Elsevier

Neuroscience Letters

Volume 497, Issue 3, 27 June 2011, Pages 185-193
Neuroscience Letters

Review
Morphometric changes and molecular mechanisms in rat models of idiopathic generalized epilepsy with absence seizures

https://doi.org/10.1016/j.neulet.2011.02.039Get rights and content

Abstract

The idiopathic generalized epilepsies (IGEs), constituting approximately a quarter of all epilepsy cases, are presumed to arise primarily from genetic abnormalities. A minority of cases have been identified to be caused by mutations in a single gene, but in the vast majority, mutations in multiple genes are presumed to contribute to the development of epilepsy. Two rat models of IGE with absence seizures, the Genetic Epilepsy Rats from Strasbourg (GAERS) and Wistar Albino Glaxo from Rijswijk (WAG/Rij), have proven valuable for translational research. These models closely mimic the behavioural, electrophysiological, and pharmacological aspects of the human condition, with the epilepsy phenotype for both likely to have polygenic determinants. Research in these models, using molecular and in vivo imaging approaches, has provided important insights into the pathophysiology of IGE. Molecular and imaging techniques have the potential to provide researchers with tangible biomarkers of disease progression and the effects of intervention, and also to provide fundamental information about the causation and epileptogenic processes associated with IGE. This review discusses the published literature concerning the molecular changes and morphometric abnormalities identified in these models, as well as their potential relevance for human IGE.

Highlights

GAERS and WAG/Rij are rat strains which exhibit genetically-determined epilepsy. ► Molecular changes in these models can aid understanding of pathophysiology. ► Structural brain alterations (MRI) may provide disease biomarkers to track progression.

Introduction

The idiopathic generalized epilepsies (IGEs) represent approximately 20–30% of epilepsy cases [35], [58]. Patients with IGE have seizures that arise synchronously in both hemispheres on the EEG without any identifiable macroscopic or microscopic structural brain abnormality or intellectual disability, with the aetiology of the epilepsy presumed to genetic [20]. Patients with IGE syndromes can experience a number of different types of seizures, including generalized tonic–clonic seizures, myoclonic seizures and absence seizures. The underlying pathophysiological basis of the IGEs are still incompletely understood, but in the majority of cases it is believed that several genetic anomalies combine to determine the epilepsy phenotype in an individual (i.e. polygenic origin of disease) [36]. While single gene mutations have been found to cause epilepsies resembling IGEs in rare families in which the epilepsy shows a mendelian inheritance pattern, these are believed to account for a small minority of cases.

Absence seizures are one of the most common type of seizures seen in patients with IGE, occurring in a number of different syndromes, including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE) and juvenile myoclonic epilepsy (JME) [21]. Absence seizures are characterised by recurrent non-convulsive episodes with loss of awareness and responsiveness, and are commonly accompanied by minor motor manifestations, but without lost of postural tone. The EEG recording during absence seizures shows bihemispheric, synchronous, generalized spike-and-wave discharges (SWDs) at approximately 3 cycles per second, which start and end abruptly on an otherwise normal background EEG. In all of the well-characterised genetic animal models of IGE, the animals manifest absence-like seizures.

Scientific studies using animal models over many decades have been important in generating knowledge regarding the fundamental neurobiological processes that result in epilepsy. With regard to the IGEs, animal models play a particularly important role as these epilepsies are not amenable to epilepsy surgery, making invasive electrophysiological recordings or excised epileptogenic brain tissue from humans rarely available to study. Many animal models of absence seizures and epilepsy have been described, and these can be broadly divided into models where the seizures are provoked by application of a pharmacological or electrical insult, and models of epilepsy where the animal manifests spontaneous seizures [84]. Amongst the latter group, which have a more prima facie relevance to human IGE, are a number of well-described mouse models that experience spontaneous absence-like seizures accompanied by generalized SWDs on the EEG, such as stargazer [54], lethargic [13] and tottering [30]. However, while important information relevant to the absence seizures has been derived from studies in these mouse models, they differ fundamentally from the common IGEs in humans in that they have a monogenic basis (i.e. the phenotype is determined by mutations in a single gene) and have other neurological abnormalities, such as ataxia.

While there is no model currently available that can be considered truly “ideal”, since each has its respective advantages and limitations [84], the rodent epilepsy models that have been best characterised to model human IGE with absence seizures are the presumed polygenic rat models: Genetic Absence Rats from Strasbourg (GAERS) [59] and the Wistar Albino Glaxo rat from Rijswijk (WAG/Rij) [28]. This article will therefore focus on these rat models, reviewing the published literature related to the molecular and morphological abnormalities that have been reported and the potential insights into the pathophysiology of human IGE that may be drawn from them.

Section snippets

The presumed polygenic rat models of IGE

GAERS [59] and WAG/Rij rats [28] were both independently derived from selective inbreeding of Wistar rat colonies to produce rats that reliably manifest spontaneous absence-like seizures with behavioural arrest accompanied by generalized SWDs on the EEG. In both strains, the rats usually begin to display seizures in the second and third month post-natal, becoming longer, more frequent and better developed as the animals mature, being fully manifest in most WAG/Rij and in all GAERS by four

Molecular alterations in rodent models of IGE

The IGEs have a strong genetic basis, although up until recently, identification of genetic causes of absence seizures in rodent models has been elusive. Studies in both the polygenic rat models of IGE have been performed to identify potential genes that may be linked to the epilepsy phenotype. In GAERS, 3 quantitative trait loci (QTL) on different chromosomes (4, 7 and 8) [78] and in WAG/Rij rats, 2 QTL on chromosomes 5 and 9 [32] were identified as regions controlling specific SWD

Morphometric abnormalities in rodent models of IGE

Up until recently, brain structural modifications, as assessed with routine in vivo imaging such as MRI, had been rarely observed in patients with IGE, despite post-mortem histopathological studies reporting wide-spread microscopic cortical anomalies in a large percentage of patients [60], [61]. However, emerging literature now documents the presence of abnormal regional brain volumes in IGE [6], [14], [16], [37], [48], [76], suggesting that these changes may be causal to the pathophysiology of

Concluding statements

The research described above provides a number of examples of molecular changes and morphometric abnormalities identified in rodent IGE models, many of which have strong a priori rationale to be at least associated with the pathogenesis of the disease. Tracking the ontological development of these changes, and their relationship to the severity of the epilepsy, is crucial for understanding the role of these abnormalities in the pathogenesis of IGE. Extrapolation of research characterising

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