G.D. Kuznetsova

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.

Spike-wave discharges are necessary for the expression of behavioral depression-like symptoms

Purpose:  The WAG/Rij strain of rats, a well‐established model for absence epilepsy, has comorbidity for depression. These rats exhibit depression‐like behavioral symptoms such as increased immobility in the forced swimming test and decreased sucrose intake and preference (anhedonia). These depression‐like behavioral symptoms are evident in WAG/Rij rats, both at 3–4 and 5–6 months of age, with a tendency to aggravate in parallel with an increase in seizure duration. Here we investigated whether the behavioral symptoms of depression could be prevented by the suppression of absence seizures.

Some peculiarities of time-frequency dynamics of spike-wave discharges in humans and rats

OBJECTIVE Time-frequency dynamics of spike-wave discharges (SWDs) were investigated in patients with absence seizures and in WAG/Rij rats, a genetic model of absence epilepsy using a specially developed wavelet transform. METHODS Two types of SWDs were analyzed in both species: the most frequently occurring discharges (of minimal 3.6-4.0 s or more) and shorter ones recorded from various cortical regions. RESULTS The more prolonged discharges had two phases: during the initial part (from tenth of seconds to 1 s) of the seizure the frequency decreased quickly from 5 to 3.5 Hz in patients and from about 15 to 10 Hz in rats. A slower frequency decrease with periodical fluctuations was observed in both species during the second part of the discharge: the frequency decreased towards the end of the discharge to 3 Hz in patients and to 6-7 Hz in rats. The frequency of the short discharges decreased fast during the whole discharge: from 5 to 2-2.5 Hz and from about 15 to 5 Hz in patients and rats, respectively. CONCLUSIONS Comparison of data obtained in patients with typical absence epilepsy and WAG/Rij rats with genetic absence epilepsy revealed that the time-frequency dynamics of SWDs had similar properties but in a different frequency range. SIGNIFICANCE The study of time-frequency dynamics using this specially developed wavelet transform revealed two different types of SWDs, which most likely represent different dynamics in the cortico-thalamo-cortical loop during shorter and more prolonged discharges.

Generalized absence epilepsy and catalepsy in rats

Adult WAG/Rij rats are considered adequate genetic models for human generalized absence epilepsy. Rats of this strain of 8, 12, and 18 weeks old and age-matched control Wistar rats were exposed to sound stimulation. After offset of stimulation, all WAG/Rij rats showed cataleptic or even cataplexic reactions, which could persist for up to 20 min. Age effects could be demonstrated. None of the Wistar rats showed cataleptic reactions. Electroencephalographic studies in WAG/Rij rats of 21 weeks showed that spike-wave discharges were abundantly present in the background electroencephalogram prior to sound stimulation. Age-matched Wistar rats had almost no spike-wave discharges. Spike-wave discharges in WAG/Rij rats disappeared during sound stimulation and were then increased compared to the prestimulation and stimulation periods. The electroencephalogram during the cataleptic state was also characterized by the presence of large amplitude 2 Hz waves, interspersed with spike-wave discharges. The data suggest that the cataleptic state can be elicited in genetically epilepsy-prone rats. The youngest WAG/Rij rats showed no spike-wave discharges during the cataleptic state. In all, the data suggest that epilepsy-prone animals are sensitive for catalepsy at an age at which the EEG signs of generalized absence epilepsy are not yet manifest.

The brain 5HTergic response to an acute sound stress in rats with generalized (absence and audiogenic) epilepsy

The brain serotoninergic (5HTergic) system of epileptic subjects can influence their vulnerability to stress. We studied the putative dependency of 5HT neurotransmission parameters on emotional stress, and the presence, types and severity of seizures using rats with genetic generalized (absence and/or audiogenic) epilepsy, of WAG/Rij and Wistar strains. The animals were stressed by exposure to a short aversive noise or left without sound stimulation. Tissue concentrations of 5HT, tryptophan (TRT) and 5-hydroxyindolacetic acid (5HIAA) were assessed by HPLC. The stressor activated the 5HTergic system within thalamus (5HIAA elevated), frontal cortex (5HT, TRT elevated), hypothalamus (increased TRT) in all rats. However, the normal (non-epileptic) rats displayed the highest response in the frontal cortex and the lowest one in the thalamus, as compared to the epileptic rats. Absence-epileptic rats exhibited higher thalamic 5HIAA increase than their controls. Significant correlations existed between propensity of absence epilepsy and 5HTergic parameters measured in the cortex and hypothalamus of absence-epileptic rats. No major difference was found between groups with and without audiogenic epilepsy. The results imply that the stress response depends on the presence of epileptic pathology and the seizure type and severity. The brain 5HT may be involved in the control of the paroxysms and behaviour in absence-epileptic subjects.

