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.
Methods:   Ethosuximide (ETX; 300 mg/kg/day, in the drinking water) was chronically applied to WAG/Rij rats from postnatal day 21 until 5 months. Behavioral tests were done before the cessation of the treatment. Electroencephalography (EEG) recordings were made before and after cessation of treatment to measure seizure severity at serial time-points.
Results:   ETX-treated WAG/Rij rats exhibited no symptoms of depression-like behavior in contrast to untreated WAG/Rij rats of the same age. Moreover, treated WAG/Rij rats did not differ from control age-matched Wistar rats. ETX treatment led to almost complete suppression of spike-wave discharges (SWDs) in 5–6 month old WAG/Rij rats. Discontinuation of chronic treatment was accompanied by a gradual emergence of SWDs; however, a persistent reduction in seizure activity was still present 47 days after discontinuation of the chronic treatment.
Discussion:   The results suggest that seizure activity is necessary for the expression of depression-like behavioral symptoms and confirm that epileptogenesis can be prevented by early and chronic treatment.     

Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures

Neocortical networks play a major role in the genesis of generalized spike-and-wave (SW) discharges associated with absence seizures in humans and in animal models, including genetically predisposed WAG/Rij rats. Here, we tested the hypothesis that alterations in GABA(B) receptors contribute to neocortical hyperexcitability in these animals. By using Real-Time PCR we found that mRNA levels for most GABA(B(1)) subunits are diminished in epileptic WAG/Rij neocortex as compared with age-matched non-epileptic controls (NEC), whereas GABA(B(2)) mRNA is unchanged. Next, we investigated the cellular distribution of GABA(B(1)) and GABA(B(2)) subunits by confocal microscopy and discovered that GABA(B(1)) subunits fail to localize in the distal dendrites of WAG/Rij neocortical pyramidal cells. Intracellular recordings from neocortical cells in an in vitro slice preparation demonstrated reduced paired-pulse depression of pharmacologically isolated excitatory and inhibitory responses in epileptic WAG/Rij rats as compared with NECs; moreover, paired-pulse depression in NEC slices was diminished by a GABA(B) receptor antagonist to a greater extent than in WAG/Rij rats further suggesting GABA(B) receptor dysfunction. In conclusion, our data identify changes in GABA(B) receptor subunit expression and distribution along with decreased paired-pulse depression in epileptic WAG/Rij rat neocortex. We propose that these alterations may contribute to neocortical hyperexcitability and thus to SW generation in absence epilepsy.     

Comparison of the antiepileptogenic effects of an early long‐term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy

Purpose: Epilepsy is a heterogeneous syndrome characterized by recurrent, spontaneous seizures; continuous medication is, therefore, necessary, even after the seizures have long been suppressed with antiepileptic drug (AED) treatments. The most disturbing issue is the inability of AEDs to provide a persistent cure, because these compounds generally suppress the occurrence of epileptic seizures without necessarily having antiepileptogenic properties. The aim of our experiments was to determine, in the WAG/Rij model of absence epilepsy, if early long‐term treatment with some established antiabsence drugs might prevent the development of seizures, and whether such an effect could be sustained. Methods: WAG/Rij rats were treated for ～3.5 months (starting at 1.5 months of age, before seizure onset) with either ethosuximide (ETH; drug of choice for absence epilepsy) or levetiracetam (LEV; a broad‐spectrum AED with antiabsence and antiepileptogenic properties). Results: We have demonstrated that both drugs are able to reduce the development of absence seizures, exhibiting antiepileptogenic effects in this specific animal model. Discussion: These findings suggest that absence epilepsy in this strain of rats very likely follows an epileptogenic process during life and that early therapeutic intervention is possible, thereby opening a new area of research for absence epilepsy and AED treatment strategies.     

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

The WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current–deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial ‘insult’ responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then non-genetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.     

