric EEG recordings combined with continuous video monitoring to characterize the development of spontaneous seizures after KA-induced status epilepticus, and investigated associated neurodegenerative changes, astrocyte and microglia proliferation in the subiculum and other parahippocampal brain areas. The onset of spontaneous seizures was heterogeneous, with an average latency of 15 ± 1.4 days (range 3–36 days) to the initial status epilepticus. The frequency of late spontaneous seizures was higher in rats in which the initial status epilepticus was recurrent after its interruption with diazepam compared to rats in which this treatment was more efficient. Seizure-induced neuropathological changes were assessed in the subiculum by losses in NeuN-positive neurons and by Fluoro-Jade C staining of degenerating neurons. Neuronal loss was already prominent 24 h after KA injection and only modestly progressed at the later intervals. It was most severe in the proximal subiculum and in layer III of the medial entorhinal cortex and distinct Fluoro-Jade C labeling was observed there in 75% of rats even after 3 months. Glutamatergic neurons, labeled by in situ hybridization for the vesicular glutamate transporter 1 followed a similar pattern of cell losses, except for the medial entorhinal cortex and the proximal subiculum that appeared more vulnerable. Glutamate decarboxylase65 (GAD65) mRNA expressing neurons were generally less vulnerable than glutamate neurons. Reactive astrocytes and microglia were present after 24 h, however, became prominent only after 8 days and remained high after 30 days. In the proximal subiculum, parasubiculum and entorhinal cortex the number of microglia cells was highest after 30 days. Although numbers of reactive astrocytes and microglia were reduced again after 3 months, they were still present in most rats. The time course of astrocyte and microglia proliferation parallels that of epileptogenesis.
doi:10.1016/j.neuropharm.2012.06.009
PMCID: PMC3409872  PMID: 22722023
Temporal lobe epilepsy; Subiculum; Entorhinal cortex; Animal epilepsy model; EEG; Epileptogenesis
4.  Development of later life spontaneous seizures in a rodent model of hypoxia induced neonatal seizures 
Epilepsia  2011;52(4):753-765.
Summary
Purpose
To study the development of epilepsy following hypoxia-induced neonatal seizures in Long Evans rats and to establish the presence of spontaneous seizures in this model of early life seizures.
Methods
Long-Evans rat pups were subjected to hypoxia-induced neonatal seizures at postnatal day 10 (P10). Epidural cortical electroencephalography (EEG) and hippocampal depth electrodes were used to detect the presence of seizures in later adulthood (>P60). In addition, subdermal wire electrode recordings were used to monitor age at onset and progression of seizures in the juvenile period, at intervals between P10–P60. Timm staining was performed to evaluate mossy fiber sprouting in the hippocampi of P100 adult rats that had experienced neonatal seizures.
Key Findings
In recordings made from adult rats (P60–P180), the prevalence of epilepsy in cortical and hippocampal EEG recordings was 94.4% following early life hypoxic seizures. These spontaneous seizures were identified by characteristic spike and wave activity on EEG accompanied by behavioral arrest and facial automatisms (electroclinical seizures). Phenobarbital injection transiently abolished spontaneous seizures. EEG in the juvenile period (P10–60) showed that spontaneous seizures first occurred approximately 2 weeks after the initial episode of hypoxic seizures. Following this period, spontaneous seizure frequency and duration progressively increased with time. Furthermore, significantly increased sprouting of mossy fibers was observed in the CA3 pyramidal cell layer of the hippocampus in adult animals following hypoxia-induced neonatal seizures. Notably, Fluoro-Jade B staining confirmed that hypoxic seizures at P10 did not induce acute neuronal death.
Significance
The rodent model of hypoxia-induced neonatal seizures leads to the development of epilepsy in later life, accompanied by increased mossy fiber sprouting. In addition, this model appears to exhibit a seizure-free latent period, following which there is a progressive increase in the frequency of electroclinical seizures.
doi:10.1111/j.1528-1167.2011.02992.x
PMCID: PMC3071424  PMID: 21366558
Neonatal Seizures; electroencephalogram; epilepsy; infant; animal model
5.  Long-lasting pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of concomitant pathology 
Epilepsia  2012;53(11):1887-1897.
Summary
Purpose
Dysfunction of the blood–brain barrier (BBB) is a common finding during seizures or following epileptogenic brain injuries, and experimentally induced BBB opening promotes seizures both in naive and epileptic animals. Brain albumin extravasation was reported to promote hyperexcitability by inducing astrocytes dysfunction. To provide in vivo evidence for a direct role of extravasated serum albumin in seizures independently on the pathologic context, we did the following: (1) quantified the amount of serum albumin extravasated in the rat brain parenchyma during status epilepticus (SE); (2) reproduced a similar concentration in the hippocampus by intracerebroventricular (i.c.v.) albumin injection in naive rats; (3) measured electroencephalography (EEG) activity in these rats, their susceptibility to kainic acid (KA)–induced seizures, and their hippocampal afterdischarge threshold (ADT).
