Spike-wave seizures, slow-wave sleep EEG and morphology of substantia nigra pars compacta in WAG/Rij rats with genetic predisposition to absence epilepsy.

Spike-wave discharges (SWDs) are EEG hallmarks of absence epilepsy, and they spontaneously appear in adult WAG/Rij rats. SWDs are known to be vigilance-dependent and are modulated by monoaminergic mechanisms. It is also known that loss of neurons in the center of the nigrostriatal dopamine system, substantia nigra pars compacta (SNc), is associated with a variety of sleep disorders. We hypothesized that a disorder of the nigrostriatal dopamine system described for WAG/Rij rats might facilitate generation of SWDs through changes in vigilance state and the quality of sleep. Our study was conducted in 'epileptic' and 'non-epileptic' phenotype (less than 1 SWDs per h). Analysis included (1) EEG examination, i.e., analysis of SWDs, rudimentary SWDs and slow wave sleep EEG and (2) microstructural examination of SNc, i.e., measuring its size and the number of neurons and glial cells. No differences in size and cellular content of SNc were found between 'epileptic' and 'non-epileptic' phenotypes. Meanwhile in 'epileptic' subjects, the number of SWDs correlated with the number of neurons in SNc (SWDs more frequently occurred in subjects with fewer neurons in SNc). Rudimentary SWDs were found in both phenotypes. No differences in number and duration of rudimentary SWDs were found between 'epileptic' and 'non-epileptic' phenotypes. Spike-wave EEG activity showed strong association with the number of neurons in SNc: subjects with fewer neurons in SNc were characterized by higher number of SWDs and longer rudimentary SWDs. In sum, our data suggested that intense epileptic EEG activity (in the form of SWDs and rudimentary SWDs) might lead to sleep disruption. However, the lack of direct correlations between sleep parameters and SWDs number indicated that the link between sleep features, SNc cellularity and spike-wave EEG activity could be more complex than we had expected.

Maternal care affects EEG properties of spike-wave seizures (including pre- and post ictal periods) in adult WAG/Rij rats with genetic predisposition to absence epilepsy.

WAG/Rij rats have a genetic predisposition to absence epilepsy and develop spontaneous spike-wave discharges in EEG during late ontogenesis (SWD, EEG manifestation of absence epilepsy). Changes in an environment during early postnatal ontogenesis can influence the genetically predetermined absence epilepsy. Here we examined the effect of maternal environment during weaning period on the EEG manifestation of absence epilepsy in adulthood. Experiments were performed in the offspring of WAG/Rij and Wistar rats. The newborn pups were fostered to dams of the same (in-fostering) or another strain (cross-fostering). Age-matched control WAG/Rij and Wistar rats were reared by their biological mothers. Absence seizures were uncommon in Wistar and were not aggravated in both in- and cross-fostered groups. In WAG/Rij rats, fewer SWD were found in the cross-fostered as compared to the in-fostered group. The cross-fostered WAG/Rij rats showed higher percentage of short-lasting SWD with duration <2s. The mean frequency of EEG at the beginning of SWD in the cross-fostered WAG/Rij rats was lower than in control (8.82 vs 9.25Hz), but it was higher in a period of 1.5s before and after SWD. It was concluded that a healthier maternal environment is able to alleviate genetically predetermined absence seizures in adulthood through changes in EEG rhythmic activity.

Reduction of epileptic spike-wave activity in WAG/Rij rats fostered by Wistar dams.

In WAG/Rij rat genetic model of absence epilepsy, the first spike-wave discharges (EEG hallmark of absence epilepsy) are known to appear after puberty, and their incidence increases with age. WAG/Rij rats are known to have a genetic predisposition to absence epilepsy, and further development of epilepsy might be influenced by epigenetic factors. This preliminary study examined the effect of early postnatal factors on the incidence of epileptic spike-wave discharges in adulthood. The newborn WAG/Rij rats were fostered by Wistar dams (from birth throughout the weaning age), and their EEG was examined continuously from 5 to 13 months of age. It was found that the number and duration of absence seizures was reduced in WAG/Rij rats adopted by Wistar dams as compared with the age-matched control WAG/Rij rats nursed by their own mothers. These data indicate that natural (epigenetic) factors, such as maternal care during suckling period, affect development of seizure activity in genetically prone subjects. It is suggested that improvement of primarily care-giving environment in subjects with genetic predisposition to absence epilepsy is a way to reduce epileptic activity in later life.

Cellular neuropathology of absence epilepsy in the neocortex: a population of glial cells rather than neurons is impaired in genetic rat model.

It is well accepted that absence epilepsy is not accompanied by structural brain abnormalities. In the present report, we challenged this view based on microscopic analysis of neocortex in a genetic model of absence epilepsy, WAG/Rij rats. Density of neurons and glial cells was measured in the motor, somatosensory and cingular cortical areas in epileptic WAG/Rij rats and in non-epileptic control ACI rats. More extensive and significant differences between two strains were found in a population of glial cells and less significant - in neurons. In contract to ACI rats, WAG/Rij rats showed (1) a deficit of glial cells and a lower glia-neuron index in the somatosensory and cingulate areas (deep layers); (2) a reduced number of neurons locally in the motor cortex. The somatosensory cortex (deep layers) is known to play a key role in triggering of epileptic discharges, and an impairment of glia-neuron interactions in this area might underlie pathological processes in a primary epileptic focus. In the motor cortex, epileptiform activity is known to reach the highest amplitude, and this may cause or result from a deficit of neurons. Our data suggest the critical role of glial cells and glia-neuron interactions in pathogenesis of absence epilepsy.