The involvement of limbic structures in typical and atypical absence epilepsy

Epilepsy Research (2013) 103, 111—123

journal homepage: www.elsevier.com/locate/epilepsyres

REVIEW

The involvement of limbic structures in typical and atypical absence epilepsy Filiz Yılmaz Onat a,∗, Gilles van Luijtelaar b, Astrid Nehlig c, O. Carter Snead III d,e a

Marmara University, School of Medicine, Department of Pharmacology, Istanbul, Turkey Biological Psychology, Donders Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands c INSERM U 666, Strasbourg, France d Neuroscience and Mental Health Program, Faculty of Medicine, University of Toronto; The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8 e Division of Neurology, Hospital for Sick Children, Faculty of Medicine, University of Toronto; The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8 b

Received 5 April 2012; received in revised form 15 August 2012; accepted 22 August 2012 Available online 16 September 2012

KEYWORDS ‘‘Absence seizures’’; GAERS; WAG/Rij; GBL; MAM-AY9944; ‘‘Brain circuitry’’

Summary Typical and atypical seizures of absence epilepsy are thought to be generated by a rhythmogenic interplay between the cortex and the thalamus. However, the question remains as to which other subcortical and extrathalamic structures are involved in the pathophysiology of typical and atypical absence epilepsy. Limbic structures are not thought to be involved in typical absence seizures, since in animal models and human patients there is no evidence for the occurrence of spike-and-wave discharges of absence seizures in the limbic regions. However, there are a number of observations from animal models of absence epilepsy that point to a possibly important link between absence seizure mechanisms and limbic structures. Atypical absence seizures are distinct in many ways from typical absence seizures although they bear considerable clinical, EEG, and pharmacological resemblance to typical absence seizures. The differences between typical and atypical seizures of absence epilepsy appear to be circuitry dependent. While both typical and atypical absence seizures involve the cortico-thalamo-cortical circuitry, they each engage different neuronal networks within that circuitry. This review examines the involvement of limbic structures in typical and atypical absence seizures, shows that limbic circuitry forms an integral component of the absence epilepsy network and concludes that further knowledge of this component is important for understanding the complex relationships involved in absence epilepsy. © 2012 Elsevier B.V. All rights reserved.

∗ Corresponding author at: Marmara University, School of Medicine, Department of Pharmacology and Clinical Pharmacology, Istanbul 34668, Turkey. Tel.: +90 216 349 2816; fax: +90 216 347 5594. E-mail addresses: [email protected], [email protected] (F.Y. Onat).

0920-1211/$ — see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2012.08.008

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Contents Introduction............................................................................................................ General features of absence epilepsy; clinical, EEG, and pharmacological features of typical and atypical absence epilepsy ............................................................................................................. Animal models of typical and atypical absence epilepsy ............................................................. Pharmacologically induced models — typical absence seizures ................................................ Pharmacologically induced models — atypical absence seizures............................................... Genetic models of typical absence seizures................................................................... Genetic models of atypical absence seizures ................................................................. The cortical and thalamic circuitry involved in typical absence epilepsy............................................. Limbic involvement in typical and atypical absence epilepsy models ................................................ Limbic activity related to typical absence seizures and epilepsy (Fig. 1A) .................................... Limbic involvement in atypical absence seizures and epilepsy (Fig. 1B)....................................... Conclusion ............................................................................................................. Acknowledgements..................................................................................................... References .............................................................................................................

Introduction Epilepsies have been defined as generalized or localizationrelated (focal), on the basis of their clinical and electroencephalographic (EEG) features. The prototypical idiopathic generalized epilepsy (IGE), childhood absence epilepsy, is characterized by multiple daily episodes of typical absence seizures which consist of a brief, intermittent impairment of consciousness associated with a brief interruption of behavior and a simultaneous, time-locked EEG finding of bilateral, synchronous, and symmetrical 2.5—4 Hz spike-and-wave discharges (SWDs) (Niedermeyer, 1993; Panayiotopoulos et al., 1989; Panayiotopoulos, 1999; Crunelli and Leresche, 2002; Leresche et al., 2012). The interconnected circuitry of the cortex and the thalamus is recognized as playing a crucial role in the typical absence seizures that characterize childhood absence epilepsy (Avanzini et al., 1992; McCormick and Contreras, 2001; Snead, 1995; Steriade and Contreras, 1995, 1998). The typical absence seizures of childhood absence epilepsy are considered to be generated by a rhythmogenic interplay between the cortex and the thalamus. Recent data indicate that SWDs may emerge from bilateral frontal lobe circuitry (Bai et al., 2011; Gupta et al., 2011; Holmes et al., 2004; Killory et al., 2011; Lüttjohann et al., 2011; Meeren et al., 2002; Polack et al., 2007; Stefan et al., 2009). It has generally been accepted that limbic structures are not involved in typical absence seizures, since in animal models and human patients there is no evidence for SWD activity in the limbic regions, nor is there synchronized unit activity in these regions along with the cortical SWDs (Inoue et al., 1993). In contrast to this, cortico-thalamo-cortical neurons show increased firing rates most often preceding or during the spike of the SWD (Vergnes et al., 1990; Seidenbecher et al., 1998; Pinault et al., 1998, 2001; Pinault, 2003). However, recent observations in models of absence epilepsy have pointed to a possibly important link between typical absence epilepsy and limbic structures. Atypical absence seizures share the same anticonvulsant drug pharmacology as typical absence seizures but differ in semiology, associated EEG abnormalities, severity, refractoriness to medical therapy, co-morbid cognitive