Methods
Brain albumin concentration was measured in the rat hippocampus and other forebrain regions 2 and 24 h after SE by western blot analysis. Brain distribution of serum albumin or fluorescein isothiocyanate (FITC)-albumin was studied by immunohistochemistry and immunofluorescence, respectively. Naive rats were injected with rat albumin or FITC-albumin, i.c.v., to mimic the brain concentration attained after SE, or with dextran used as control. Inflammation was evaluated by immunohistochemistry by measuring glial induction of interleukin (IL)-1β. Western blot analysis was used to measure inward rectifying potassium channel subunit Kir4.1 protein levels in the hippocampus. Seizures were induced in rats by intrahippocampal injection of 80 ng KA and quantified by EEG analysis, 2 or 24 h after rat albumin or dextran administration. ADT was measured by electrical stimulation of the hippocampus 3 months after albumin injection. In these rats, EEG was continuously monitored for 2 weeks to search for spontaneous seizures.
Key Findings
The hippocampal serum albumin concentration 24 h post-SE was 0.76 ± 0.21 μm. Similar concentrations were measured in other forebrain regions, whereas no changes were found in cerebellum. The hippocampal albumin concentration was similarly reproduced in naive rats by i.c.v. administration of 500 μg/4 μl rat albumin: albumin was predominantly detected extracellularly 2 h after injection, whereas at 24 h it was visible inside pyramidal neurons and in only a few scattered chondroitin sulphate proteoglycan (NG2)-positive cells, but not in glial fibrillary acidic protein (GFAP)-positive astrocytes or CR-3 complement receptor (OX-42)-positive microglia. The presence of albumin in naive rat hippocampus was associated with induced IL-1β in GFAP-positive astrocytes and a concomitant tissue down-regulation of Kir4.1. Spiking activity was evoked by albumin in the hippocampus lasting for 2 h. When KA was intrahippocampally applied either 2 or 24 h after albumin injection, the number of total interictal spikes in 3 h EEG recording was significantly increased by twofold on average. Three months after albumin injection, neither albumin nor inflammation was detected in brain tissue; at this time, the ADT was reduced by 50% but no spontaneous seizures were observed.
Significance
Transient hippocampal exposure to albumin levels similar to those attained after prominent BBB breakdown resulted in increased seizure susceptibility and long-term reduction in seizure threshold, but it did not evoke spontaneous seizures. These effects may be mediated by albumin-induced astrocytes dysfunction and the associated induction of proinflammatory molecules.
doi:10.1111/j.1528-1167.2012.03666.x
PMCID: PMC3651831  PMID: 22984896
Afterdischarge; Astrocytes; Blood–brain barrier; Inflammation; Neurodegeneration; Seizures
6.  Parvalbumin interneurons and calretinin fibers arising from the thalamic nucleus reuniens degenerate in the subiculum after kainic acid-induced seizures 
Neuroscience  2011;189(1-2):316-329.
The subiculum is the major output area of the hippocampus. It is closely interconnected with the entorhinal cortex and other parahippocampal areas. In animal models of temporal lobe epilepsy (TLE) and in TLE patients it exerts increased network excitability and may crucially contribute to the propagation of limbic seizures. Using immunohistochemistry and in situ-hybridization we now investigated neuropathological changes affecting parvalbumin and calretinin containing neurons in the subiculum and other parahippocampal areas after kainic acid-induced status epilepticus. We observed prominent losses in parvalbumin containing interneurons in the subiculum and entorhinal cortex, and in the principal cell layers of the pre- and parasubiculum. Degeneration of parvalbumin-positive neurons was associated with significant precipitation of parvalbumin-immunoreactive debris 24 h after kainic acid injection. In the subiculum the superficial portion of the pyramidal cell layer was more severely affected than its deep part. In the entorhinal cortex, the deep layers were more severely affected than the superficial ones. The decrease in number of parvalbumin-positive neurons in the subiculum and entorhinal cortex correlated with the number of spontaneous seizures subsequently experienced by the rats. The loss of parvalbumin neurons thus may contribute to the development of spontaneous seizures. On the other hand, surviving parvalbumin neurons revealed markedly increased expression of parvalbumin mRNA notably in the pyramidal cell layer of the subiculum and in all layers of the entorhinal cortex. This indicates increased activity of these neurons aiming to compensate for the partial loss of this functionally important neuron population. Furthermore, calretinin-positive fibers terminating in the molecular layer of the subiculum, in sector CA1 of the hippocampus proper and in the entorhinal cortex degenerated together with their presumed perikarya in the thalamic nucleus reuniens. In addition, a significant loss of calretinin containing interneurons was observed in the subiculum. Notably, the loss in parvalbumin positive neurons in the subiculum equaled that in human TLE. It may result in marked impairment of feed-forward inhibition of the temporo-ammonic pathway and may significantly contribute to epileptogenesis. Similarly, the loss of calretinin-positive fiber tracts originating from the nucleus reuniens thalami significantly contributes to the rearrangement of neuronal circuitries in the subiculum and entorhinal cortex during epileptogenesis.
Graphical Abstract
•••
Highlights
▶A subpopulation of PV neurons degenerates in subiculum and entorhinal cortex after KA seizures. ▶Surviving PV neurons exhibit increased PV mRNA expression. ▶The loss in PV neurons in subiculum and entorhinal cortex correlates to spontaneous seizures. ▶Degeneration of PV neurons in the subiculum may be related to seizure-induced loss of feed-forward inhibition. ▶CR-ir neurons in the N. reuniens thalami and their projections to the subiculum degenerate.
doi:10.1016/j.neuroscience.2011.05.021
PMCID: PMC3152681  PMID: 21616128
status epilepticus; temporal lobe epilepsy; epileptogenesis; entorhinal cortex; epilepsy models; CR, calretinin; EC, entorhinal cortex; -ir, immunoreactive; KA, kainic acid; NeuN, neuron specific nuclear protein; O-LM, oriens-lacunosum moleculare; PV, parvalbumin; ROD, relative optical densities; SE, status epilepticus; TBS, tris-buffered saline; TLE, temporal lobe epilepsy
7.  Low Frequency Stimulation of Hippocampal Commissures Reduces Seizures in Chronic Rat Model of Temporal Lobe Epilepsy 
Epilepsia  2011;53(1):147-156.
