Temporal Lobe Model

Alumina gel injections into the temporal lobe of rhesus monkeys were used in an attempt to mimic complex partial seizures associated with temporal lobe epilepsy in humans (Ribak et al., 1998). Our analysis is based on injections of alumina gel into several regions of the temporal lobe in rhesus monkeys. Thus structures that were injected include the hippocampus, entorhinal and perirhinal cortices, and the amygdala. In all cases, complex partial and secondarily generalized seizures were...

Summary And Future Prospects

The use of gene targeting (transgenesis, gene knock-outs and knock-ins) to generate mouse models of epilepsy is expanding rapidly. In the years ahead projects will be initiated that aim to generate a wide variety of mutant alleles for each of the estimated approximately 20,000 to 25,000 genes in the mouse genome and to measure all of the associated phenotypes (Austin et al., 2004 Auwerx et al., 2004). Complementary projects will study the expression patterns of all these genes (Su et al., 2002...

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Control animals are maintained under similar conditions but are fed the ISOMIL diet without ethanol. This method can be associated with significant mortality (9-23 N'Gouemo et al., 1996). Alcohol intoxication is initiated by administration of a loading dose of ethanol (1.6g kg 8 , wt vol). Some investigators administer the alcohol dehydrogenase inhibitor pyrazole to enhance and stabilize the blood ethanol concentrations (Goldstein and Pal, 1971). Animals are then placed in a closed...

Metabolic Changes Following Alcohol Withdrawal

Alcohol intoxication decreases local cerebral glucose utilization (LCGU) in many areas of the brain, including the limbic system, cerebellum, and motor system (Eckardt et al., 1992). The most striking effects on LCGU are observed in the IC (Grunwald et al., 1993), in accordance with other evidence indicating that this brain site is a major target of alcohol. Alcohol withdrawal is associated with increased brain glucose uptake, oxygen consumption, and blood flow (Eckardt et al., 1992 Hemmingsen...

Alcohol Withdrawal Seizures

ROGAWSKI Ethyl alcohol (ethanol) is a central nervous system (CNS) depressant that exerts diverse behavioral actions. At low blood concentrations, alcohol produces euphoria and behavioral excitation, and at concentrations greater than 0.08 g dl (17 mM), it significantly impairs motor skills. Concentrations of 0.15 to 0.30 g dl induce acute intoxication, which manifests as drowsiness, ataxia, slurred speech, stupor, and coma. The acute effects of alcohol on brain...

What Types Of Epileptic Activity Can Be Modelled

The organization, generation, and propagation of seizures in temporal lobe epilepsy (TLE) can be understood via the concept of the epileptic zone (Talairach et al., 1974). TLE is indeed a disease (or perhaps a set of disorders) involving neuronal networks within the temporal lobe. In TLE, seizures engage different structures, not only at their onset (ictogen-esis) but also during their course of propagation. Most past studies of TLE have concentrated on the hippocampus as the key structure in...

Specific Culture Methods

CNS neurons can be cultured in a variety of formats, depending on the desired experimental paradigm. For most physiologic experiments, neurons are cocultured with glial cells in a relatively enriched medium (Dichter, 1978). For other experiments neurons can be grown in an almost glial-free environment with carefully controlled and characterized media (Brewer, 1995 Brewer et al., 1993 Evans et al., 1998). Cells can be grown at varying densities, depending on the nature of the experiment to be...

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FIGURE 3 Rhythmic, spindle-shaped discharges induced by a low systemic dose of pentylenetetrazol (PTZ) in a Wistar rat. These discharges with a crescendo-decrescendo pattern were associated with freezing behavior (motionless stare). Electrocorticograms from RF, right frontal (sensorimo-tor) cortex RO, right occipital (visual) cortex LF, left frontal cortex LO, left occipital cortex. zures. Twitches and tonic-clonic seizures are recorded throughout development. However, there is limited...

Neuropathological Effects Of Alcohol Withdrawal

In humans, alcohol withdrawal seizures have been associated with ventricular and sulcal enlargement as well as significantly smaller volume of temporal lobe white matter and hippocampal sclerosis (Essardas-Daryanani et al., 1994). In animal models, there is evidence that alcohol intoxication can lead to selective damage to specific brain regions, including the hippocampus (Ikonomidou et al., 2000 Walker et al., 1980). Withdrawal from long-term alcohol consumption can aggravate alcohol-induced...