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impairment, and association with the catastrophic pediatric epilepsy syndrome of Lennox—Gastaut (Nolan et al., 2005; Markand, 2003). These differences between typical and atypical absence seizures appear to be circuitry dependent. While both involve the cortico-thalamo-cortical circuitry, they each engage different neuronal networks within that circuitry (Perez Velazquez et al., 2007). This review is concerned with the involvement of limbic structures in typical and atypical absence seizures and epilepsy.

General features of absence epilepsy; clinical, EEG, and pharmacological features of typical and atypical absence epilepsy Epilepsies and/or epileptic syndromes have been placed in two major classes as generalized and localization-related (focal) according to the topical (or spatial) distribution of ictal discharges. According to previous classifications, the epilepsies and/or epileptic syndromes were further subcategorized into idiopathic, symptomatic and cryptogenic according to etiology by the Classification and Terminology Commission of the International League Against Epilepsy (ILAE) (Epilepsia, 1981, 1989). The ILAE Commission has recently revised concepts and terminology for classifying seizures and forms of epilepsy as a result of the impressive advances in the neurophysiology and molecular biology of the epilepsies and as a result, a new system of classification is under consideration (Berg et al., 2010; Berg and Scheffer, 2011). Generalized tonic—clonic, myoclonic and absence seizures are the major seizure types seen in IGE. Either one or more of those three major seizure types may be seen in all IGE syndromes which are named according to the major seizure type, or types, present in that particular syndrome and to the age-range of onset, like, ‘childhood absence epilepsy’, or, ‘juvenile myoclonic epilepsy’. Childhood absence epilepsy occupies a prominent position in the IGEs because they are quite common, accounting for 10—17% of all cases of epilepsy diagnosed in school-aged children (Berg et al., 2000). The typical absence seizure

The involvement of limbic structures in typical and atypical absence epilepsy in childhood absence epilepsy is manifested as a transient impairment of consciousness and/or a brief interruption in the ongoing activity, with an abrupt onset and offset. Atonic phenomena or minor behavioral automatisms may sometimes accompany absences in childhood absence epilepsy. Unlike localization-related (focal) epilepsy, typical absence seizures observed in childhood absence epilepsy are not associated with an aura or postictal state. Ictal EEG findings related to typical absence seizures and childhood absence epilepsy consist of bilateral, generalized, high-voltage, synchronous paroxysmal 2.5—4 Hz SWDs. The onset—offset of these paroxysmal EEG abnormalities is time locked to the ictal event. Those absence seizures with the above described clinical and EEG characteristics of IGE syndromes are also referred as ‘typical absence seizures’. Although bearing a considerable clinical, EEG, and pharmacological resemblance to typical absence seizures, ‘atypical absence seizures’ are distinct in many ways from typical absence seizures. Atypical absence seizures are commonly seen in non-benign, non-idiopathic epilepsies and epileptic encephalopathies with intractable seizures, such as the Lennox—Gastaut syndrome (Nolan et al., 2005; Markand, 2003). Atypical absence seizures usually last longer than typical absences, they start and end more insidiously, the onset and offset of SWDs in atypical absence seizures are frequently not time locked to ictal semiology. As well, consciousness may sometimes be partially intact during the seizure (Nolan et al., 2005). Occasionally, atypical absence seizures may evolve into a non-convulsive status epilepticus which may last several days, or even, weeks. Unlike typical absence epilepsy which are often easily controlled and not usually associated with mental deterioration, atypical absence seizures are severe, refractory to medication, and almost always associated with a severe co-morbid impairment in cognition (Markand, 2003). Although the highly interconnected circuitry of the cortex and the thalamus (Fig. 1) is widely regarded as playing an important role in the pathophysiology of both typical and atypical absence epilepsy seizures (Gloor et al., 1990; Avanzini et al., 1999; Huguenard, 2000; Leresche et al., 2012; Wang et al., 2009), a question remains as to which other subcortical and extrathalamic structures are involved in the mechanisms of each of these types of absence seizures. Although the hippocampus and temporal lobe circuitry have been shown to be involved in atypical absence seizures (Cortez et al., 2001; Chan et al., 2004; Wang et al., 2009; Han et al., 2010), it has long been thought that limbic structures are not involved in typical absence seizures due to the fact that SWDs could not be recorded in the hippocampus and amygdala simultaneously with cortical SWDs in GAERS and WAG/Rij rats (Vergnes et al., 1990; Inoue et al., 1993; Banerjee et al., 1993; Kandel et al., 1996; Perez Velazquez et al., 2007). Thus the amygdala and the hippocampus have been thought not to be involved in the expression or generation of SWDs, and therefore to play no role in the pathophysiology of typical absence seizures. However, there are a number of observations from animal models of typical absence epilepsy that point to a possibly important interaction of absence seizure mechanisms with limbic structures.