SUMMARY
Purpose
To investigate the effects of low frequency stimulation (LFS) of a fiber track for the suppression of spontaneous seizures described by Nissinen in a rat model of human temporal lobe epilepsy.
Methods
Stimulation electrodes were implanted into the ventral hippocampal commissure (VHC) in a rat post-status epilepticus (SE) model of human temporal lobe epilepsy (n = 7). Two recordings electrodes were placed in the CA3 regions bilaterally and neural data was recorded for a minimum of six weeks. LFS (60 minute train of 1Hz biphasic square wave pulses, each 0.1ms in duration and 200μA in amplitude, followed by 15 minutes of rest) was applied to the VHC for, two weeks, 24 hours a day.
Key Findings
The baseline mean seizure frequency of the study animals was 3.7 seizures per day. The seizures were significantly reduced by the application of LFS in every animal (n=7). By the end of the two-week period of stimulation, there was a significant 90% (<1 seizure/day) reduction of seizure frequencies (p < 0.05) and a 57% reduction during the period following LFS (p < 0.05) when compared to baseline. LFS also resulted in a significant reduction of hippocampal interictal spike frequency (71%, p < 0.05), during two weeks LFS session. The hippocampal histological analysis showed no significant difference between rats that received LFS and SE-induction and those that had only received SE-induction. None of the animals showed any symptomatic hemorrhage, infection or complication.
Significance
LFS applied at a frequency of 1Hz significantly reduced both the excitability of the neural tissue as well as the seizure frequency in a rat model of human temporal lobe epilepsy. The results support the hypothesis that LFS of fiber tracts can be an effective method for the suppression of spontaneous seizures in a temporal lobe model of epilepsy in rats and could be lead to the development of the new therapeutic modality for human patients with temporal lobe epilepsy.
doi:10.1111/j.1528-1167.2011.03348.x
PMCID: PMC3568386  PMID: 22150779
DBS; LFS; VHC; TLE; temporal lobe epilepsy; brain stimulation; amygdala
8.  An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure Threshold 
PLoS Biology  2010;8(4):e1000352.
Studies in rodent brain slices suggest that seizures in focal epilepsies are sustained and propagated by the reciprocal interaction between neurons and astroglial cells
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron–astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
Author Summary
In focal epilepsy, seizures are generated by a localized, synchronous neuronal electrical discharge that may spread to large portions of the brain. Despite intense experimental research in this field, a key question relevant to the human epilepsy condition remains completely unanswered: what are the cellular events that lead to the onset of a seizure in the first place? In various in vitro models of seizures using rodent brain slices, we simultaneously recorded neuronal firing and Ca2+ signals both from neurons and from astrocytes, the principal population of glial cells in the brain. We found that activation of astrocytes by neuronal activity and signalling from astrocytes back to neurons contribute to the initiation of a focal seizure. This reciprocal excitatory loop between neurons and astrocytes represents a new mechanism in the pathophysiology of epilepsy that should be considered by those aiming to develop more effective therapies for epilepsies that are not controlled by currently available treatments.
doi:10.1371/journal.pbio.1000352
PMCID: PMC2854117  PMID: 20405049
9.  Therapeutic effect of low frequency electric stimulation on the epileptogenic focus in amygdale-kindled rats 
This study was to examine the therapeutic effect of low-frequency electric stimulation (LFS) on the epileptogenic focus in amygdale-kindled rats, and to find out the optimal stimulus parameters. A microelectrode was implanted into the right amygdale of adult male rats. After fully kindling, LFS was delivered to the right amygdale (through the electrode) between seizures to induce stimulus trains (10 repetitive sequences). Next, we undertook controlled experiment in order to exclude the influence of seizure induction intervals on seizure. Fully kindled rats experienced trials for 4 days, the intervals of the repetitive seizure inducing stimulation was randomized for 5 min, 10 min, 15 min, and 20 min respectively. Finally, we applied an orthogonal design to test the 4 factors of parameters (frequency, pulse duration, current intensity and persistence time), in order to find out the best stimulus parameters. Results showed that compared to control group, the stage-4 seizure induction rate decreased dramatically in LFS group and animals in experiment group were more likely to be non-responsive to seizure-inducing stimuli. There were no statistical differences in the different seizure induction intervals. Significant differences were observed in different stimulus frequencies and stimulus train persistence times on the stage-4 seizure induction rate. These findings indicated that 1 Hz LFS is the best. Training for 5 min is more efficacious in controlling seizure. Thus, our results suggest that LFS applied directly to the site of seizure was effective and further studies are required to explore the most effective parameters for developing implanted stimulator.
PMCID: PMC4276176  PMID: 25550918
Kindling; low-frequency electric stimulation; best parameters; orthogonal design
10.  Effects of Anterior Thalamic Nucleus Deep Brain Stimulation in Chronic Epileptic Rats 
PLoS ONE  2014;9(6):e97618.
