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FIGURE 2 The two types of seizures in the Wistar Albino Glaxo/Rijswijk strain (WAG/Rij) of rat. The first is a type II SWD, which is followed by a type I SWD (similar to that shown in Figure 1). The trace shows a differential elec-troencephalographic (EEG) recording with two active EEG electrodes, one at the frontal and one at the parietal cortex (courtesy of Ulrich Schridde).

FIGURE 2 The two types of seizures in the Wistar Albino Glaxo/Rijswijk strain (WAG/Rij) of rat. The first is a type II SWD, which is followed by a type I SWD (similar to that shown in Figure 1). The trace shows a differential elec-troencephalographic (EEG) recording with two active EEG electrodes, one at the frontal and one at the parietal cortex (courtesy of Ulrich Schridde).

vated discrimination task during the presence of a SWD was also typical for WAG/Rij rats, although the postictal responses were less accurate. In addition, WAG/Rij rats do not evaluate correctly the time that has passed when a SWD occurs, just as in children with absence epilepsy (van Luijtelaar et al., 1991a, b). Together, these findings suggest that the animals are less able to initiate or execute an adequate motor response during or after a SWD and that their perception of elapsed time is disturbed (Drinkenburg et al., 1995). However, this disturbance does not imply that all cognitive functions are impaired during SWDs: When auditory stimuli were presented during a SWD, WAG/Rij rats were able to discriminate between a previously rewarded and a previously nonrewarded tone (Drinkenburg et al., 2003).

Ontogeny

In GAERS, SWDs are first detected around 30 days of age, whereas they are observed at around 60 to 80 days in WAG/Rij (Vergnes et al., 1986; Coenen and van Luijtelaar, 1987; Schridde and van Luijtelaar, 2004). At 40 days about 30% of the GAERS are affected, and this percentage increases gradually with age to reach 100% at the age of 3 months. The first SWDs are rare (1 or 2 per hour) and short-lasting (1-3 seconds), with a lower frequency of SWDs during a discharge (4-5 per second). With age, the number, the duration, and the frequency of SWDs increase, whereas their amplitude is not modified. Their number reaches a maximum at around 4 to 6 months. A similar but delayed development can be observed in WAG/Rij rats. At the age of 3 months, 50% of the WAG/Rij display fully developed SWDs, and at 6 months of age 100% of the animals show SWDs (Coenen and van Luijtelaar, 1987). SWDs can be recorded in both strains until the death of the animals (van Luijtelaar et al., 1995; Vergnes et al., 1986).

Neuropathology

Depth-recording EEG, intracerebral microinjection, and lesion and in vivo electrophysiologic studies have shown that the thalamocortical interconnections are critical in the generation of SWDs in both GAERS and WAG/Rij (see later discussion on generating circuits). In these structures, no gross histologic modifications were ever observed. In particular, no neuronal loss was detected in the reticular and ventrolateral-posterior nuclei of the thalamus in GAERS (Sabers et al., 1996). Furthermore the synaptic organization of the reticular nucleus of WAG/Rij appears very similar to that of controls (van de Bovenkamp-Janssen et al., 2004b). An increase of glial fibrillary acidic protein (GFAP) expression has been reported in the cortex and the thalamus in both adult and young GAERS, suggesting that reactive astrocytes are already present before the onset of absence seizures (Dutuit et al., 2000). Recently, detailed morphometric studies of the upper granular layer showed that pyramidal cells in layer II-III of the somatosensory cortex in WAG/Rij rats exhibit aberrant dendritic arborization, increased length of dendritic segments, and differences in the number of free terminations of apical dendrites compared with control rats (Karpova et al., 2005). How these dendritic changes are related to increased excitability or capacity to synchronize remains to be established.

Imaging and Metabolic Changes

Local cerebral metabolic rates for glucose (LCMRglc) have been measured in several brain structures using the [14C]-2-deoxyglucose method in adult GAERS to map the neuronal circuits involved in the generation and control of SWDs (Nehlig et al., 1991, 1994) (see also Chapter 47). An overall increase in LCMRglc was observed in most structures whether they exhibit SWDs (i.e., neocortex and thalamus) or not (e.g., limbic and brainstem structures). However, because of the long duration of a 2-deoxyglucose experiment (i.e., 45 minutes), the cerebral metabolic level recorded represents a combination of ictal and interictal phases. These results suggest that GAERS may have a higher glucose metabolism than nonepileptic controls, which seems to reflect primarily the interictal periods (see Chapter 47).

Using laser-Doppler flowmetry, it was shown that SWD in GAERS were associated with a decrease in the level of cerebral blood flow at the surface of the parietal cortex, which started 2 to 7 seconds after the onset of the cortical SWDs. At the end of SWDs, cerebral blood flow returned to baseline level (Nehlig et al., 1996). In a recent study using an intracerebral probe that combines laser-Doppler flowme-try and extracellular microelectrode recording, a parallel increase of cerebral blood flow and neuronal activity was observed in the somatosensory cortex of WAG/Rij (Nersesyan et al., 2004). Whether these opposite data are due to the difference in the techniques used, to the difference between the two strains, or to the differences in localization remains to be further examined.