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Animal models of typical and atypical absence epilepsy It has long been known that absence epilepsy as a form of idiopathic generalized epilepsy can serve as a model for an approach to generalized epilepsies. However, since absence epilepsies are still not understood from a pathophysiological point of view, a necessary step may be to look at animal models of absence epilepsy in order to see whether such models can lead to a better understanding of the pathophysiology of absence epilepsy. In order to be a valid investigative tool, an animal model of either typical or atypical absence seizures should reflect the clinical and pharmacological characteristics of these disorders (Cortez and Snead, 2006; Snead, 1995; Snead et al., 1999, 2006). In addition to the criteria outlined in Table 1, the model should also be reproducible, predictable, quantifiable, and amenable to standardization. Experimental animal models of both typical and atypical absence seizures that meet these criteria can be classified as either pharmacological or genetic models. The genetic models may be divided into naturally occurring mutations in rats (Depaulis and van Luijtelaar, 2006), single locus mutations in mice, and transgenic mouse models (Noebels, 1999, 2006; Tan et al., 2007; Wu et al., 2007; Stewart et al., 2009). Pharmacologically induced models — typical absence seizures Although in vivo pharmacological seizure models may mimic many aspects of human absence, one should recognize that in these models, experimental seizures are being triggered in healthy animals with normal brains by some noxious chemical substances (Cortez et al., 2006). There are several chemical substances used locally or systemically to induce typical absence seizures that meet the criteria outlined in Table 1 (Snead et al., 1999). Pharmacologically induced models of typical absence seizures utilize a variety of drugs including penicillin, low-dose pentylenetetrazole, THIP [4,5,6,7 tetrahydroxyisoxazolo (4,5,c) pyridine 3-ol], and ␥-hydroxybutyrate (GHB) (Gloor and Testa, 1974; Fisher and Prince, 1977; Marescaux et al., 1984; Fariello and Golden, 1987). There are also a few reports of different acute typical absence seizure models such as the muscimolinduced absence seizure model and the intraventricular opiate model (Snead and Bearden, 1982; Zhang et al., 1996). Topical cortical application of bicuculline in anesthetized cats has also been used to elicit SWDs (Steriade and Contreras, 1998). All of these pharmacological models have the limitation of being acutely induced typical absence seizures and thus do not model typical absence epilepsy, i.e. spontaneous recurrent seizures. Pharmacologically induced models — atypical absence seizures There are two pharmacological models for atypical absence epilepsy. These are the AY-9944 (Cortez et al., 2001; Cortez and Snead, 2006) and the methylazoxymethanol acetate (MAM)-AY-9944 (Serbanescu et al., 2004) models in rats. Administration of the 7-dehydrocholesterol reductase inhibitor, AY9944, early in life to either rats or mice results

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Figure 1 (A) Schematic representation of the neuronal circuitry of typical absence seizures which includes the well established (Meeren et al., 2002; Polack et al., 2007) involvement of reciprocal connections between layer 5/6 of the perioral region of somatosensory cortex where the seizures are initiated, the ventrobasal thalamus (VBT) (1 and 3), and the caudal reticular nucleus of the thalamus (TRN) (2). To this classical circuit the limbic thalamus was added, consisting of the anterior thalamic (AT), centromedian (CM), medial dorsal (MD) and reuniens (Re) nuclei, all of which project to the limbic regions, hippocampus and amygdala, and to the TRN (4). The latter also has its own connections to hippocampus and amygdala. (B) Hypothesized circuitry of atypical absence seizures. The initiating epileptiform event for an atypical absence seizure is postulated to occur in layer 5/6 of the medial prefrontal cortex (mPFC) and then project to the Re of the thalamus (7) which projects back to the mPFC and monosynaptically to the CA1 (6) which in turn projects to the mPFC (5). This reverberating circuit is modulated and driven by reciprocal intrathalamic connections between the Re and rostral TRN (8). (−) indicates inhibition; (+) indicates excitation. The figure has been adapted and modified from Wang et al. (2009) with permission from Elsevier.

in the spontaneous recurrent occurrence of atypical absence seizures which last throughout the animal’s lifetime. The MAM-AY9944 model is a double hit model of medically refractory atypical absence epilepsy since cortical dysplasias are first induced in rat by prenatal administration of MAM and then AY9944 is administered during the first 3 weeks postnatally. Genetic models of typical absence seizures In rats, the Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) and the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), are well-validated genetic rat models of typical absence epilepsy (Vergnes et al., 1982; Avanzini and Marescaux, 1991; van Luijtelaar and Coenen, 1986; Danober et al., 1998; Depaulis and van Luijtelaar, 2006; van Luijtelaar and Sitnikova, 2006). GAERS were selected from a stock of Wistar rats and have now been fully inbred for more than 60 generations in a few laboratories all over the world.