Deep brain stimulation (DBS) has been investigated for the treatment of epilepsy. In rodents, an increase in the latency for the development of seizures and status epilepticus (SE) has been reported in different animal models but the consequences of delivering stimulation to chronic epileptic animals have not been extensively addressed. We study the effects of anterior thalamic nucleus (AN) stimulation at different current intensities in rats rendered epileptic following pilocarpine (Pilo) administration. Four months after Pilo-induced SE, chronic epileptic rats were bilaterally implanted with AN electrodes or had sham-surgery. Stimulation was delivered for 6 h/day, 5 days/week at 130 Hz, 90 µsec. and either 100 µA or 500 µA. The frequency of spontaneous recurrent seizures in animals receiving stimulation was compared to that recorded in the preoperative period and in rats given sham treatment. To investigate the effects of DBS on hippocampal excitability, brain slices from animals receiving AN DBS or sham surgery were studied with electrophysiology. We found that rats treated with AN DBS at 100 µA had a 52% non-significant reduction in the frequency of seizures as compared to sham-treated controls and 61% less seizures than at baseline. Animals given DBS at 500 µA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values. In non-stimulated controls, the average frequency of seizures before and after surgery remained unaltered. In vitro recordings have shown that slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude compared to non-stimulated controls. In contrast, a higher spike amplitude was recorded in slices from animals given AN DBS at 500 µA.
doi:10.1371/journal.pone.0097618
PMCID: PMC4043725  PMID: 24892420
11.  Synaptic reorganization in subiculum and CA3 after early-life status epilepticus in the kainic acid rat model 
Epilepsy research  2006;73(2):156-165.
Purpose
The immature rat brain is highly susceptible to seizures, but has a resistance to pathological changes induced by seizures as compared to adult rats. However, prolonged seizures during early-life enhance cellular injury and hyperexcitability induced by convulsive insults later in adulthood. The mechanisms underlying these phenomena are not understood. In adult models, the CA1 axons reorganize their projections to subiculum. Seizure induced plasticity in this pathway has not been investigated in immature seizure models, and may contribute to the vulnerability to later seizures.
Methods
On postnatal day 15, rats experienced convulsive status epilepticus with kainic acid (KA). Seizure induced plasticity was examined with Timm histochemistry and iontophoretic injections of sodium selenite, a retrograde tracer. Cellular injury was evaluated with Fluoro-Jade B histochemistry.
Results
Retrograde tracing experiments determined a 67% larger dorsoventral extent of retrograde labeling in the CA1 pyramidal region after tracer injections in subiculum. The synaptic reorganization of the CA1 projection to subiculum was noted in the absence of overt neuronal injury in subiculum or CA1. In contrast, mossy fiber sprouting was detected into the stratum oriens of CA3 with limited neuronal injury to CA3 pyramidal neurons. No mossy fiber sprouting into the inner molecular layer of the dentate gyrus, or CA1 sprouting into the stratum moleculare of CA1 were noted.
Conclusions
The results indicate that the developing brain has distinct mechanisms of seizure induced reorganization as compared to the adult brain. Our experiments show that the concept of “resistance of the immature brain to excitotoxicity” is considerably more complicated than generally believed. Morphological plasticity in the immature brain appears more extensive in distal, but not proximal, projections of hippocampal pathways, and across hippocampal lamellae. The abnormal connectivity between hippocampal lamellae might play a role in the increased susceptibility to injury and hyperexcitability associated with later convulsive insults.
doi:10.1016/j.eplepsyres.2006.09.004
PMCID: PMC1876715  PMID: 17070016
sprouting; seizures; immature; retrograde tracing; Zinc
12.  Oral administration of fructose-1,6-diphosphate has anticonvulsant activity 
Neuroscience letters  2008;446(2-3):75-77.
Recently it has been shown that fructose-1,6-diphosphate (FDP) has dose-dependent anticonvulsant activity in rat models of acute generalized motor seizures induced with chemical convulsants. This present study asked whether FDP also has activity in an epileptic brain after oral administration and activity against non-convulsive seizures. Animals (n=14) were administered pilocarpine to induce status epilepticus. Several weeks later, these animals had spontaneous seizures and a baseline rate of seizure frequency was determined over a 6 day period. Animals were then continued without treatment (n=8) or 0.5% FDP was added to the drinking water (n=6). In animals treated with FDP the seizures completely stopped after 7 days. Removal of FDP from the water resulted in the return of seizure activity in 4 of the 6 animals by 16 days of observation. To induce non-convulsive seizures, animals (n=6) received a single injection of γ-butyrolactone (GBL, 100 mg/kg ip). All animals had spike-wave activity recorded in the cortex within minutes after GBL administration. Administration of a single injection of FDP (500 g/kg ip) had no effect on the baseline cortical activity, nor on the spike-wave activity induced by GBL (n=5). These experiments suggest that oral administration of FDP may have utility in the treatment of partial or generalized convulsive seizure disorders, but not absence seizures.
