Vladimir V. Raevsky

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.

Networks constructed of neuroid elements capable of temporal summation of signals

In this chapter some neurobiological premises are presented that permit to simulate correctly neurons, which realize the temporal summation of signals and networks constructed from them. The formalism of these networks is presented that describes their characteristics with respect to the structural multilevel processing of information. It is also shown that such a statistical analysis is used for textual information processing in the program TextAnalyst® (by Microsystems, Moscow), designed for the automatic semantic analysis of texts.

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.

Compensatory Changes in the Brain Dopaminergic System of WAG/Rij Rats Genetically Predisposed to Absence Epilepsy

Involvement of the brain dopaminergic system in the age-related dynamics of absence epilepsy in WAG/Rij rats was examined by histological, immunohistochemical, and electrophysiological (EEG) methods. We revealed reduced expression of dopamine receptors in various brain structures prior to first manifestations of the disease (at the age of 1–3 months), reduced density of neurons in the center of nigrostriatal system (substantia nigra pars compacta) in 10-month-old rats in comparison with 1-month-old rats, and positive correlation between neural density in the substantia nigra and intensity of epileptic activity in EEG. It is hypothesized that loss of dopaminergic neurons and reduced nigrostriatal dopaminergic innervation of the brain could prevent the development of absence epilepsy in WAG/Rij rats.

Sensory information—The major factor of ontogeny

On the basis of their own data the authors postulate that the increase in sensory input during early ontogeny results in a delay in the development of the sensory systems formed earlier. In connection with this, the sensory basis of behavioral patterns becomes ineffective, causing their reorganization and the appearance of new forms of behavior. Limitation of sensory input during the critical periods of development stimulates the accelerated manifestation of behavioral patterns. However, this acceleration also has long-lasting negative effects— alterations in the processes of learning and memory in adult animals.

The Influence of Pre- and Postnatal Factors on Early Behavior Formation

The maternal impact on the early behavioral responses in pups was studied in cross-fostering experiments with the newborn Wistar rats (the primiparous females were fostering the pups born to the females parturiated for the second time and vise versa). The maternal experience had a significant influence on the function development in both pre- and postnatal periods. Specific features of prenatal ontogeny of pups born by experienced females resulted in further, more stable development of the early behavioral responses. In the postnatal period, the maternal experience determined synchronization of the behavioral responses, which promoted the formation of the functional systems important for the newborn survival.

The Responses of Neurons of the Somatosensory Cortex to Stimulation of the Posterior Thalamus (PO) in WAG/Rij Rats Genetically Predisposed to Absence Epilepsy

In genetically predisposed WAG/Rij rats and healthy Wistar rats, we studied functioning of the paralemniscal region of the thalamo-cortical system. The responses of neurons of the somatosensory cortex to single electrical stimulation of the posterior nucleus of the thalamus were recorded in two- to three-monthold rats within the period when the epileptic activity was not developed. We revealed lower number of shortterm inhibitory responses in WAG/Rij rats as compared to Wistar rats. This may create preconditions for the spreading of spike-wave activity in the somatosensory cortex, which is an electrophysiological sign of absence epilepsy.

Lesions of the nucleus basalis magnocellularis do not alter the proportions of pirenzepine- and gallamine-sensitive responses of somatosensory cortical neurones to acetylcholine in the rat

The effects of S-alpha-amino-3-hydroxy-4-isoxozolepropionic acid (AMPA) lesions of the nucleus basalis magnocellularis on the M1/M2 nature of the responses of somatosensory cortical neurones to acetylcholine (ACh) in Sprague-Dawley rats were investigated by iontophoretic application and extracellular single unit recording. The responses were characterised using pirenzepine, an M1 receptor antagonist, and gallamine, an M2 antagonist. Eighty two neurones in control and 94 neurones in lesioned animals were studied. In control animals, 37% of responses to ACh were sensitive to pirenzepine, gallamine or to both antagonists. This increased to 62% in lesioned animals, the proportions of pirenzepine- and gallamine-sensitive responses remaining unchanged. These results provide the first electrophysiological confirmation that both pirenzepine- and gallamine-sensitive (M1 and M2) receptors occur postsynaptic to afferent cholinergic terminals and that their postsynaptic stimulation may produce both inhibition and excitation.

Changes in Sensitivity of Rat Front Cortex Neurons to Acetylcholine (ACh) after α-Amino-3-Hydroxy-4-Isoxozole Propionic Acid (AMPA) Lesions of Nucleus Basalis Magnocellularis and After Embryonic Basal Forebrain Transplants

The effects of unilateral S-AMPA lesions of nucleus basalis magnocellularis (nbm) and of subsequent ipsilateral embryonic basal forebrain transplants on the sensitivity of pyramidal cells in the frontal cortex to iontophorized acetylcholine (ACh) and carbachol were studied in anaesthetized rats. Each drug was applied with an ejection current of 30 nA for 20 s and the average response of 3 applications (separated by 1 min recovery periods) was obtained. Neurons were considered to be sensitive when their firing rate increased or decreased (Wilcoxon, P<0.05), either during or within 20 s of drug application. Neuronal firing rates were significantly reduced in the frontal cortex 8-10 weeks postlesion, when acetylcholinesterase (AChE)positive fibre staining was almost completely absent, but the percentage of ACh-sensitive neurons increased (68/82 neurons from 7 rats compared with 72/144 neurons from 12 control rats, P<0.0001); the duration of ACh’s action also significantly increased. Comparison with controls showed that this enhanced sensitivity to ACh after lesion could be explained solely by an increase in the proportion of neurons excited by ACh (Table 1). The modulatory effects of ACh were also studied on responses of cortical neurons evoked by afferent electrical stimulation (single square wave pulses, 5 ms duration, 1-3 mA, were delivered at intervals of not less than 10 s and 10 stimulations used for each procedure). ACh modulation of neuronal responses evoked by sensory stimulation was not significantly changed after the lesion. Sensitivity to carbachol and glutamate was unchanged after lesion. In normal rats, acute administration of an AChE-inhibitor, di-isopropyl fluorophosphate (DFP) significantly increased the frontal cortex neurons’ responsiveness to ACh from 50% in the control group to 87.4% in the DFP treated group (P<0.0001). DFP also decreased the latency and increased the duration of ACh action without changing the frontal cortex firing rate. The sensitivity of frontal cortex to carbachol and glutamate was not changed after DFP. Chronic administration of scopolamine (10 mg/kg s.c. in 0.9% NaC1 daily for 16 days) significantly increased the sensitivity of frontal cortex neurons to both ACh and carbachol. It also significantly increased the neuronal firing rate, prolonged the duration of ACh and carbachol action and decreased the latency of action of both drugs. In contrast, chronic administration of oxotremorine (0.5 mg/kg s.c. in 0.9% NaC1 twice daily for 11 days and 10 mg/kg in sesame oil for 9 days) significantly decreased the frontal cortex neurons’ sensitivity to both ACh and carbachol. It also significantly decreased the neuronal firing rate, decreased the duration and increased the latency of ACh and carbachol action. Cholinergic-rich transplants to the frontal cortex normalised neuronal sensitivity to ACh and its duration of action but did not restore the firing rate. Non-cholinergic transplants or cholinergie-rich transplants to the somatosensory cortex were ineffective. Histological examination showed a sprouting of ChAT and AChE from the transplant into the neocortex of