Relevance Of Alcohol Withdrawal Seizures In Rodents To The Human Condition

Although alcohol withdrawal seizures in rodents do not represent a perfect model of human alcohol withdrawal seizures, the available evidence indicates that the animal models are valid in many respects. As noted, most alcohol withdrawal seizures in humans are generalized tonic-clonic seizures. Similarly, the various forms of alcohol withdrawal seizures in rodents represent generalized convulsions. In both humans and rodents, the peak incidence of alcohol withdrawal related generalized seizures...

Consequences of Chronic Epileptiform Activity

The severity of hippocampal sclerosis in human autopsy specimens is positively correlated with the number and severity of the patient's seizures. This relationship has engendered considerable discussion about whether hip-pocampal sclerosis is a cause or consequence of epilepsy. We have used cultured hippocampal slices to test the hypothesis that seizure-induced neuronal injury is itself epilepto-genic. We established that chronic epileptiform activity, produced by applying the convulsants...

Caas Craas

Prince, 1978 De Deyn, 1992 Snead, 2002 Depaulis et al 1989 Marescaux, 1992 van Luijtelaar, 2001 Cortez et al 2001 Serbanescu et al 2004 AS, Absence Seizures AY-9944, AY CAAS, Chronic Atypical Absence Seizures CRAAS, Chronic Refractory Atypical Absence Seizures, CTAS, Chronic Typical Absence Seizures GAERS, Genetic Absence Epilepsy Rat from Strasbourg LD, Low Dose PCL, Penicillin PTZ, Pentylenetetrazol TAS, Typical Absence Seizures WAG Rij, rat strain. and the experimental models of typical...

Orthologous Versus Orphan Gene Models Of Epilepsy

In addition to the preceding issue whether to use a gene-driven or phenotype-driven modeling approach there is a parallel question that the genetic modeler must address Which should come first, the human disease or the disease model Despite the attraction of the transgenic approach, if the goal is to obtain a mouse model of human epilepsy, there is significant risk in selecting an engineered model of epilepsy for study. If a gene is deleted and no seizures result in the animal, has the...

Insights Into Human Disorders

Underlying Mechanisms Primary Generalized Epilepsies In both rodent and feline models of absence seizures, the evidence suggests that the mechanisms that underlie the SWD bursts that characterize this seizure type may be related to the thalamocortical mechanism that mediates spindles and recruiting responses (Crunelli and Leresche, 2002). Seizures with SWD complexes preferentially evolve from sleep oscillations. They are initiated in the neocortex and spread to the thalamus after a few seconds...

Methods Of Generation

For the GAERS strain, epileptic rats were first selected from Wistar colonies that displayed spontaneous SWDs on routine cortical EEG. Breeding of selected pairs over three or four generations produced a strain with 100 of rats displaying SWDs (Vergnes et al., 1982 for review, see Danober et al., 1998). A control strain, free of SWD, was also selected over five or six generations. Since then more than 50 generations have been bred (see genetic description later). Through serendipity it was...

Description Of The Model

Zebrafish Well Plate Swim

The clinical significance of any experimental model of epilepsy is limited unless, like humans, a stereotyped set of behavioral changes are observed concomitant with a seizure. Because a wealth of behavioral information is available from the rodent literature, including a detailed and well-accepted set of behavioral seizure stages (Racine, 1972), we began by investigating freely swimming zebrafish larvae exposed to PTZ. One approach to quantify seizure behaviors was to videotape the zebrafish...

In Vitro Models Of Corticocortical Circuitry In Epilepsy

FIGURE 4 Preparation of rat thalamocortical slices. A The brain is placed on a ramp with the caudal end elevated above the rostral end at an angle of 10 degrees. Th, approximate location of the thalamus. B Dorsal view showing angle of initial vertical cut made with a razor blade. C The cut surface of the brain is then glued to the vibratome stage. Horizontal lines indicate the approximate position of collected slices. Typically two or three slices (550-650 mm in thickness) retain full...

Testing Pharmacological Agents In Animal Models Of Alcohol Withdrawal Seizures

Because alcohol withdrawal-related AGS and HIC can be elicited at the will of the experimenter during a defined period after cessation of alcohol intake, the anticonvulsant properties of pharmacologic agents can be easily studied (unlike the situation with spontaneous seizure models, where seizures occur unpredictably, requiring sophisticated monitoring systems and less robust trial designs). A limitation of these models is that AGS or HIC do not occur in every animal. However, the incidence...