doi:10.1016/j.neulet.2008.09.042
PMCID: PMC2633033  PMID: 18832008
epilepsy; pilocarpine; seizures; gamma-butyrolactone
13.  Noninvasive transcranial focal stimulation via tripolar concentric ring electrodes lessens behavioral seizure activity of recurrent pentylenetetrazole administrations in rats 
Epilepsy affects approximately one percent of the world population. Antiepileptic drugs are ineffective in approximately 30% of patients and have side effects. We have been developing a noninvasive transcranial focal electrical stimulation with our novel tripolar concentric ring electrodes as an alternative/complementary therapy for seizure control. In this study we demonstrate the effect of focal stimulation on behavioral seizure activity induced by two successive pentylenetetrazole administrations in rats. Seizure onset latency, time of the first behavioral change, duration of seizure, and maximal seizure severity score were studied and compared for focal stimulation treated (n = 9) and control groups (n = 10). First, we demonstrate that no significant difference was found in behavioral activity for focal stimulation treated and control groups after the first pentylenetetrazole administration. Next, comparing first and second pentylenetetrazole administrations, we demonstrate there was a significant change in behavioral activity (time of the first behavioral change) in both groups that was not related to focal stimulation. Finally, we demonstrate focal stimulation provoking a significant change in seizure onset latency, duration of seizure, and maximal seizure severity score. We believe that these results, combined with our previous reports, suggest that transcranial focal stimulation may have an anticonvulsant effect.
doi:10.1109/TNSRE.2012.2198244
PMCID: PMC3601189  PMID: 22692938
Epilepsy; pentylenetetrazole; noninvasive transcranial focal electrical stimulation; tripolar concentric ring electrode; seizure
14.  Hippocampal Interictal Spikes Disrupt Cognition in Rats 
Annals of neurology  2010;67(2):250-257.
Objective
Cognitive impairment is common in epilepsy, particularly in memory function. Interictal spikes are thought to disrupt cognition, but it is difficult to delineate their contribution from general impairments in memory produced by etiology and seizures. We investigated the transient impact of focal interictal spikes on the hippocampus, a structure crucial for learning and memory and yet highly prone to interictal spikes in temporal lobe epilepsy.
Methods
Bilateral hippocampal depth electrodes were implanted into fourteen Sprague-Dawley rats, followed by intrahippocampal pilocarpine or saline infusion unilaterally. Rats that developed chronic spikes were trained in a hippocampal-dependent operant behavior task, delayed-match-to-sample. Depth EEG was recorded during 5,562 trials among five rats, and within-subject analyses evaluated the impact of hippocampal spikes on short-term memory operations.
Results
Hippocampal spikes that occurred during memory retrieval strongly impaired performance (p<0.001). However, spikes that occurred during memory encoding or memory maintenance did not affect performance in those trials. Hippocampal spikes also affected response latency, adding approximately 0.48 seconds to the time taken to respond (p<0.001).
Interpretation
We found that focal interictal spike-related interference in cognition extends to structures in the limbic system, which required intrahippocampal recordings. Hippocampal spikes seem most harmful if they occur when hippocampal function is critical, extending human studies showing that cortical spikes are most disruptive during active cortical functioning. The cumulative effects of spikes could therefore impact general cognitive functioning. These results strengthen the argument that suppression of interictal spikes may improve memory and cognitive performance in patients with epilepsy.
doi:10.1002/ana.21896
PMCID: PMC2926932  PMID: 20225290
15.  Role of subdural electrocorticography in prediction of long-term seizure outcome in epilepsy surgery 
Brain  2009;132(4):1038-1047.
Since prediction of long-term seizure outcome using preoperative diagnostic modalities remains suboptimal in epilepsy surgery, we evaluated whether interictal spike frequency measures obtained from extraoperative subdural electrocorticography (ECoG) recording could predict long-term seizure outcome. This study included 61 young patients (age 0.4–23.0 years), who underwent extraoperative ECoG recording prior to cortical resection for alleviation of uncontrolled focal seizures. Patient age, frequency of preoperative seizures, neuroimaging findings, ictal and interictal ECoG measures were preoperatively obtained. The seizure outcome was prospectively measured [follow-up period: 2.5–6.4 years (mean 4.6 years)]. Univariate and multivariate logistic regression analyses determined how well preoperative demographic and diagnostic measures predicted long-term seizure outcome. Following the initial cortical resection, Engel Class I, II, III and IV outcomes were noted in 35, 6, 12 and 7 patients, respectively. One child died due to disseminated intravascular coagulation associated with pseudomonas sepsis 2 days after surgery. Univariate regression analyses revealed that incomplete removal of seizure onset zone, higher interictal spike-frequency in the preserved cortex and incomplete removal of cortical abnormalities on neuroimaging were associated with a greater risk of failing to obtain Class I outcome. Multivariate logistic regression analysis revealed that incomplete removal of seizure onset zone was the only independent predictor of failure to obtain Class I outcome. The goodness of regression model fit and the predictive ability of regression model were greatest in the full regression model incorporating both ictal and interictal measures [R2 0.44; Area under the receiver operating characteristic (ROC) curve: 0.81], slightly smaller in the reduced model incorporating ictal but not interictal measures (R2 0.40; Area under the ROC curve: 0.79) and slightly smaller again in the reduced model incorporating interictal but not ictal measures (R2 0.27; Area under the ROC curve: 0.77). Seizure onset zone and interictal spike frequency measures on subdural ECoG recording may both be useful in predicting the long-term seizure outcome of epilepsy surgery. Yet, the additive clinical impact of interictal spike frequency measures to predict long-term surgical outcome may be modest in the presence of ictal ECoG and neuroimaging data.
doi:10.1093/brain/awp025
PMCID: PMC2668945  PMID: 19286694
clinical neurophysiology; paediatric epilepsy surgery; intracranial electroencephalography (EEG); irritative zone
16.  Impaired cognition in rats with cortical dysplasia: additional impact of early-life seizures 
Brain  2011;134(6):1684-1693.