Amygdala kindling in the WAG/Rij rat model of absence epilepsy

PURPOSE: The kindling model in rats with genetic absence epilepsy is suitable for studying mechanisms involved in the propagation and generalization of seizure activity in the convulsive and nonconvulsive components of epilepsy. In the present study, we compared the amygdala kindling rate and afterdischarge characteristics of the nonepileptic Wistar control rat with a well-validated model of absence epilepsy, the WAG/Rij rat, and demonstrated the effect of amygdala kindling on spike-and-wave discharges (SWDs) in the WAG/Rij group. METHODS: Electrodes were stereotaxically implanted into the basolateral amygdala of rats for stimulation and recording and into the cortex for recording. After a recovery period, the animals were stimulated at their afterdischarge thresholds. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated by using Racine's 5-stage scale. RESULTS: All nonepileptic control and four of seven WAG/Rij animals reached a stage 5 seizure state, whereas three animals failed to reach stage 3, 4, or 5 and stayed at stage 2 after application of 30 stimulations. Interestingly, WAG/Rij rats, resistant to kindling, demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation than did the kindled WAG/Rij animals. Additionally, the cumulative total duration and the number of SWDs after the kindling stimulation were statistically increased compared with SWDs before kindling stimulation. CONCLUSIONS: The results of our study demonstrate that the progress of amygdala kindling is changed in rats with genetic absence epilepsy, perhaps as a consequence of the hundreds of daily SWDs.     

Vigabatrin has antiepileptogenic and antidepressant effects in an animal model of epilepsy and depression comorbidity

To evaluate the effects of Vigabatrin (VGB) treatment, on both absence seizure and depressive-like behaviour development in the WAG/Rij rat model of absence seizures. Early long-term treatment with VGB could alter the development of absence pathology, by significantly reducing seizure generation and synchronization in contrast to its pro-absence effects observed after acute or subchronic administration. We have demonstrated the antidepressant effects of a sub-chronic treatment with VGB in both wistar and WAG/Rij rats. In contrast, following an early long-term treatment, VGB antidepressant effects were only observable in WAG/Rij rats. In conclusion, VGB has antiepileptogenic and antidepressant properties in the WAG/Rij rat model despite its pro-absence effects suggesting that epilepsy and depression, in this animal model, are directly related and that seizure development inhibition also reduces the development of depressive behaviour.     

Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenic seizures

Some rats of the WAG/Rij (Wistar Albino Glaxo from Rijswijk) and Wistar strain are susceptible for audiogenic (convulsive) seizures. In the present study, behavior of susceptible and non-susceptible rats from the WAG/Rij strain, genetically predisposed to absence epilepsy, and outbred Wistar strain, genetically not predisposed to absence epilepsy, was compared to assess the level of anxiety (in the open field, light-dark choice and elevated plus-maze tests) and the level of depression (in the sucrose consumption and forced swimming tests). Increased level of anxiety was found only in audiogenic susceptible rats both from WAG/Rij and Wistar strain, but increased level of depression was found only in WAG/Rij rats independently of their susceptibility to audiogenic seizures. The results suggest that enhanced level of depression in WAG/Rij strain rats is associated with absence epilepsy but enhanced level of anxiety with susceptibility to audiogenic seizures.     

Mixed forms of epilepsy in a subpopulation of WAG/Rij rats

Mixed forms of epilepsy in patients are often refractory. Therefore, animal models of comorbid convulsive and nonconvulsive seizure are needed for experimental research. Susceptibility to audiogenic convulsions was studied in a large group of young and adult WAG/Rij rats with inherited absence epilepsy. In 30% of adult rats, sound stimulation provoked audiogenic seizures of moderate intensity. The seizures had two excitation periods separated by a remarkably stable "arrest" of paroxysmal movements. Up to 20% of young WAG/Rij rats were also susceptible to audiogenic seizures, with a longer latency, lower intensity, and more simple seizure patterns. No difference in manifestations of spike-wave discharges was observed between the WAG/Rij rats with and without audiogenic seizures. This subpopulation of WAG/Rij rats genetically predisposed to absence and audiogenic seizures is proposed as an animal model suitable for investigation of basal mechanisms and pharmacological profiles of this mixed form of epilepsy.     

