A.M.L. Coenen

Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats.

Based on the reviewed literature and the data presented in this paper, conclusions can be drawn with respect to the validity of the WAG/Rij strain of rats as a model for absence epilepsy in humans. The view that the WAG/Rij model has “face validity” is supported by the simultaneous presence of clinical and electroencephalographic signs characterizing absences in rat and humans, by the decrease in responsiveness during the presence of spike-wave discharges in both species, by the agreement between model and patient with respect to the preferential occurrences of spike-wave discharges at transitions in states of vigilance, by the corresponding modulation of spike-wave discharges by physical and mental activities in both and, finally, by the fact that in both humans and rats absence epilepsy is inherited. Against this view, however, argue two points. In rats, absences appear after puberty and are maintained during life, while in humans the seizures occur before puberty and then disappear or convert to more serious forms of epilepsy. The second point is the frequency difference of the spikes and waves in the discharge train: 8–10 Hz in the rat and 3 Hz in the human (though there are no a priori reasons why the frequency of spike waves in the burst must be the same in all species). The absence model also has predictive validity, based on pharmacological data that demonstrate the specificity of certain drugs as being effective in convulsive epilepsies and not in absence epilepsy. So far, all drugs affect spike-wave activity the same way in rats and humans, with lamotrigine being, perhaps, the only exception. Furthermore, sleep deprivation is a powerful provocation for the initiation of spike-wave discharges in both rats and humans. Potential explanations for the presence of absence seizures in rats have been found at the levels of activities in networks and nuclei; of neurons, membrane properties, and ion channels; of proteins and enzymes; and, finally, of genes and chromosomes. Further descriptions of the cellular processes can be found extensively in the literature (e.g., McCormick and Contreras, 2001) and those of the thalamo–cortico–thalamic network in this review as well as in others (Avanzini et al., 1999). Considering the extensive involvement of the phenomena under study with theoretical issues such as the relationship between sleep spindles and spike-wave discharges, and the origin of seizure activity, it can be concluded that the model also has construct validity as far as the present neurobiological theories holding for absence epilepsy in humans are concerned. The WAG/Rij model can therefore be recommended for continued use in evaluating antiepileptic drugs for monotherapy and polytherapy, as well as for the toxicological side effects of putative new antiabsence drugs.

Genetic models of absence epilepsy, with emphasis on the WAG/Rij strain of rats

In this review, the main characteristics of genetic models of absence epilepsy, in particular with respect to WAG/Rij rats, are presented. Genetic models are important and relevant, since evidence exists that these models mimic spontaneously occurring human epilepsy more than models in which epilepsy is artificially induced. Genetic models can be divided into models in which seizures are elicited and into those in which epilepsy appears without any sensory stimulation. The majority of genetic models show that absence type of epilepsy; during the last few years, we and others have noticed that rats of various strains exhibit spontaneously occurring spike-wave discharges in the EEG. Among the strains highly affected is the WAG/Rij strain, which is a fully inbred strain. Individuals are homozygous and because of this property, genetic studies are meaningful. Electrophysiological studies have indicated that abnormal discharges in the cortical EEG are generalized and that the hippocampus is not involved. Parts of the thalamus, together with the thalamic reticular nucleus, apparently act as a pacemaker for the abnormal discharges. There is a circadian modulation in the number of spike-wave discharges. Discharges mainly occur during intermediate levels of vigilance such as passive wakefulness and light slow-wave sleep and at transitions of sleep states. Pharmacological studies with clinically effective antiepileptic drugs have shown a close agreement in seizure response between man and rat. Studies with new compounds have emphasized the role of the GABAergic and glutamatergic system in this type of epilepsy. Particularly striking is the role of the GABAergic system. GABA agonists enhance and GABA antagonists reduce the occurrence of spike-wave discharges, which deviates from the effects of GABAergic drugs in non-convulsive epilepsy. Even more striking is the role of the benzodiazepines, generally seen as GABA agonists; these drugs do not act as such in absence epilepsy since they reduce spike-wave discharges. Also good evidence for an involvement of other neurotransmitters such as noradrenaline, dopamine and opioid peptides exists in absence epilepsy. Genetic data obtained from the WAG/Rij model for absence epilepsy show a relatively simple pattern of inheritance with one gene determining whether an individual is epileptic or not, and with other genes regulating the number and duration of seizures. This is in good agreement with the more restricted human data. Cognitive studies have shown two important features of epilepsy in the WAG/Rij strain: modulation of the number of spike-wave discharges by mental or physical activity and on the other hand, the disruption of cognitive activity by spike-wave discharges.(ABSTRACT TRUNCATED AT 400 WORDS)