Two studies used functional magnetic resonance imaging (fMRI) to characterize more fully, in a noninvasive way, the neural circuits involved in the generation of absence seizures in the WAG/Rij (Nersesyan et al., 2004; Tenney et al., 2004). Using T2-weighted echo planar imaging, the blood-oxygenation-level dependent (BOLD) signal coupled with EEG was analyzed (1) in awake rats previously habituated to the experimental conditions (Tenney et al., 2004) or (2) in fentanyl-haloperidol anesthetized animals (Nersesyan et al., 2004). Comparisons of images during spontaneous SWDs and interictal activity showed in both studies an increase of more than 6% of the BOLD signal in the sensory, parietal, and temporal cortices as well as in the reticular, mediodorsal, ventroposterior, and posterior nuclei of the thalamus. No significant changes were seen in temporal or limbic structures (e.g., hippocampus), and no significant negative BOLD signal was observed for any seizures. These data are thus in agreement with neurophysiologic data showing the role of the sensorimotor cortex and relay tha-lamic nuclei in the generation of SWD (see later). When seven Tesla MRI was used, however, an increase in BOLD signal was also observed in the hippocampus, the basal ganglia nuclei, and the tectum and tegmental nuclei. The local changes in BOLD signal recorded with a 7 Tesla magnet are also in agreement with increases in LCMRglc recorded in 21-day-old GAERS before the occurrence of SWD in this strain (Nehlig et al., 1998). These changes confirm that although SWDs are recorded only in the thala-mocortical circuit, the mutations allowing the expression of absence epilepsy are ubiquitously expressed across the whole nervous system and most likely affect also the functional activity of structures located outside the generating circuit. It must be noted that no significant or consistent SWD-related decreases of fMRI have been observed in both studies using WAG/Rij. This contrasts with other fMRI/EEG studies performed on either other animal models (Tenney et al., 2003) or in patients (Archer et al., 2003; Salek-Haddadi et al., 2003). In these studies, numerous cortical areas have shown a decrease in BOLD signal following SWD. However, more work is necessary to draw any conclusion about the functional significance of the distinction between increase and decrease in the BOLD signal. fMRI/EEG is a promising technique that will certainly be of great help in understanding the organization of the different circuits involved in the generation, propagation, and control of SWD. It should bring further insights in epileptic mechanisms when it becomes possible to disentangle neuronal processes from fMRI data by using detailed generative model of fMRI signals (Aubert and Costalat, 2002; Friston et al., 2003).

Response to Antiepileptic and Proconvulsant Drugs

Classic AEDs have been tested on GAERS and WAG/Rij rats to check how pharmacologically predictable models are. Indeed, SWDs are suppressed by the four main AEDs that are effective against human absence seizures (ethosux-imide, trimethadione, valproate, and benzodiazepines). On the contrary, they are worsened by drugs that are either ineffective or aggravating in humans (carbamazepine, pheny-toin) (Table 1) (Micheletti et al., 1985). Phenobarbital evokes biphasic effects: it is suppressive at 2.5 to 10mg/kg, but not at 20mg/kg (Micheletti et al., 1985; Peeters et al., 1988).

Almost all recently developed AEDs have been tested in either GAERS or WAG/Rij to evaluate their possible efficacy on absence seizures (see Table 1). Drugs like vigabatrin, tiagabine, and gabapentin have been shown

TABLE 1 Effects of Antiepileptic Drugs on Spike-Wave Discharges in Humans with Typical Absence Epilepsy and in Rat Models of Absence Epilepsy

Antiepileptic drugs

Humans*

Rat models

Benzodiazepines

Suppression

Suppression

Barbiturates

Biphasic effects

Biphasic effects

Valproate

Suppression

Suppression

Ethosuximide

Suppression

Suppression

Trimethadione

Suppression

Suppression

Carbamazepine

Aggravation

Aggravation

Phenytoin

Aggravation

Aggravation

Gabapentin

Aggravation

Aggravation

Lamotrigine

Suppression

No effects

Levetiracetam

Suppression

Suppression

Pregabalin

Suppression

Suppression

Progabide

No effects

No effects

Tiagabine

Aggravation

Aggravation

Topiramate

Suppression

Suppression

Vigabatrin

Aggravation

Aggravation

*From Panayiotopoulos 1999.

*From Panayiotopoulos 1999.

to aggravate SWDs, whereas progabide is ineffective (Bouwman et al., 2004; Coenen et al., 1995; Marescaux et al., 1992a, b; van Luijtelaar et al., 2002). On the contrary, topiramate, levetiracetam, and pregabalin suppress SWDs (Gower et al., 1995; Rigoulot et al., 2003). Together, the data in the two animal models show a great similarity with the pharmacologic reactivity of typical absence epilepsy in human (Panayiatopoulos, 1999; Schlumberger et al., 1994).