One of the most common and serious co-morbidities in patients with epilepsy is cognitive impairment. While early-life seizures are considered a major cause for cognitive impairment, it is not known whether it is the seizures, the underlying neurological substrate or a combination that has the largest impact on eventual learning and memory. Teasing out the effects of seizures from pre-existing neurological disorder is critical in developing therapeutic strategies. We therefore investigated the additional cognitive effects of seizures on rodents with malformations of cortical development induced with methylazoxymethanol acetate. Pregnant rats were injected with saline or methylazoxymethanol acetate at embryonic Day 15 or 17 to induce differing malformation severity. From the day of birth to 9 days of age, half the pups received 50 flurothyl-induced seizures. All rats underwent testing in the Morris water maze to test spatial memory at 25 days of age (immediate post-weaning) or during adolescence at 45 days of age. Post-weaning rats had severe spatial cognitive deficits in the water maze and seizures worsened performance. In contrast, in animals tested during adolescence, there was no longer an additional adverse effect of seizures. We also investigated whether the severity of the structural abnormality and seizures impacted brain weight, cortical thickness, hippocampal area and cell dispersion area. The mean brain weight in control animals was greater than in rats exposed to methylazoxymethanol acetate at embryonic Day 17, which was greater than rats exposed to methylazoxymethanol acetate at embryonic Day 15. Rats exposed to methylazoxymethanol acetate at embryonic Day 15 had a thinner cortical mantle compared with rats exposed at embryonic Day 17 and control animals. The hippocampal area was similar in rats exposed at embryonic Days 15 and 17 but was smaller compared with controls. Methylazoxymethanol at embryonic Day 17 caused dispersion of the CA1–4 cell layers in the hippocampus, whereas methylazoxymethanol at embryonic Day 15 caused focal nodules in or above the CA1 layer, but the CA1–4 layers were intact and similar to control. Early-life seizures did not have a significant impact on any of these parameters. These observations indicate that the major factor responsible for the cognitive impairment in the rats with cortical dysplasia was the underlying brain substrate, not seizures. These findings have significant implications for the understanding of cognitive impairments in childhood epilepsy and suggest that early aggressive therapy of seizures alone may not be an adequate strategy for minimizing cognitive effects.
doi:10.1093/brain/awr087
PMCID: PMC3102240  PMID: 21602270
epilepsy; cognitive impairment; cortical dysplasia; cortical malformations; spatial cognition
17.  Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study 
Epilepsia  2008;49(10):1777-1786.
SUMMARY
Purpose
To examine antiepileptogenic and antiictogenic potential of retigabine under conditions of rapid kindling epileptogenesis during different stages of development.
Methods
The experiments were performed in postnatal day 14 (P14), P21 and P35 male Wistar rats. After stereotaxic implantation of hippocampal stimulating and recording electrodes, the effects of retigabine on baseline afterdischarge properties were studied. Next, the animals underwent rapid kindling (sixty 10 second trains, bipolar 20 Hz square wave pulses delivered every five minutes). The progression of seizures (kindling acquisition), and responses to test stimulations after kindling (retention) were compared between retigabine and vehicle-treated rats. Additionally, the effects of retigabine on the severity of seizures in previously kindled animals were examined.
Results
When administered intraperitoneally in doses that induced only mild, or no motor deficits, retigabine significantly dampened brain excitability, evident as the increase of afterdischarge threshold and shortening of afterdischarge duration. During kindling, retigabine delayed the development of focal seizures in P14 rats, and prevented the occurrence of full limbic seizures at all three ages. At P14 and P21, but not at P35, pretreatment with retigabine prevented the establishment of kindling-induced enhanced seizure susceptibility. Administration of retigabine to kindled animals decreased the severity of seizures induced by test stimulation. The effect was most prominent at P14.
Discussion
Retigabine exerted both antiepileptogenic and antiictogenic effects under conditions of rapid kindling model. These effects were apparent during post-neonatal, early childhood and adolescent stages of development.
doi:10.1111/j.1528-1167.2008.01674.x
PMCID: PMC2577127  PMID: 18503560
Antiepileptic drugs; development; epileptogenesis; kindling; retigabine
18.  The mTOR Inhibitor Rapamycin Has Limited Acute Anticonvulsant Effects in Mice 
PLoS ONE  2012;7(9):e45156.
Objective
The mammalian target of rapamycin (mTOR) pathway integrates signals from different nutrient sources, including amino acids and glucose. Compounds that inhibit mTOR kinase activity such as rapamycin and everolimus can suppress seizures in some chronic animal models and in patients with tuberous sclerosis. However, it is not known whether mTOR inhibitors exert acute anticonvulsant effects in addition to their longer term antiepileptogenic effects. To gain insights into how rapamycin suppresses seizures, we investigated the anticonvulsant activity of rapamycin using acute seizure tests in mice.
Methods
Following intraperitoneal injection of rapamycin, normal four-week-old male NIH Swiss mice were evaluated for susceptibility to a battery of acute seizure tests similar to those currently used to screen potential therapeutics by the US NIH Anticonvulsant Screening Program. To assess the short term effects of rapamycin, mice were seizure tested in ≤6 hours of a single dose of rapamycin, and for longer term effects of rapamycin, mice were tested after 3 or more daily doses of rapamycin.
Results
The only seizure test where short-term rapamycin treatment protected mice was against tonic hindlimb extension in the MES threshold test, though this protection waned with longer rapamycin treatment. Longer term rapamycin treatment protected against kainic acid-induced seizure activity, but only at late times after seizure onset. Rapamycin was not protective in the 6 Hz or PTZ seizure tests after short or longer rapamycin treatment times. In contrast to other metabolism-based therapies that protect in acute seizure tests, rapamycin has limited acute anticonvulsant effects in normal mice.