Distribution of D1-like and D2-like dopamine receptors in the brain of genetic epileptic WAG/Rij rats

The densities of the dopamine (DA) D1-like and D2-like receptors were studied by autoradiography in brain regions of rats with (WAG/Rij strain) and without (ACI strain) genetic absence epilepsy. The core of the nucleus accumbens in WAG/Rij rats had a lower density of D1-like receptors than in ACI rats, a reduction of both D1-like and D2-like DA receptors was also found for the dorsal striatum (dorsal caudate-putamen). On the other hand, the density of D2-like receptors was higher in cortical (frontal and parietal) regions and lower in the CA3 region of the hippocampus of WAG/Rij, as compared to ACI rats. These results give new information about possible malfunction of the brain dopaminergic system in the WAG/Rij rat model of absence epilepsy. It seems that there are differences between WAG/Rij and other models of absence epilepsy, especially concerning the role of striatum.     

The Effect of Generalized Absence Seizures on the Progression of Kindling in the Rat

Summary:  The involvement of the thalamus in limbic epileptogenesis has recently drawn attention to the connectivity between the nuclei of the thalamus and limbic structures. Thalamo-limbic circuits are thought to regulate limbic seizure activity whereas thalamocortical circuits are involved in the expression and generation of spike-and-wave discharges (SWDs) in the absence epilepsy models. Genetic Absence Epilepsy Rats From Strasbourg (GAERS) and WAG/Rij (Wistar Albino Glaxo from Rijswijk) are well-defined genetic animal models of absence epilepsy. We aimed to examine the duration of behavioral changes in the kindling process and the relation of SWD activity to the kindling progress in the GAERS and WAG/Rij animals. Electrodes were stereotaxically implanted into the basolateral amygdala and the cortex of rats for stimulation and recording. The animals were stimulated at the threshold for producing afterdischarges. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated using Racine's 5-stage scale. None of the GAERS animals reached stage 3, 4, or 5 after application of 30 stimulations. The WAG/Rij animals showed different rate of kindling, therefore they were further categorized into the kindling-resistant, slow-kindled, and rapid-kindled groups. The kindling-resistant animals demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation and shorter duration of afterdischarge than did the kindled WAG/Rij animals. Behavioral durations at stage 2 were longer in kindled Wistar and WAG/Rij animals compared to kindling-resistant WAG/Rij and GAERS. These results suggest that mechanisms involved in the generation of SWDs act as a counterbalance to the excitability induced by kindling.     

Diminution of the NMDA receptor NR2B subunit in cortical and subcortical areas of WAG/Rij rats

Modulation of glutamatergic NMDA receptors affects the synchronization of spike discharges in in WAG/Rij rats, a valid genetic animal model of absence epilepsy. In this study, we describe the alteration of NR_2B subunit of NMDA receptors expression in WAG/Rij rats in different somatosensory cortical layers and in hippocampal CA1 area. Experimental groups were divided into four groups of six rats of both WAG/Rij and Wistar strains with 2 and 6 months of age. The distribution of NR_2B receptors was assessed by immunohistochemical staining in WAG/Rij and compared with age‐matched Wistar rats. The expression of NR_2B subunit was significantly decreased in different somatosensory cortical layers in 2‐ and 6‐month‐old WAG/Rij rats. In addition, the distribution of NR_2B in hippocampal CA1 area was lower in 6‐month‐old WAG/Rij compared with age‐matched Wistar rats. The reduction of NR_2B receptors in different brain areas points to disturbance of glutamate receptors expression in cortical and subcortical areas in WAG/Rij rats. An altered subunit assembly of NMDA receptors may underlie cortical hyperexcitability in absence epilepsy. Synapse 67:839–846, 2013 . © 2013 Wiley Periodicals, Inc.     