The pharmacologic predictability of these models is further confirmed by the aggravation of SWDs induced by drugs like pentylenetetrazol, gamma-hydroxybutyrate, tetrahydroisoxazolopyridinol (THIP), or penicillin that are known to induce "absence-like" discharges in normal rats (Marescaux et al., 1984, 1992a; Snead, 1988, 1994). More generally the reactivity of seizures to g-aminobutyric acid (GABA)ergic compounds differs from what is generally observed in models of convulsive seizures. In GAERS, intraperitoneal administration of GABAa agonists (muscimol and THIP), GABA transaminase inhibitors (gamma-vinyl GABA and L-cycloserine), or GABA reuptake inhibitors (SKF 89976 and tiagabine) induces a dose-dependent increase in the duration of SWDs (Coenen et al., 1995; Marescaux et al., 1992b; Vergnes et al., 1984). Similarly the injection of R-baclofen, a GABAB agonist, increased SWDs in GAERS or in old Wistar rats, whereas administration of CGP 35348 and other GABAB antagonists suppresses seizures (Marescaux et al., 1992c; Puigcerver et al., 1996). GAERS and WAG/Rij also appear more sensitive to the convulsive effects of systemic injections of GABAA antagonists (picrotoxin, bicuculline, or pentylenetetrazol [PTZ]) and benzodiazepine inverse agonists compared with rats of the nonepileptic strain (Klioueva et al., 2001; Vergnes et al., 2001). This sensitivity suggests a possible dysfunction of GABAA receptors in absence epilepsy (see later discussion).

It is interesting to note that SWDs also appear to be modulated by ligands of the dopamine receptors, as in human patients (see Starr, 1996). Systemic injections of agonists of the D1 and D2 receptors were shown to suppress absence seizures in both GAERS and WAG/Rij (van Luijtelaar et al., 1996; Warter et al., 1988). On the contrary, antagonists of these receptors such as haloperidol significantly increase the number and duration of SWD and may lead to an absence status. However, no seizures are induced by these compounds in nonepileptic animals. This pharmacologic reactivity to dopaminergic ligands may result from their effects on the basal ganglia circuits known to modulate SWDs (De Bruin et al., 2001; Deransart et al., 2000). It is interesting to note that, in the WAG/Rij, an inverse reactivity to dopaminergic agonists is observed for type II SWDs, which are suppressed by haloperidol but aggravated by the DA agonist apomorphine (Midzianovskaia et al., 2001). However, AEDs like tiagabine or vigabatrin increased both type I and type II SWDs (Bouwman et al., 2004; Coenen et al., 1995).

Many other ligands of receptors influence SWDs. The best studied are the effects of glutamatergic and cholinergic drugs and opioid peptides (e.g., Danober et al., 1998; Lason et al., 1995; Peeters et al., 1990a). However, it is beyond the scope of this review to discuss the effects of these compounds.

Genetic Transmission and Chromosomal Mapping

WAG/Rij are fully inbred rats, which means that they are homozygous for all autosomal genes. All individuals display SWDs on their EEG. In the initial colonies of Wistar rats in Strasbourg, 30% of the animals showed spontaneous SWDs. Breeding of selected parents over three or four generations produced a strain in which 100% of the rats were affected. Indeed, both data sets demonstrate that transmission of SWDs is inherited (Marescaux et al., 1992a; Peeters et al., 1990b, 1992). In epileptic x nonepileptic F1 generations, more than 95% of the animals showed SWDs after 6 months, suggesting a dominant transmission, and similar SWDs were recorded in male and female animals, indicating that the transmission is autosomal. Interindividual variability for age of appearance and duration of SWDs is extremely high, supporting the view that the inheritance of SWD is probably not due to a single gene locus or that environmental effects might play a role. This mode of inheritance was confirmed in F2 (F1 x F1) and backcross (F1 x control) generations in both GAERS and WAG/Rij (Marescaux et al., 1992a; Peeters et al., 1992). Recent efforts to manipulate characteristics (e.g., the number, incidence, mean duration) of type I and type II SWDs by housing WAG/Rij in an enriched environment demonstrated that type I SWDs were less sensitive to environmental factors such as housing. This result demonstrates that genetic factors are more important than the contribution of the environment to the phenotypical expression of SWD. Type II SWD, however, appear more easily affected by the environment (Schridde and van Luijtelaar, 2004).

After EEG recordings in an F2 population of rats resulting from the breeding of GAERS and Brown Norway rats, the polygenic inheritance of SWD-related phenotypes was demonstrated (Rudolf et al., 2004). Three quantitative trait loci (QTLs) were identified on chromosomes 4, 7, and 8, which appear to control different variables of SWD (e.g., frequency, amplitude, severity). In this study, age was a major factor influencing the detection of genetic linkage to the various components of the SWDs. Using a similar method, two different QTLs were characterized in a WAG/Rij x ACI F2 population, which are located in chromosomes 5 and 9 (Gauguier et al., 2004). Each of these QTLs appear to control independently the two types of SWDs which have been described in this model. Although some differences in the experimental designs may account for different QTLs for GAERS and WAG/Rij rats, the identification of distinct QTLs suggests that SWDs have been fixed in these two strains (Gauguier et al., 2004).

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