All individuals of these strains show spontaneous, bilateral and synchronous SWD paroxysms, each consisting of highvoltage spike and subsequent slow wave components in the EEG. Episodes of SWDs are accompanied by concomitant behaviors including a momentary impairment in responding to environmental events, head tilting, accelerated breathing and facial myoclonic twitchings. In the WAG/Rij model, the Wistar Albino Glaxo strain was first inbred in the United Kingdom and then kept in Rijswijk (WAG/Rij) and later in Nijmegen (both cities in The Netherlands). It was already fully inbred when the occurrence of absence seizures was discovered in these rats (Depaulis and van Luijtelaar, 2006). The SWDs in GAERS and WAG/Rij are very similar, high-amplitude asymmetric synchronized rhythmic activity expressed as SWD complexes with a fundamental frequency of 7—11 Hz, which mature gradually, increasing in frequency, duration and number. In GAERS, all of the animals show a mature pattern of SWDs by 3 months (Marescaux

The involvement of limbic structures in typical and atypical absence epilepsy Table 1

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Comparison of features of typical and atypical absence seizures in rodent models and human. Rat/mouse

EEG Bilaterally synchronous SWD SWD frequency (Hz)a SWD from thalamus and cortex SWD from hippocampusa Ictal behavior Staring; myoclonus Move during SWDa Precise EEG/behavioral correlationa Pharmacology Blocked by ETO, VPA, TMD Exacerbated by GABAA&B R agonists Blocked by GABAB R antagonists Severe cognitive disabilitya

Human

Typical

Atypical

Typical

Atypical

+ 7—11 + −

+ 4—6 + +

+ 2.5—4 + −

+ 1.5—3 + +

+ − +

+ + −

+ − +

+ + −

+ + + −

+ + + +

+ +

+ + No data

−

+

ETO, ethosuximide; VPA, valproic acid; TMD, trimethadione; SWD, spike-and-wave discharge; GABAB R1bR2 transgenic hybrid mouse is a mutant mouse over expressing GABAB receptor subunits R1b and R2 in forebrain neurons. a Characteristics that separate atypical absence seizures from typical absence seizures.

et al., 1992; Carcak et al., 2008). WAG/Rij rats show a steady increase in the number of animals affected from 2 to 3 months onwards, with a more mature SWD-type EEG event, and an increase in number and mean duration of SWDs per hour over months, reaching their maximum by 6-months (Coenen and Van Luijtelaar, 1987; Tolmacheva et al., 2004; Schridde and van Luijtelaar, 2005). Recently the strains were compared with respect to SWD characteristics and GAERS had more and earlier SWDs than WAG/Rij rats, but many other features were rather similar (Akman et al., 2010). Although the development of frequency and persistence of SWDs throughout the life of the rat differ from the patterns seen in humans, these seizures share similar electrophysiological, behavioral and pharmacological characteristics in humans and rats (van Luijtelaar and Sitnikova, 2006). The sensitivity of the typical absence seizures to anticonvulsants is similar to that of human absence seizures. Ethosuximide, valproate, benzodiazepines (diazepam, clobazam and clonazepam), topiramate, levetiracetam, and GABAB receptor antagonists suppress typical absence seizures in GAERS and WAG/Rij rats as in humans (Gören and Onat, 2007; Depaulis and van Luijtelaar, 2006). Lamotrigine is considerably effective in humans, but not very effective in Genetic Absence Epilepsy Rats (Glauser et al., 2010; van Rijn et al., 1994). Phenytoin, carbamazepine, oxcarbazepine, vigabatrin, gabapentin, tiagabine or GABAB receptor agonists have no effect or exacerbate the seizures in both forms of absence epilepsy in humans and in GAERS or WAG/Rij rats (Manning et al., 2003; Depaulis and van Luijtelaar, 2006; Powell et al., 2009). In mice, single locus mutations that show absence epilepsy include tottering (tg/tg), lethargic (lh/lh), stargazer (stg/stg), ducky (du/du) and Petrou models (Caddick et al., 1999; Fletcher et al., 1996; Letts et al., 1998; Noebels, 1979, 1996, 1999; Noebels and Sidman, 1979; Zhang et al., 2002; Tan et al., 2007; Hill et al., 2011). These models are characterized by the loss of the