Acute Slices

There are multiple variations of preparation techniques for acute slices. The precise method should depend on the purpose of the study and the area of interest. Initially most laboratories used a tissue chopper for cutting the tissue into thin slices later, vibratomes were adopted in many laboratories because they appeared to make slices with less mechanical damage. Efforts have been made to determine which cutting parameters (with the vibratome) are most important for preservation of fine...

Studying Epilepsy Using The Slice Preparation

Many different types of epilepsy exist. Hence multiple models have been developed, for example, partial or generalized epilepsies and convulsive or nonconvulsive epilepsies. A similar diversity of models has been reported using the hippocampal slice preparation (and variations thereon), most focusing on generating activity relevant to TLE. Many different issues can be addressed in the slice preparation. A major area of investigation has been the issue of ictogene-sis, including where ictal...

Low Magnesium Induced Seizure Like Events

Epileptiform activity can be induced in virtually all epilepsy-sensitive regions of the brain by omitting Mg2+ from the ACSF. Induction of this activity depends on increased neuronal excitability resulting from reduced surface charge screening, facilitated transmitter release, and activation of NMDA receptors due to removal of the Mg2+ block of NMDAreceptor-operated ion channels. Initially these events are always sensitive to application of NMDA receptor antagonists, which is consistent with...

In Vitro Models Of Absence Epilepsy

The Ferret Dorsal Lateral Geniculate Nucleus Slice A Model for the Transformation of Spindle Waves into Spike-Wave Discharges A number of thalamic in vitro models have been developed to investigate the mechanisms underlying the generation and spread of spike wave (SW)-like discharges in this brain structure. The ferret primary visual thalamic relay nucleus (dorsal part of the lateral geniculate nucleus, LGNd) and the associated section in the RT nucleus (termed the perigeniculate nucleus, PGN)...

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0 20 0 20 40 60 80 100 FIGURE 7 Quantification of the occurrence of discharges in the hippocampus and neocortex along with behavioral activity and motor seizures after intraperitoneal administration of 14mg kg of kainic acid (KA). Duration of phenomena in seconds was recorded within each 5-minute interval and plotted as a histogram (means from eight rats are shown, standard error of the means were omitted for clarity). Occurrence of discharges prevailed over the occurrence of behavioral...

Summary And Conclusions

The major advantage of the epileptic Papio and GEPRs models is their clearly defined predisposition to convulsive epilepsies and the heritable nature of this predisposition. As in patients with idiopathic generalized epilepsy, the disorder in these genetic models is multigenic rather than monogenic. The epileptic P. papio is a good model of idiopathic secondarily generalized focal seizures that are triggered by flickering light. These mammals appear to have a reduced seizure threshold in both...

Characteristics And Defining Features

Animals demonstrate immobility and some vibrissal twitching. This model appears to be a generalized absence model based on electroclinical correlation however, to date no pharmacologic data support this hypothesis, nor are there ontogeny data or data concerning possible thalamocortical mechanisms in the generation of these discharges. This model differs from others described in this review because THIP-induced absence-like seizures in rats are exacerbated by valproate (Vergnes...

Advantages And Limitations Of The Zebrafish Model

The application of our larval zebrafish model to epilepsy research is probably limited only by one's imagination. As discussed in the previous section, a simple application of this model would be to evaluate drugs useful in generalized epilepsy syndromes. One might also consider forward- and FIGURE 4 Response to antiepileptic drugs. a Representative tectal field recordings obtained from a zebrafish bathed in normal Ringer's medium plus 15 mM pentylenetetrazol (PTZ) (baseline) and 45 minutes...

Outsourcing Mouse Model Production

Two of the most important questions an investigator should ask before committing the significant resources needed to develop a mouse model are, Is the mouse I want to make already available and Should I do some or all of the work in my own laboratory The first question can be much more difficult to answer than it first appears. Although most scientists are familiar with the literature in their own areas of expertise and would probably be aware of a published model, many transgenic and gene...

Methods Of Preparation And Generation Of Epileptiform Discharges

The methods used to isolate and maintain in vitro a guinea pig brain have been extensively described (de Curtis et al., 1991, 1998 Llinas et al., 1981, 1989 Muhlethaler et al., 1993). Young adult guinea pigs weighing 150 to 250g are anesthetized with 70mg kg tiopenthal, administered intraperioneally. A study of the time course of barbiturate washout in this preparation demonstrated that within 1 hour from the in vitro isolation, the brain concentration of the anesthetic measured by...