Unilateral cortical spreading depression is an early marker of audiogenic kindling in awake rats

Spreading depression (SD), a self-propagating wave of reversible cellular depolarization, is thought to play an important role in brain pathophysiology. SD and seizures are closely related events but little is known about involvement of SD in chronic epileptogenesis. Here we show that cortical SD is the first and highly reproducible manifestation of audiogenic kindling induced by repeated sound stimulation of WAG/Rij rats with genetic audiogenic and absence epilepsy. Repetition of sound-induced running seizures in freely moving rats led to an appearance and gradual intensification of post-running facial and forelimb clonic convulsions coupled with afterdischarge in the fronto-parietal cortex. Before the development of these traditional manifestations of audiogenic kindling, an unilateral cortical SD wave began to be triggered by audiogenic seizures. Once cortical SD appeared, it became a permanent component of subsequent seizures. SD was always recorded in the hemisphere ipsilateral to the running direction. Only at the late stages of audiogenic kindling SD developed bilaterally. To estimate the contribution of SD in postictal effects of audiogenic seizures, we compared cortical activity after seizures induced SD or not. It was found that only seizures with cortical SD were followed by postictal suppression of spontaneous spike-wave discharges displayed by WAG/Rij rats. The results show that (1) cortical SD is readily triggered by brief sensory-induced seizures in awake animals; (2) SD may be responsible for postictal changes in cortical activity; (3) unilateral initiation of SD suggests asymmetrical recruitment of the cortex into seizure network during audiogenic kindling.

Unilateral cortical spreading depression induced by sound in rats

Cortical spreading depression (SD) is thought to underlie the migraine aura but the mechanisms of triggering SD in the human cortex remain unknown. Because growing evidence points to a key role of brainstem circuits in initiating migraine attacks, the present study examined whether recurrent episodes of brainstem activation in rats could induce cortical SD. Explosive running elicited by sounds in rodents with inherited hypersensitivity to acoustic stimuli (reflex audiogenic epilepsy), is known to reflect a transient aberrant activation of the brainstem. Repeated induction of such audiogenic responses enhances the excitability of the cortex, culminating in its epileptic activation (audiogenic kindling). In Wistar rats with inherited hypersensitivity to sounds, 15 brief episodes of running were induced by sound stimulation, and slow potential shifts as well as the EEG were recorded in the cortex. Single unilateral SD began to occur in the cortex following a running episode after the 5th to 15th test (mean 9.4+/-1.2). Once appeared, SD was regularly recorded in subsequent tests. The side of the SD initiation closely correlated with the direction of running. Triggering SD was not associated with epileptic activation of the cortex in most rats. The present findings suggest that the sensory-induced brainstem excitation could be a potent trigger of SD in the hyperexcitable cortex, providing an experimental evidence of a possible causative role of the brainstem activation in initiating the migraine aura.

Vigabatrin in low doses selectively suppresses the clonic component of audiogenically kindled seizures in rats

Summary:  Purpose: The effect of systemic administration of the γ‐aminobutyric acid (GABA)‐transaminase inhibitor vigabatrin (VGB) on different components of convulsions was tested in the model of audiogenically kindled seizures, which consist of brainstem (running, tonus) and forebrain (clonus) elements.

Brain histamine in the WAG/Rij rat, an animal model of absence epilepsy

The involvement of brain histamine in epileptogenesis has been studied in convulsive epilepsies [1], but not non-convulsive ones. As histamine controls the arousal maintenance, it possibly has a role in “paroxysmal loss of consciousness” (absence epilepsy) [2]. We have used the WAG/Rij rat strain as a model for absence epilepsy. This brain pathology manifests as spike-wave discharges (SWDs) in EEGs. Up to 95% of WAG/Rij rats display SWDs, mostly during passive awake or slow-wave sleep states. Minor behavioral changes, and unresponsiveness to external stimuli accompany SWDs [3, 4]. Additionally, about 30% of WAG/Rij rats show audiogenic convulsions, thus being a model for mixed epilepsy (absence epilepsy and audiogenic epilepsy).

Metoprine induced behavioral modifications and brain regional histamine increase in WAG/Rij and Wistar rats

The effects of metoprine, an inhibitor of histamine N-methyltransferase, on open field activity and brain regional histamine (HA) content were examined in rats with mixed, absence and audiogenic, epilepsy (WAG/Rij-AGS), rats with audiogenic epilepsy (Wistar-AGS) and in non-epileptic control rats (Wistar-nAGS). HA content was increased by metoprine (20mg/kg, i.p.) in the cortex, striatum, thalamus, hypothalamus and hippocampus of the rats from all three tested groups. However, WAG/Rij rats showed a lower rate of metoprine-induced HA accumulation in the striatum and thalamus than Wistar rats. For the open field test, the main effect of metoprine (20mg/kg, i.p.) was a general increase of locomotor activity although distinctive features, such as hyperlocomotion and exaggerated sniffing, were characteristic for the epileptic rats (WAG/Rij-AGS and Wistar-AGS, respectively). Individual rats from all the groups showed stereotyped behavior of shuttle type and head bobbing. Electroencephalographic data obtained in WAG/Rij-AGS rats confirmed that metoprine-induced behavioral activation was accompanied by suppression of spike-wave discharges, the main hallmark of absence seizures. Taken together, these results show that inhibition of the histamine catabolism may induce motor activation of particular patterns in epileptic rats and provoke stereotyped behavior.