given genes encoding subunits of the voltage-gated Ca2+ channel, the sodium hydrogen exchanger protein, the hyperpolarization-activated cation channel (HCN), the synaptosomal-associated protein (SNAP25), AP3d, and the GABAA receptor ␥2 subunit (Ludwig et al., 2003; Tan et al., 2007). These mouse models with a single-locus mutation display generalized absence seizures featuring sudden behavioral arrest and unresponsiveness accompanied by SWDs in the EEG which are blocked by ethosuximide. However, these mutant mice with spontaneous absence seizures also display other neurological abnormalities such as ataxia or behavioral abnormalities, abnormal gaits, or severe tremors and may do not survive beyond postnatal day 19 (Tan et al., 2007). This all limits the degree to which they can be regarded as comparable to a human condition. There are only a few data about these genetic models of absence epilepsy concerning limbic involvement in the absence-like seizure activity. Genetic models of atypical absence seizures GABAB receptor (GABAB R)-mediated mechanisms are involved in the pathogenesis of absence seizures (Crunelli and Leresche, 2002; Bowery, 2010). GABAB R agonists have been shown to exacerbate typical (Snead, 1996) and atypical (Cortez et al., 2001; Cortez and Snead, 2006; Wu et al., 2007) absence seizures (Table 1). Conversely, GABAB R antagonists block both types of seizures (Puigcerver et al., 1996; Snead et al., 1999; Cortez et al., 2001; Wu et al., 2007). Based on work showing over-expression of GABAB R1a and R1b subtypes of the GABAB R in the AY9944 model of atypical absence seizures in rodents it was shown that over expression of the GABAB receptor R1a subtype in the forebrain neurons of transgenic mice resulted in spontaneous atypical absence seizures. The resultant transgenic animal, GABAB R1atg , showed a phenotype with all the features of atypical absence seizures including impaired hippocampal synaptic plasticity, significantly impaired

116 learning ability, and the involvement of the hippocampus in the slow spike—wave discharges (SSWDs) that characterize atypical absence seizures (Wu et al., 2007). Subsequently Stewart et al. (2009) demonstrated that the GABAB R1b transgenic mouse showed an atypical absence seizure phenotype, although not as severe as that observed in the R1a transgenic mouse model of atypical absence seizures.

The cortical and thalamic circuitry involved in typical absence epilepsy Even though given types of absence epilepsy have been clinically and electrographically considered as a pure form of epilepsy with a benign prognosis, relative to the other forms of epilepsy, absence epilepsy is still one of most enigmatic forms of epilepsy. The EEG manifestation of a typical absence seizure and the bilaterally synchronous 2.5—4 Hz SWDs on the EEG involve the cerebral cortex and the thalamus, generally referred to as the ‘‘cortico-thalamic circuitry’’. Therefore malfunctions in the cortico-thalamocortical network are the prominent component of absence seizures and indeed of absence epilepsy (de Curtis and Avanzini, 1994; Blumenfeld, 2002; Leresche et al., 2012). Although the classical view emphasized the role of the (lateral) thalamus for the initiation of the SWDs, others proposed a leading role for the cortex (Avanzini et al., 1996, 1999; Meeren et al., 2002, 2005). Recent evidence indicates that a cortical focus initiates a cascade of events leading to the occurrence of SWDs. The evidence for a focal initiation role of the cortex followed by cortico-cortical and corticothalamo-cortical spread comes from multi-site local field potential studies of spontaneously occurring or bicucullineinduced seizures in cats under ketamine-xylazine anesthesia (Neckelmann et al., 1998, 2000), from non-linear association analyses of spontaneously occurring SWDs in freely moving WAG/Rij rats (Meeren et al., 2002) as well as from single-unit and multi-unit recordings between the cortical and thalamic principal cells and intracellular recordings of thalamic, relay and reticular neurons in GAERS under neurolept analgesia (Pinault, 2003). Meeren et al. (2002) showed that the area of origin is the peri-oral region of the somatosensory cortex and that the cortex leads the thalamus in the first 500 msec of the SWD activity, and Pinault (2003) reported that cortico-thalamic discharges usually phase-lead the firing of thalamo-cortical relay and reticular cells. A laminar analysis of intracellular and local field potentials revealed that the SWDs in GAERS originate from the subgranular layers of the somatosensory cortex (Polack et al., 2007). Although the leading role of the cortex seems well established in the in vivo animal models, the contribution of the thalamus, including the thalamic reticular nucleus (TRN) is imperative. Functional inactivation and lesion studies of the lateral thalamus in the genetic models including the rostral pole of the TRN showed an loss of cortically recorded SWDs, suggesting that SWDs require a functional cortex and thalamus (Vergnes and Marescaux, 1992; Avanzini et al., 1992; Meeren et al., 2009). It is thought that the thalamus with its widespread cortical projections including the intralaminar nuclei may be involved in synchronization of thalamic neurons, spreading SWDs over the thalamus and cortex and reinforcing their maintenance (Seidenbecher et al., 1998;