Significance
The efficacy of rapamycin as an acute anticonvulsant agent may be limited. Furthermore, the combined pattern of acute seizure test results places rapamycin in a third category distinct from both fasting and the ketogenic diet, and which is more similar to drugs acting on sodium channels.
doi:10.1371/journal.pone.0045156
PMCID: PMC3440313  PMID: 22984623
19.  Remote effects of focal hippocampal seizures on the rat neocortex 
Seizures have both local and remote effects on nervous system function. While propagated seizures are known to disrupt cerebral activity, little work has been done on remote network effects of seizures that do not propagate. Human focal temporal lobe seizures demonstrate remote changes including slow waves on electroencephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex. Ictal neocortical slow waves have been interpreted as seizure propagation, however we hypothesize that they reflect a depressed cortical state resembling sleep or coma. To investigate this hypothesis, we performed multi-modal studies of partial and secondarily-generalized limbic seizures in rats. Video/EEG monitoring of spontaneous seizures revealed slow waves in the frontal cortex during behaviorally mild partial seizures, contrasted with fast poly-spike activity during convulsive generalized seizures. Seizures induced by hippocampal stimulation produced a similar pattern, and were used to perform functional magnetic resonance imaging (fMRI) weighted for blood oxygenation (BOLD) and blood volume (CBV), demonstrating increased signals in hippocampus, thalamus and septum, but decreases in orbitofrontal, cingulate, and retrosplenial cortex during partial seizures; and increases in all these regions during propagated seizures. Combining these results with neuronal recordings and CBF measurements, we related neocortical slow waves to reduced neuronal activity and cerebral metabolism during partial seizures, but found increased neuronal activity and metabolism during propagated seizures. These findings suggest that ictal neocortical slow waves represent an altered cortical state of depressed function, not propagated seizure activity. This remote effect of partial seizures may cause impaired cerebral functions, including loss of consciousness.
doi:10.1523/JNEUROSCI.2014-08.2008
PMCID: PMC2590649  PMID: 18768701
consciousness; BOLD decreases; cortex; fMRI; slow oscillations; temporal lobe epilepsy
20.  Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents 
Leptin is a hormone that reduces excitability in some hypothalamic neurons via leptin receptor activation of the JAK2 and PI3K intracellular signaling pathways. We hypothesized that leptin receptor activation in other neuronal subtypes would have anticonvulsant activity and that intranasal leptin delivery would be an effective route of administration. We tested leptin’s anticonvulsant action in 2 rodent seizure models by directly injecting it into the cortex or by administering it intranasally. Focal seizures in rats were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. These seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures. Leptin also reduced neuronal spiking in an in vitro seizure model. Leptin inhibited α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor–mediated synaptic transmission in mouse hippocampal slices but failed to inhibit synaptic responses in slices from leptin receptor–deficient db/db mice. JAK2 and PI3K antagonists prevented leptin inhibition of AMPAergic synaptic transmission. We conclude that leptin receptor activation and JAK2/PI3K signaling may be novel targets for anticonvulsant treatments. Intranasal leptin administration may have potential as an acute abortive treatment for convulsive seizures in emergency situations.
doi:10.1172/JCI33009
PMCID: PMC2147669  PMID: 18097472
21.  Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats 
There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium–pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor α (TNFα) antibody and mimicked by intracerebroventricular injection of rat recombinant TNFα. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1β(interleukin-1β) and TNFα] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a long-lasting increase in seizure susceptibility that is strongly dependent on TNFα.
doi:10.1523/JNEUROSCI.1901-08.2008
PMCID: PMC3547980  PMID: 18596165 CAMSID: cams2598
development; lipopolysaccharide; seizure; cytokine; tumor necrosis factor α; interleukin-1β
22.  Seizure Control of Current Shunt on Rats with Temporal Lobe Epilepsy and Neocortical Epilepsy 
PLoS ONE  2014;9(1):e86477.
Purpose
To examine the effects of current shunt on rats with temporal lobe epilepsy and neocortex epilepsy.
Experimental Design
A kainic acid (KA)-induced model of temporal lobe seizure and a penicillin-induced model of neocortical partial seizure were used in this study. Rats of each model were randomly allocated into two groups: control and model groups. The model group was further divided into the KA or penicillin group, sham conduction group and conduction group. The current shunt was realized through the implantation of a customized conduction electrode. After surgery, electroencephalogram (EEG) was recorded for two hours for each rat under anesthesia. Subsequently, the rats were video monitored for 72 h to detect the occurrence of behavioral seizures upon awakening. The average number and duration of seizures on EEG and the number of behavioral seizures were measured.
Results
In KA model, the number of total EEG seizures in conduction group (9.57±2.46) was significantly less than that in sham conduction group (15.13±3.45) (p<0.01). The duration of EEG seizures in conduction group (26.13±7.81 s) was significantly shorter than that in sham conduction group (34.17±7.25 s) (p = 0.001). A significant reduction of behavioral seizures was observed in the conduction group compared with KA (p = 0.000) and sham conduction groups (p = 0.000). In penicillin model, there was a 61% reduction in total EEG seizures in conduction group compared with sham conduction group (p<0.01), and the duration of EEG seizures in conduction group (6.29±2.64 s) was significantly shorter than that in the sham conduction group (12.07±3.81 s) (p = 0.002). A significant reduction of behavioral seizures was observed in conduction group compared with penicillin (p<0.01) and sham conduction groups (p<0.01).