Neonatal tricyclic antidepressant clomipramine treatment reduces the spike-wave discharge activity of the adult WAG/Rij rat

Recently it was revealed that the absence-like epileptic activity of the WAG/Rij (Wistar Albino Glaxo/Rijswijk) rat is associated with depression-like behavioural symptoms. Whether these depressive-like symptoms are accompanying epileptic activity (manifested in spike-wave discharges, SWDs, in the EEG) or whether they are causative for each other are open questions. Neonatally administered tricyclic antidepressant clomipramine is a well characterized animal model of major depression. It evokes behavioural symptoms of depression and changes sleep pattern in normal adult rats. We investigated whether in the WAG/Rij rat the neonatally administered clomipramine would aggravate the depression-like behavioural symptoms and the SWD activity. Male WAG/Rij pups from postnatal day 8 (PD8) to PD21 were treated with clomipramine (20mg/kg) or saline (control animals) twice daily intraperitoneally (i.p.). In the 8 months old rats, sleep parameters and sucrose solution intake (as hedonic index) as well as the SWD activity were measured. While the neonatal clomipramine treatment significantly increased the rapid eye movement sleep (REM) amount and decreased the sucrose preference score, it surprisingly attenuated the adult (8 months old) SWD activity. We concluded that neonatal clomipramine treatment produced aggravation of depression-like symptoms while decreased the SWD activity in the adult (8 months old) WAG/Rij rat.     

Convulsive and nonconvulsive epilepsy in rats: effects on behavioral response to novelty stress

Behavioral response to a new environment of Wistar and WAG/Rij rats with absence and/or audiogenic seizures (AGSs) was investigated. Behavior was observed in open-field (OF) and light-dark choice (LD) tests. Correlations of test performance with seizure parameters were evaluated. AGS-susceptible Wistar rats exhibited reduced exploration (rearing) in both tests and a tendency toward hyperlocomotion in the OF test. Genetically absence-epileptic WAG/Rij rats demonstrated agitation (increased vertical/horizontal locomotion, enhanced defecation/urination) in the LD test, whereas they exhibited reduced exploration, increased grooming, and hyperlocomotion in the OF test. Anxiety level, as estimated by grooming time in the OF test and latency to first "risk assessment" in the LD test, correlated positively with the propensity for absence seizures in WAG/Rij rats not susceptible to AGSs. It can be concluded that the behavioral response to novelty stress in epileptic subjects depends on the type and severity of seizures.     

Audiogenic kindling in Wistar and WAG/Rij rats: kindling-prone and kindling-resistant subpopulations

Purpose: Audiogenic kindling (AK) is a model of naturally occurring epileptogenesis triggered by repeated sound stimulation of rats genetically prone to audiogenic seizures. It is accepted that limbic seizure networks underlie progressive changes in behavioral seizure pattern during AK. The present study investigated AK progression in rats susceptible and unsusceptible to absence seizures. Methods: Progression of AK as indicated by an appearance and intensification of limbic clonus was examined in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats with genetic absence epilepsy and in Wistar rats. Results: Subpopulations of kindling‐prone and kindling‐resistant rats were found in both Wistar and WAG/Rij strains. Despite identical seizure responses to the first sound stimulation, AK progression dramatically differed between the two subpopulations. AK‐prone rats exhibited rapid kindling development up to maximal stage‐5 severity. In AK‐resistant rats, limbic clonus did not appear after 30 stimulations or if it appeared, it did not progress beyond stage 2. The proportions of AK‐prone and AK‐resistant animals within Wistar and WAG/Rij strains were similar. Comparison of Wistar and WAG/Rij rats within the kindling‐prone and kindling‐resistant groups did not reveal a significant strain effect on AK progression. However, within the WAG/Rij strain, a significantly higher incidence of absence seizures was found in AK‐resistant rats compared to AK‐prone rats. Conclusions: The present study demonstrates that sensitivity to sound‐induced epileptogenesis differs dramatically within Wistar and WAG/Rij strains, whereas genetic susceptibility to absence seizures does not change AK progression significantly. It is supposed that an increased incidence of nonconvulsive seizures and resistance to kindling result from a common seizure modulating mechanism.     