F.Y. Onat et al. Pinault et al., 2001). However, total hemithalamectomy did not prevent the occurrence of topical bicuculline-elicited cortical SWDs in cats (Steriade and Contreras, 1998). This suggests that there is a difference with respect to the involvement of the thalamus between genetic epilepsy models such as WAG/Rij rats and GAERS on the one hand and acute pharmacological seizure models on the other. Most likely changes in the TRN, e.g. increased expression of T-type Ca2+ and P/Q-type Ca2+ channels located at presynaptic terminals, a dramatic decrease of ␣3 GABA-subunits, an enhanced expression of mGlu4 receptors, and downregulated CB1 receptors (Tsakiridou et al., 1995; van de Bovenkamp-Janssen et al., 2006; Liu et al., 2007; Ngomba et al., 2008; van Rijn et al., 2010) may contribute to the larger role of the TRN in the genetic absence epilepsy models than in the acute seizure models. SWDs arise from the deep layers of the peri-oral region of the somatosensory cortex where neurons are more excitable (Polack et al., 2007, 2009), through not well understood mechanisms: hyperpolarization-activated, cyclic nucleotide-gated channel 1 (HCN1) and sodium channel deficits have been demonstrated in the genetic models (Klein et al., 2004; Schridde et al., 2006; Kole et al., 2007). Others described morphological changes in cortical pyramidal cells that can be held responsible for increased excitability and/or decreased inhibition in the somatosensory cortex (Karpova et al., 2005). GABAB receptor dysfunctions (Merlo et al., 2007; Inaba et al., 2009) and changes in NMDA receptors (Pumain et al., 1992; D’Arcangelo et al., 2002) or its subunit and in the expression of mGlu2/3 receptors (Ngomba et al., 2005) have also been described. Interestingly, a deficit in layer 2/3 pyramidal neurons of the somatosensory cortex in cortical inhibition of the GABAA ␥2 (R43Q) mutant mouse relative to the wild type has been described (Tan et al., 2007). There are also clinical data to support the cortical initiation of typical absence seizures. Cortical activations and deactivations in default mode have been shown to occur significantly earlier than thalamic responses in typical absence seizures in patients (Moeller et al., 2010). Similarly, high density EEG and MEG studies have also demonstrated the presence of SWDs in discrete, frontal and parietal cortical regions that may precede those in the thalamus (Holmes et al., 2004; Westmijse et al., 2009; Stefan et al., 2009; Leresche et al., 2012). A hypothesis of a potential role of astrocytes in the occurrence of SWDs in GAERS was recently raised. Neuron—astrocyte interactions were studied in both 1month-old GAERS, i.e., before the occurrence of seizures and in adult GAERS expressing epilepsy (Melo et al., 2007). This study was performed by injecting 13 C-labeled glucose and acetate, which are the primary substrates for neuronal and astrocytic metabolism, respectively, and analyzing brain extracts by nuclear magnetic resonance spectroscopy. In immature GAERS, interactions between glutamatergic neurons and astrocytes appeared normal whereas increased astrocytic metabolism took place in adult GAERS. These alterations in astrocytic metabolism of adult GAERS may participate in the neuronal process leading to the occurrence of SWDs and could be either a consequence of, a cause of, or a concurrent occurrence with the SWDs. It also appears that in GAERS seizures occur when cortical glutamatergic

The involvement of limbic structures in typical and atypical absence epilepsy metabolism is sufficiently enhanced and accompanied by a slight reduction in inhibitory neurotransmission (Melo et al., 2007).

Limbic involvement in typical and atypical absence epilepsy models Limbic activity related to typical absence seizures and epilepsy (Fig. 1A) The content of this section is based on known thalamohippocampal and thalamo-amygdala connections, as direct and indirect evidence of limbic activity in typical absence seizures, and refers to the findings obtained during SWDs and in seizure-free periods. The direct evidence comes from a number of studies performed during SWD episodes. In a study by Nersesyan et al. (2004), blood oxygen level-dependent (BOLD) MRI and simultaneous EEG recordings obtained from all parts of the brain during typical SWDs in the WAG/Rij model demonstrated transient and focal increases in BOLD signals, which were present in several brain regions including the hippocampus and basal ganglia as well as the cortex and thalamus. Thus, hippocampal activation is associated with the presence of cortical and thalamic SWDs in the WAG/Rij model. Further evidence for such a relationship has demonstrated that the SWD activity in the cortico-thalamo-cortical circuitry enhances the propensity of the hippocampus to synchronize in the GHB model, but does not appear to be sufficient to drive the hippocampal circuitry into a full paroxysmal discharge (Perez Velazquez et al., 2007). In addition to the direct evidence linking SWD episodes to changes in limbic structures, the first indirect evidence linking limbic activity to SWDs indicated that cerebral glucose utilization rates in adult GAERS, in which absence seizures are fully expressed, increased not only in the corticothalamo-cortical circuit but also in limbic and motor regions (Nehlig et al., 1991). In humans with typical childhood absence epilepsy, increases in cerebral functional activity were recorded in all brain areas whether or not they expressed SWDs (Engel et al., 1985; Ochs et al., 1987). In addition, in 3-week-old GAERS, before the occurrence of absence seizures, glucose metabolism is increased only in limbic regions and in structures belonging to the remote control system of seizures, involving GABAergic neurons with cell bodies localized in the pars reticulata of the substantia nigra and with nerve terminals ending in the superior colliculus (Depaulis et al., 1994). This remote control system is most likely indicative of pre-ictal activity present in the brain before the occurrence of SWDs (Nehlig et al., 1998). There are experimental studies in rats with genetic absence epilepsy that show a resistance to, or a delay of, secondary generalization of focal limbic seizures induced either by kindling or by intra-amygdaloid kainic acid (KA) injection and these suggest limbic involvement in absence epilepsy, which is not directly related to the SWD periods (Es¸kazan et al., 2002; Onat et al., 2005; Gurbanova et al., 2008; Akman et al., 2008; Onat et al., 2009). In kindling studies when GAERS or WAG/Rij animals are stimulated at their afterdischarge threshold, limbic seizures fail to generalize in these absence epilepsy rats. In addition,