Conclusion
Current shunt effectively reduces the onset and severity of seizures. Current shunt therapy could be an effective alternative minimally invasive approach for temporal lobe epilepsy and neocortex epilepsy.
doi:10.1371/journal.pone.0086477
PMCID: PMC3907408  PMID: 24497949
23.  Increased Seizure Susceptibility and Up-regulation of nNOS Expression in Hippocampus Following Recurrent Early-life Seizures in Rats 
Journal of Korean Medical Science  2010;25(6):905-911.
This study aimed to determine the long-term change of seizure susceptibility and the role of nNOS on brain development following recurrent early-life seizures in rats. Video-EEG recordings were conducted between postnatal days 50 and 60. Alterations in seizure susceptibility were assayed on day 22 or 50 using the flurothyl method. Changes in nNOS expression were determined by quantitative immunoblotting on day 50. On average, rats had 8.4±2.7 seizures during 10 daily 1 hr behavioral monitoring sessions. As adults (days 50-60), all rats displayed interictal spikes in the hippocampus and/or overlying cortex. Brief electrographic seizures were recorded in only one of five animals. Rats appeared to progress from a period of marked seizure susceptibility (day 22) to one of lessened seizure susceptibility (day 50). Up-regulation of nNOS expression following early-life recurrent seizures was observed on day 50. In conclusion, these data suggested that recurrent early-life seizures had the long-term effects on seizure susceptibility late in life and up-regulatory nNOS expression on the hippocampus during brain development, and nNOS appeared to contribute to the persistent changes in seizure susceptibility, and epileptogenesis.
doi:10.3346/jkms.2010.25.6.905
PMCID: PMC2877220  PMID: 20514313
Early-life; Recurrent Seizures; Seizure Susceptibility; nNOS; Epileptogenesis; Hippocampus; Rat
24.  Seizure suppression by EEG-guided repetitive transcranial magnetic stimulation in the rat 
Objective
To test the anticonvulsive potential of a range of repetitive transcranial magnetic stimulation (rTMS) frequencies by novel methods for simultaneous EEG and rTMS in a rat seizure model.
Methods
Seizures were triggered by intraperitoneal kainic acid (KA; 10 mg/kg). Rats (n = 21) were divided into three groups in which individual seizures were treated with rTMS trains at one of three frequencies: 0.25, 0.5 or 0.75 Hz. EEG was continuously viewed by an operator who identified each seizure onset. Consecutive seizures in each animal were (1) treated with active rTMS, (2) treated with sham rTMS, or (3) were untreated. EEG was re-analyzed post hoc by visual inspection, and seizure durations were compared within and between treatment groups.
Results
KA-induced seizures were abbreviated by 0.75 Hz (P = 0.019) and 0.5 Hz (P = 0.033) active EEG-guided rTMS. In contrast, neither active 0.25 Hz rTMS nor the control conditions affected seizure duration (P > 0.2).
Conclusions
We demonstrate that EEG-guided rTMS can suppress seizures in the rat KA epilepsy model, and that the effect is frequency dependent, with 0.75 and 0.5 Hz rTMS being superior to 0.25 Hz rTMS.
Significance
These data support the use of rat seizure models in translational research aimed at evaluation and development of effective rTMS anticonvulsive protocols. We also offer a proof of principle that real-time analysis of EEG can be used to guide rTMS to suppress individual seizures.
doi:10.1016/j.clinph.2008.09.003
PMCID: PMC2668608  PMID: 18977170
Transcranial magnetic stimulation; Seizure; Rat; EEG
25.  Increased GABA-ergic Inhibition in the Midline Thalamus Affects Signaling and Seizure Spread in the Hippocampus-Prefrontal Cortex Pathway 
Epilepsia  2011;52(3):523-530.
Purpose
The midline thalamus is an important component of the circuitry in limbic seizures, but it is unclear how synaptic modulation of the thalamus affects that circuitry. In this study, we wished to understand how synaptic modulation of the thalamus can affect inter-regional signaling and seizure spread in the limbic network.
Methods
We examined the effect of GABA modulation of the mediodorsal (MD) region of the thalamus on responses in the prefrontal cortex (PFC) by stimulation of the subiculum (SB). Muscimol, a GABA-A agonist, was injected into the MD, and the effect on local responses to subiculum stimulation were examined. Evoked potentials were induced in the MD and the PFC by low frequency stimulation of the SB, and seizures were generated in the subiculum by repeated 20 Hz stimulations. The effect of muscimol in the MD on the evoked potentials and seizures was measured.
Key Findings
Thalamic responses to stimulation of the subiculum were reduced in the presence of muscimol. Reduction of the amplitudes of evoked potentials in the MD resulted in an attenuation of the late, thalamic components of the responses in the PFC, as well as of seizure durations.
Significance
Activation of GABA- A receptors in the midline thalamus not only causes changes within the thalamus, but has broader effects on the limbic network. This work provides further evidence that synaptic modulation within the midline thalamus alters system excitability more broadly and reduces seizure activity.
doi:10.1111/j.1528-1167.2010.02919.x
PMCID: PMC3058300  PMID: 21204829
GABA; mediodorsal nucleus; subiculum; prefrontal cortex; seizures; limbic system

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