Mechanisms of the development and integration of nerve processes: Age-related dynamics of the development of absence epilepsy,changes in the concentration of monoamines and their metabolites in the brain structures of WAG/Rij and Wistar rats,and the dynamics of the disruption of learning and memory

We studied peak-wave activity in WAG/Rij rats at ages of 2 and 6 months. We found age-dependent enhancement of peak-wave discharges. At 2 months, the discharges were rare and weak, whereas 6-month-old rats had robust peak-wave discharges. We measured the concentrations of monoamines and their metabolites in 2- and 6-month-old WAG/Rij and Wistar rats in five brain structures: the prefrontal cortex, nucleus accumbens, hypothalamus, striatum, and hippocampus. In 2-month-old WAG/Rij rats, we found a decrease in the concentration of dopamine (DA) metabolites (HVA) in the prefrontal cortex and striatum compared to Wistar rats. In 6-month-old WAG/Rij rats, we found a considerable decrease in the activity of DA system compared to Wistar rats in all five studied brain structures. Concentrations of both DA and its metabolites decreased. We found impairments of learning and memory of WAG/Rij rats compared to Wistar rats. Impairment of learning and memory were more pronounced in 6-month-old WAG/Rij rats compared to 2-month-old WAG/Rij rats. We believe that the DA system not only responds to emotionally positive states but is also a reward and reinforcement system. An increase in the concentration of DA and its metabolites by madopar prevents disturbances of learning and memory. Our general conclusion is that enhancement of absence epilepsy induces a strong deficit of activity of the mesocorticolimbic and nigrostriatal DA system, which induces depression-like behavior and disturbance of learning and memory in WAG/Rij rats. These are the mechanisms of the development of impairments and the integration of these impairments, as well as the aggravation and widening of pathological states.     

IL-6 Receptor Blockade by Tocilizumab Has Anti-absence and Anti-epileptogenic Effects in the WAG/Rij Rat Model of Absence Epilepsy

Increased expression of interleukin-6 (IL-6) both in cerebrospinal fluid (CSF) and plasma is closely associated with convulsive epilepsy and symptom severity of depression. By comparison, at present, little is known about the role of this cytokine in childhood (non-convulsive) absence epilepsy. The aim of this work was to investigate the potential effects of acute and chronic treatment with tocilizumab (TCZ, 10 and 30 mg/kg/day), on absence seizures, their development, and related psychiatric comorbidity in WAG/Rij rats. It is known that lipopolysaccharide (LPS)-induced changes in inflammatory processes increase absence epileptic activity. In order to study the central effects of TCZ, we investigated whether administration of this anti-IL-6R antibody could modulate the lipopolysaccharide (LPS) or IL-6-evoked changes in absence epileptic activity in WAG/Rij rats. Our results demonstrate that TCZ, at both doses, significantly reduced the development of absence seizures in adult WAG/Rij rats at 6 months of age (1 month after treatment suspension) compared with untreated controls, thus showing disease-modifying effects. Decreased absence seizure development at 6 months of age was also accompanied by reduced comorbid depressive-like behavior, whereas no effects were observed on anxiety-related behavior. Acute treatment with TCZ, at 30 mg/kg, had anti-absence properties lasting ~25 h. The co-administration TCZ with i.c.v. LPS or IL-6 showed that TCZ inhibited the worsening of absence seizures induced by both proinflammatory agents in the WAG/Rij rats, supporting a central anti-inflammatory-like protective action. These results suggest the possible role of IL-6 and consequent neuroinflammation in the epileptogenic process underlying the development and maintenance of absence seizures in WAG/Rij rats. Accordingly, IL-6 signaling could be a promising pharmacological target in absence epilepsy and depressive-like comorbidity.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00893-8) contains supplementary material, which is available to authorized users.Key Words: Absence epilepsy, epileptogenesis, neuroinflammation, tocilizumab, depressive-like behavior, anxiety.     