The WAG/Rij rat model for absence epilepsy: age and sex factors

The effects of age and sex on spontaneously occurring spike-wave complexes in rats of the WAG/Rij strain were studied in 2 experiments. In the first study, 3 independent groups of male rats were tested; the first group at 75 days old, the second at 140 days and the third at 245 days. In the second study, males as well as females were repeatedly tested at the ages of 75, 125 and 175 days. Both experiments indicated an increase with age in the number of spike-waves complexes and in the number of rats with absences. In the second experiment there were no differences detected between males and females at any of the ages. Similarities to and differences with human absence epilepsy are discussed and it is once more concluded that this particular inbred strain may be useful as an additional model of absence epilepsy.

Spike-wave discharges and sleep-wake states in rats with absence epilepsy

The occurrence of spike-wave discharges was studied in relation to the daily fluctuations of vigilance level in rats. Eight rats of the WAG/Rij strain, an animal model for idiopathic generalized epilepsy of the absence type, which were equipped with cortical EEG and nuchal EMG electrodes, served as subjects. It was found that spike-wave discharges predominantly occur during light slow wave sleep and passive wakefulness. REM sleep, active wakefulness, and deep slow wave sleep are less susceptible to the occurrence of spike-wave discharges. Finally, spike-wave discharges tend to prevail in transitional states. A crucial role for the degree of stability of the level of vigilance in the genesis of absence seizures is suggested.

Effects of the GABA-uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behaviour of rats

Effects of the anticonvulsant tiagabine in doses of 1, 3 and 10 mg/kg were investigated on electroencephalogram (EEG), spike-wave discharges and behaviour of WAG/Rij rats. These rats are considered as an animal model of generalized, non-convulsive, absence epilepsy. WAG/Rij rats spontaneously show a considerable number of spike-wave discharges in their EEG. These discharges can be facilitated by GABA agonists. The facilitatory effects of these agonists are completely opposite to their effects on convulsive seizures, which are reduced by these drugs. Tiagabine enhances the effects on the GABA system, since it acts as a GABA re-uptake inhibitor. According to expectations, tiagabine enhanced in a dose-related way both the number and mean duration of spike-wave discharges. The low dose of 1 mg/kg had almost no effects, but doses of 3 and 10 mg/kg were effective. Furthermore, tiagabine in the latter two doses increased the power in the higher beta band of the background EEG, whereas no significant changes in behavioural parameters were found. An unexpected finding was the occurrence of a second type of spike-wave discharges. These were again seen with the two higher doses of tiagabine, while 1 mg/kg had no effect. An assumption is that this second type of discharges are forerunners of genuine spike-wave discharges. In general, this experiment supports that non-convulsive epilepsy is associated with a GABA hyperfunction. It also underlines the biochemical differences of convulsive and non-convulsive animal models of epilepsy. Tiagabine, with its GABA-mimetic properties, belongs to the category of drugs effective in convulsive animal models and not in non-convulsive models of epilepsy.

Stress induced by three procedures of deprivation of paradoxical sleep

Following deprivation of paradoxical sleep, stress, measured in terms of Selyes classical indices as adrenal hypertrophy, thymus atrophy, body weight loss and stomach ulceration, was determined in Wistar rats. Deprivation was induced using three different methods: the classical platform, multiple platform, and pendulum techniques. Four control groups were run. No differences between platform and the pendulum techniques were detected, suggesting that the large behavioural differences commonly found following pendulum and platform deprivation are not caused by differences in stress. Multiple platform deprivation produced less stress than the classical platform technique, a finding presumably due to a reduction of movement restriction in the latter group. In a second experiment rats were food deprived both with or without platform or pendulum techniques. Again no differences between the platform and pendulum groups were detected, again confirming that stress is not a determinant in the platform-pendulum contrast. The results of both experiments strongly suggest that, contrary to intuition, deprivation of paradoxical sleep (by any of the three techniques) induces only mild stress. This is in contrast to food deprivation, which is a greater source of stress. Despite distinct changes in stress measures obtained, in neither experiment could any sign of stomach ulceration be detected. This seems to imply that rats of the Wistar strain are less sensitive to ulceration than strains used by other researchers.