Induced Seizures In Intact Animals

An Overview of In Vitro Seizure Models In Acute and Organotypic Slices 35 UWE Hf IN IMA NN. OLIVLR KANN ANO SIBASTIAN SCHUCHMANN 10. Pharmacologic Models of Generalized Absence Seizures In Rodents 111 MIGUIL A. CO*tl Z AND O. CARTOt SN LAD Ul 5. The Use of Brain Slice Cultures for the Study of Epilepsy 45 SCOTT M THOMPSON X1ANGCA1 CtLINl DINOCOURT. AND MIOtAtl W NtSlOR 11. Models of Chemically-Induced Acute Seizures 127 6. Hippocampal Slices Designing and Interpreting Studies in Epilepsy...

Conclusion Of Status Epilepyicus

Acute seizures can be induced by administration of chemoconvulsant drugs via different delivery routes sub-Q, IP, IV, ICV, or inhalation . Main categories of convulsant drugs used for the production of acute seizures affect the inhibitory GABA or glycine transmission, affect excitatory amino acid transmission, or act on ACh receptors. The seizures are primarily or secondarily generalized, and some of their behavioral, EEG, metabolic, and neuropathologic features are age specific. An additional...

Characteristic Of The Activity Generated By Human Epileptic Neurons

One important topic in studying human epileptic tissue is whether spontaneous epileptiform network activity is maintained in vitro after tissue excision. Field potential recordings have demonstrated network synchronization as reflected in population spikes Figure 2 . These spontaneous discharges, which resemble epileptiform spikes seen with FIGURE 2 Spontaneous field potential discharges and associated intracellular responses in human neocortical A and subicular B tissue in vitro are sensitive...

Thalamic Thalamocortical and Corticocortical Models of Epilepsy with an Emphasis on Absence Seizures

THOMAS BUDDE, HANS-CHRISTIAN PAPE, SANJAY S. KUMAR, AND JOHN R. HUGUENARD Absence epilepsy is an idiopathic, generalized, and non-convulsive form of epilepsy with an as yet unknown polygenic background for review, see Crunelli and Leresche, 2002 . A typical absence episode consists of a sudden epileptic seizure with severe impairment of consciousness. Although the interictal electroencephalogram EEG appears normal, the ictal EEG is characterized by phases of bilateral, synchronous 2.5- to...

Seizures In Gerbils

The incidence of epilepsy in gerbils from randomly bred colonies and commercial vendors varies between 3 and 98 Theissen et al., 1968 Harriman, 1988 Cutler and MacKintosh, 1989 Bertorelli et al., 1995 . This wide range in seizure incidence may be attributable to genetic differences between colonies or to differences in seizure testing methods. For example, with repeated testing over months, 100 of a large, outbred group of gerbils displayed at least one seizure Scotti et al., 1998 . Some...

Mechanisms of Action of Antiepileptic Drugs

Cultures of mammalian CNS have played a critical role in our modern understanding of the cellular and molecular mechanisms of antiepileptic drugs. Almost all the currently available AEDs were developed based on animal screening models. The mechanisms of action of these drugs were completely unknown when the drugs were introduced, and to some extent these mechanisms remain unknown for several important old and new AEDs. However, we have a sophisticated understanding of the mechanisms by which...

Inhalation Of Convulsant Substances

Inhalation Chamber

Inhalation is a less usual route of delivery for a convul-sant drug. For inhalation, the drug must have some special features, such as easy evaporation at room temperature. This is true for all ether-like substances. Indeed, ethers have excitatory features, reflected in the original classification of ether-induced anesthesia as stage II. However, in most of these drugs, stage III of surgical anesthesia develops quickly and covers the excitatory stage II. Although delivery of inhalatory...

Circuit Behavior and Ictogenesis Do Cell Cultures Exhibit Seizurelike Phenomena

When neurons from cortex or hippocampus are grown in dissociated cell culture, they form extensive synaptic interactions and local circuits. The nature of the circuitry has not been extensively examined, but a few principles have emerged. Neurons in routine high-density culture do not tend to form synapses with neighbors in culture, despite extensive overlap of processes. Instead synapses are formed with more distant targets. When neurons are monitored by intracellular recordings, they tend to...