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)     

A role for the preoptic sleep-promoting system in absence epilepsy

Absence epilepsy (AE) in humans and the genetic AE model in WAG/Rij rats are both associated with abnormalities in sleep architecture that suggest insufficiency of the sleep-promoting mechanisms. In this study we compared the functionality of sleep-active neuronal groups within two well-established sleep-promoting sites, the ventrolateral and median preoptic nuclei (VLPO and MnPN, respectively), in WAG/Rij and control rats. Neuronal activity was assessed using c-Fos immunoreactivity and chronic single-unit recording techniques. We found that WAG/Rij rats exhibited a lack of sleep-associated c-Fos activation of GABAergic MnPN and VLPO neurons, a lower percentage of MnPN and VLPO cells increasing discharge during sleep and reduced firing rates of MnPN sleep-active neurons, compared to non-epileptic rats. The role of sleep-promoting mechanisms in pathogenesis of absence seizures was assessed in non-epileptic rats using electrical stimulation and chemical manipulations restricted to the MnPN. We found that fractional activation of the sleep-promoting system in waking was sufficient to elicit absence-like seizures. Given that reciprocally interrelated sleep-promoting and arousal neuronal groups control thalamocortical excitability, we hypothesize that malfunctioning of sleep-promoting system results in impaired ascending control over thalamocortical rhythmogenic mechanisms during wake–sleep transitions thus favoring aberrant thalamocortical oscillations. Our findings suggest a pathological basis for AE-associated sleep abnormalities and a mechanism underlying association of absence seizures with wake–sleep transitions.     

Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy

Wistar derived inbred line, the WAG/Rij rats, genetically absence epilepsy prone and their normal counterparts, outbred Wistar rats, were compared in respect to differences in behavior, in acute and chronic antidepressant imipramine treatment and in the immediate early gene c-fos expression in the brain regions induced by forced swimming test procedure. The WAG/Rij rats as compared with Wistar rats were found to exhibit decreased activity in the open field test, increased immobility in the forced swimming test and decreased sucrose intake (anhedonia). Interline differences indicating increased anxiety in the WAG/Rij rats were not revealed in the light-dark choice, social interaction and elevated plus-maze tests. The WAG/Rij rats in contrast to Wistar rats responded only to chronic antidepressant imipramine treatment with a reduction in their enhanced immobility in the forced swimming test. "Behavioral despair" induced by forced swimming led to c-fos expression in frontal cortex, nucleus accumbens and striatum, terminal regions of three dopaminergic brain systems (mesocortical, mesolimbic, nigrostriatal). The c-fos expression in the brain of WAG/Rij rats was substantially higher than that of Wistar rats. Moreover, the strains differed in the distribution of c-fos expression between brain regions. Results suggest that WAG/Rij rats are prone to adopt passive strategies of behavior in stressful situations, and so in this certain aspect this strain might be regarded as new experimental (genetic) model of depressive-like (passive) behavior accompanying absence epilepsy. Further testing this hypothesis is proceeding. This putative model could be used for the investigation of neurobiological basis and mechanisms of such "double pathology" and for the examination of new concepts of its therapy.     

Ovariectomy enhances spike-wave discharges in WAG/Rij rats

Objective

To determine the effect of withdrawal of ovarian hormones on the occurrence of absence seizures in WAG/Rij rats, a well-validated animal model for absence epilepsy.

Methods

Two weeks after electroencephalography (EEG) electrodes were implanted, video-EEG recordings of 16 adult female WAG/Rij rats were made. The rats were then randomly assigned to undergo ovariectomy or sham surgery. One week after surgical procedures, EEG recordings were made for five consecutive days. The EEGs were amplified and filtered between 1 and 100 Hz and digitized at 200 Hz.

Results

In the ovariectomy group, both duration and the number of spike-wave discharges increased.

Conclusion

The present data suggest that ovariectomy enhances the occurrence of spike-wave discharges and absence seizures in WAG/Rij rats.