ABSENCE EPILEPSY AND THE LEVEL OF VIGILANCE IN RATS OF THE WAG/RIJ STRAIN

In man, a relationship exists between sleep-wake states and absence epilepsy. During wakefulness, spike-wave discharges predominantly occur when the level of vigilance is not high, while during sleep they have a preference to occur during slow-wave sleep. During this latter type of sleep, spike-wave discharges prevail in periods where slow-wave sleep is light. In a series of experiments, the WAG/Rij rat model for absence epilepsy was characterized with respect to the relationships between the level of vigilance, sleep-wake states and the occurrence of spike-wave discharges. In the first experiment, continuous recordings were made for a period of 48 h and a clear circadian rhythm was established for the number of spike-wave discharges. A maximum appeared during the middle of the dark period of the rat, whereas a minimum was detected directly after the onset of the light period, the time period during which deep slow-wave sleep predominates. The relationship of spike-wave discharges with states of vigilance was elaborated in a second study. Spike-wave discharges were mainly found during light slow-wave sleep, during passive wakefulness and in transition phases from sleep to wakefulness. During REM sleep no spike-wave discharges were found. In the last three experiments, the level of alertness was enhanced by various procedures as photostimulation, a learning task and deprivation of REM sleep. In all cases, an increase of alertness decreased the amount of epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of ketamine on gating of auditory evoked potentials and prepulse inhibition in rats

Abstract Schizophrenic patients suffer from deficits in information processing. Patients show both a decrease in P50 gating [assessed in the conditioning-testing (C-T) paradigm] and prepulse inhibition (PPI), two paradigms that assess gating. These two paradigms might have a related underlying neural substrate. Gating, as measured in both the C-T paradigm (the gating of a component of the auditory evoked potential (AEP)], and PPI can easily be measured in animals as well as in humans. This offers the opportunity to model these information processing paradigms in animals in order to investigate the effects of neurotransmitter manipulations in the brain. In order to validate the animal model for disturbances in AEP gating, d-amphetamine (0.5 and 1 mg/kg, IP) was administered. Gating of an AEP component was changed due to injection of d-amphetamine (1 mg/kg) in the same way as seen in schizophrenic patients: both the amplitude to the conditioning click and the gating were significantly reduced. Next, the effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine (2.5 and 10 mg/kg, IP) was investigated to assess its effects in the two gating paradigms. It was found that ketamine (10 mg/kg) did not affect gating as measured with components of the AEP. However, ketamine (10 mg/kg) disrupted PPI of the startle response to the extent that prepulse facilitation occurred. Firstly, it is concluded that AEP gating was disrupted by d-amphetamine and not by ketamine. Secondly, PPI and the C-T paradigm reflect distinct inhibitory sensory processes, since both paradigms are differentially influenced by ketamine.

Electrophysiological and pharmacological characteristics of two types of spike-wave discharges in WAG/Rij rats

Rats of the WAG/Rij strain are commonly seen as a genetic model for generalised absence epilepsy in man. Interestingly, generalised absence epilepsy shows, in addition to the fully generalised spike-wave discharges, a second type of spike-wave discharge, which lasts for a shorter time, has a lower frequency, and a lower incidence. The originally described distinction between the two types of spike-wave discharges was mainly based on the shape, polarity and duration of the discharges. In the present study other characteristics such as the spatial and temporal distribution of the spike and wave components of the two discharges and frequency spectra were found to differ between the two types. In addition, a reciprocal regulation of the two types of spike-wave discharges by drugs affecting the dopaminergic system (haloperidol and apomorphine) was observed. The results convincingly demonstrate the difference between the two phenomena and warrant the search for neurobiological mechanisms underlying both types of spike-wave discharges.

Circadian rhythmicity in absence epilepsy in rats

In order to study putative time of day effects upon the number and mean duration of spike-wave complexes, 19 rats of the WAG/Rij strain were equipped with cortical EEG electrodes. The EEGs were recorded continuously for 48 h. A cosinor analysis was applied to both the data on each subject and the mean scores of all rats. A definite 24 h rhythm was found for the number of spike-wave complexes occurring each hour. The acrophase appeared during the early hours of the dark period, while the minimum was found to take place immediately after the onset of light. A 24 h rhythm was less prominent for the mean duration of the spike-wave complexes. Finally, there were no differences found between the 2 days of the 48 h registration period, suggesting that the number and duration of the spike-wave complexes found on a given day are representative for the following day.