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the afterdischarge threshold of these rats is higher compared to the normal Wistar animals. GAERS and WAG/Rij animals also show that a high level of basal SWD activity correlates with the resistance to kindling that involves limbic circuitry (Onat et al., 2007). Moreover, local cerebral blood flow changes have been studied during the early stages of kindling (stage 2) in adult GAERS and nonepileptic control rats (Carcak et al., 2009). Although the number of stimuli needed to produce stage 2 seizures is not different for GAERS and nonepileptic control rats, increases in blood flow in the piriform, entorhinal and perirhinal cortex, the CA2 region of hippocampus, the amygdala, hypothalamus and substantia nigra, and also in the somatosensory cortex, the ventrobasal and the anterior thalamic nuclei are larger and more widespread in GAERS than in normal control rats. These differences indicate that in GAERS there are significant functional changes not only in thalamic and neocortical structures but also in the temporal lobe and that these changes prevent the full development of kindling. The relatively higher increased blood flow in the thalamocortical structures of GAERS demonstrates an interdependence of temporal lobe and thalamocortical structures. Taken together these findings suggest that the temporal lobes are involved in the regulation of absence epilepsy or resistance to the spread of SWDs to the seizure-prone limbic circuit (Fig. 1A), as already suggested (Nehlig et al., 1991). These experimental findings in kindling and intra-amygdaloid KA studies comport with recent evidence of robust neuronal network connections between the amygdala and the TRN (Zikopoulos and Barbas, 2012). Studies examining the role of the endogenous opioid system in the control of SWDs in WAG/Rij rats found elevated levels of ␣-neoendorphin in the hippocampus of symptomatic WAG/Rij rats compared to age matched control rats, and also in comparison to presymptomatic WAG/Rij rats (Laso´ n et al., 1992). This increased level of ␣-neoendorphin represents an increase in the level of prodynorphin and this might be involved in a neurochemical mechanism that could prevent the spreading of SWDs to the limbic system. This idea is based on outcomes of neurophysiological studies indicating that prodynorphin-derived peptides exert an inhibitory influence on hippocampal neurons (Nicoll et al., 1977) and that peptides derived from prodynorphin exert antiepileptic effects in WAG/Rij rats (Przewłocka et al., 1995). Besides the findings of this genetic model, in the GHB model of typical absence seizures, elevated levels of prodynorphin were found in the hippocampus, suggesting involvement of the limbic circuitry in this pharmacologic model (Laso´ n et al., 1983). In addition, the basal extracellular levels of glutamate in the hippocampus are higher in GAERS than in normal controls (Richards et al., 2000). Similarly the density of glutamate immunolabeling in the CA3 and hilar regions of adult GAERS hippocampus was found to be affected (Sirvanci et al., 2003, 2005). Immunohistochemical analysis of all hippocampal subfields of 6-month-old WAG/Rij rats showed an increased expression of neuronal mGlu2/3 receptors compared to 6 month-old control rats (Ngomba et al., 2005). Finally, pharmacological evidence that activation of GABA-ergic interneurons by the local hippocampal administration of GABA-mimetic drugs reduced SWDs has also been reported recently (Tolmacheva and van Luijtelaar, 2007).

118 A recent publication reported intriguing data in the context of the relationship between the limbic and corticothalamo-cortical circuitry. In the lithium-pilocarpine model of epilepsy the treatment of rats at one hour after the onset of the initial status epilepticus (SE) by a new drug, carisbamate leads to two different pathological outcomes (Franc ¸ois et al., 2011). The first one is the classical pharmacoresistant temporal lobe epilepsy obtained with this model. The second one is absence-like epilepsy that shares many common features with the genetic absence epilepsy models. These are the spontaneous occurrence of bilateral SWDs with an abrupt onset and arrest, the presence of SWDs in both parietal cortex and thalamus and no accompanying EEG changes in limbic regions. These SWDs respond to drugs known to suppress absence seizures and are worsened by carbamazepine. The main difference between rats displaying SWDs after SE and GAERS is that the former have some lesions, mainly in the CA3 and hilus region of the hippocampus whereas in GAERS there is no overt lesion in any brain region (Danober et al., 1998). Further, some interictal behavioral changes in hippocampal dependent learning and memory tasks may be expected in these models. Indeed, a reduction in reference memory in a spatial learning task was found in WAG/Rij rats (van Luijtelaar et al., 1989), while hippocampal independent learning, two-way active avoidance, was not deteriorated in GAERS (Getova et al., 1997). Moreover, the changes in the limbic system might be related with or even responsible for the depressive-like phenotype in WAG/Rij rats (Sarkisova and van Luijtelaar, 2011) and the high anxiety that is found in GAERS and in some WAG/Rij rats (van Luijtelaar, 2011). There are reciprocal anatomic connections between the medial thalamic nuclei and the limbic regions, namely the hippocampus, amygdala, and entorhinal cortex (Zhang and Bertram, 2002). Connections between the thalamic nuclei (TRN and reuniens (Re)) and the hippocampal formation are organized in a similar way as the thalamo-cortical loop (Cavdar et al., 2008). There is also a functional link between the thalamocortical loop and the limbic system (Koutroumanidis et al., 1999; Carcak et al., 2009) (Fig. 1A), but the mechanisms underlying this interaction are not yet understood. However, the shift observed in these studies between temporal lobe and absence epilepsy further supports the involvement of the limbic circuit in absence epilepsy.

Limbic involvement in atypical absence seizures and epilepsy (Fig. 1B) Atypical absence seizures have the same pharmacology as typical absence seizures. Experimentally the seizures are worsened by both GABAA R and GABAB R agonists and blocked by GABAB R antagonists and clinically both types of seizures are alleviated by ethosuximide, benzodiazepines, and valproic acid and worsened by phenytoin and carbamazepine. These data suggest that typical and atypical absence seizures share a common pharmacological target, most likely the TRN and thalamo-cortical circuitry. However, the semiology, co-morbidities, and natural history of typical and atypical absence are decidedly different. Unlike typical absence seizures, atypical

F.Y. Onat et al. absence seizures are prolonged, are not time locked with the SWD on EEG, are universally associated with intellectual disability, and have an invariably poor outcome. These clinical observations provide compelling evidence that the neuronal circuitry that underpins atypical absence is quite different from that for typical absence seizures. There is clear evidence of limbic circuitry involvement in both clinical and experimental atypical absence seizures (Cortez et al., 2001; Chan et al., 2004; Wu et al., 2007). Indeed, the fact that both clinical and experimental atypical absence seizures are associated with severe cognitive impairment (Markand, 2003; Chan et al., 2004) has been attributed to the involvement of thalamo-hippocampal circuitry (Cortez et al., 2001; Chan et al., 2004; Wu et al., 2007). There is clear experimental evidence in the GABAB R1atg genetic mouse model of atypical absence seizures that bilaterally synchronous SSWD emanate solely from the TRN and medial thalamus and project to the CA1 region as well as to the cerebral cortex (Wang et al., 2009). The demonstration that SSWD emanates from the medial thalamus, but not from ventrobasal thalamus, a crucial thalamic region from which SWDs can be recorded in the typical absence models (Vergnes et al., 1990; Meeren et al., 2002; Pinault, 2003; Sitnikova and van Luijtelaar, 2007; Polack et al., 2007), plus the non-involvement of the medial thalamus in typical absence seizures (Liu et al., 1992), supports the hypothesis of a very different cortico-thalamo-cortical circuitry for atypical absence seizures as opposed to that for typical absence seizures and point to the medial thalamus as a critical region of atypical absence circuitry. The one medial thalamic nucleus that links cortex, TRN, and hippocampus is the Re (Vertes et al., 2007; Hoover and Vertes, 2012). There are reciprocal projections from Re to the medial prefrontal cortex (mPFC) (Hoover and Vertes, 2007; Vertes et al., 2007) and TRN (Cavdar et al., 2008), and pronounced direct monosynaptic projections from CA1/subiculum to mPFC (Hoover and Vertes, 2007). However, there are no direct projections from mPFC to CA1; therefore, it appears that the Re serves as a critical relay from mPFC to CA1; that is, a reverberating loop that is modulated by reciprocal intrathalamic connections between the Re and the TRN (Fuentealba and Steriade, 2005; Vertes, 2006; Vertes et al., 2007). Therefore, given the reciprocal projections of Re in the midline thalamus to the mPFC (Hoover and Vertes, 2007; Vertes et al., 2007) and TRN (Cavdar et al., 2008), and the pronounced direct monosynaptic projections from CA1/subiculum to mPFC (Hoover and Vertes, 2007) (Fig. 1B), the initiating epileptiform event for an atypical absence seizure within the proposed circuitry likely takes place in layer 5/6 of the mPFC. The proposed circuitry involving initiation of seizures in the mPFC with resultant engagement of Re, TRN, and CA1 networks (Fig. 1B) would explain the ictal semiology and the cognitive deficits observed with atypical absence seizures. With the advent of sophisticated imaging and network connectivity studies, clinical data also are beginning to emerge that support frontal lobe involvement in atypical absence seizures (Velasco et al., 1997; Chugani and Chugani, 1999; You et al., 2007; Jung et al., 2011).

The involvement of limbic structures in typical and atypical absence epilepsy

Conclusion While typical and atypical absence epilepsy both involve the cortico-thalamo-cortical circuitry, they each engage different neuronal networks within that circuitry. The repetitive occurrence of seizures and their electroencephalographic concomitants in typical and atypical absence epilepsy involve interactions of networks in different brain regions and in this context the limbic circuitry seems to be an integral component of both absence epilepsy networks.

Acknowledgements The authors thank Prof Ays¸ın Dervent for the inputs and Lee Stewart and Nihan C ¸ arc ¸ak for their technical help in the preparation of the figure.

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