Chromosomal Mapping of Genetic Loci Controlling Absence Epilepsy Phenotypes in the WAG/Rij Rat

Guyader, Dominique; Luijtelaar, Gilles van; Bihoreau, Marie Thérèse; Wilder, Steven P.; Godfrey, Richard F.; Vossen, J.M.H.; Coenen, A.M.L.; Cox, Roger D.

doi:10.1111/j.0013-9580.2004.13104.x

Cited by 49 publications

(33 citation statements)

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“…Human absence epilepsy is associated with mutations in the genes encoding the  5 ,  3 , or  2 subunits of the GABA A receptor (Hirose, 2014) and the amount of the  3 subunit in the NRT has been shown to be reduced in WAG/Rij rats as compared to non-epileptic control rats (Gauguier et al, 2004;Liu et al, 2007); instead, GABA A receptors are preserved in the neocortex of WAG/Rij epileptic rats, which are defective in several GABA B receptor isoforms (Liu et al, 2007;Merlo et al, 2007).…”

Section: Gabamentioning

confidence: 99%

“…Genetic analysis of this strain by quantitative trait loci (QTL) mapping demonstrated the polygenic control of SWD phenotypes, which was earlier hypothesized considering that WAG/Rij rats are a fully inbred strain from Wistar rats. Mendelian cross-breeding studies suggested that one dominant gene determines the occurrence and other genes modulate the number and duration of SWDs ; subsequently, Gauguier et al identified the above mentioned QTLs, T1swd/wag on chromosome 5 controlling type-1 SWD average duration and T2swd/wag on chromosome 9 controlling the total duration of type-2 SWDs (Gauguier et al, 2004).…”

Section: Current Limitations and Future Directionsmentioning

confidence: 99%

“…Finally, only quantitative trait loci on chromosomes 5 and 9 of WAG/Rij rats have been identified (Gauguier et al, 2004) and no identified specific gene mutation accounts for the development of spontaneous seizures in this model (van Luijtelaar and Sitnikova, 2006); this latter point creates a clear difference between the above-mentioned model of Dravet syndrome (with a single defined (loss-of-function) mutation on Na + channels) and WAG/Rij rats. Nevertheless, the same hypothetical mechanism can be suggested; namely, in genetic models, one or more factors may create (directly or indirectly; i.e.…”

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confidence: 94%

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

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

128

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Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development.Neuroscience and Biobehavioral Reviews http://dx.doi.org/10. 1016/j.neubiorev.2016.09.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe 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 nongenetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.

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Section: Gabamentioning

confidence: 99%

Section: Current Limitations and Future Directionsmentioning

confidence: 99%

mentioning

confidence: 94%

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

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

128

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“…There are several genetic models of absence epilepsy in rodents. The most commonly used of these models are the genetic absence epilepsy rat from Strasbourg (GAERS) rat (46), Wistar albino Glaxo from Rijswijk (WAG/Rij) rats (47), and more recently, C3H/He mice (30). While these models exhibit absence seizures, their polygenic mode of inheritance makes it difficult to find the genetic mechanisms responsible for the disease.…”

Section: Is Reduced Cortical Inhibition Sufficient To Cause Absence Ementioning

confidence: 99%

Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

Tan

Reid

Single³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

198

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Mutations in the GABAA receptor ␥2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a ␥2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of ␥2(R43Q) was seen in heterozygous mice in the absence of any change in ␣1 subunit surface expression, ruling out a dominant-negative effect. GABA Amediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.GABAA receptor ͉ genetics ͉ electroencephalogram ͉ trafficking ͉ synapse G ABA A receptors in the adult brain are important for inhibiting the activity of neurons in which they reside. Dysfunction of these receptors caused by familial mutations can give rise to febrile seizures (FS) and a variety of generalized epilepsy phenotypes (1-3). To date, five mutations have been reported in the GABA A ␥2 subunit gene with an array of seizure types seen in patients (1, 4-7). Childhood absence epilepsy (CAE) and FS were the main phenotypes in a large Australian family with an arginine to glutamine mutation at position 43 (R43Q) in the GABA A ␥2 subunit gene (1,8).Understanding how the GABA A ␥2(R43Q) mutation causes epilepsy is difficult. GABA A receptors themselves serve several roles. They regulate moment-to-moment brain function (9), play an important role in brain development (10), and have key roles in neuronal plasticity (11, 12) and response to brain injury (13-15). Epilepsy itself is a complex phenomenon involving the interaction of multiple cell types in networks within and between different brain regions that are likely to be influenced by GABA A receptor dysfunction caused by the R43Q mutation. Furthermore, in vitro analyses of the consequences of this mutation have shown inconsistent findings with a range of deficits in receptor pharmacology, trafficking, kinetics, or assembly (16-23) potentially implicated in disease pathogenesis.Clearly, the complex nature of epileptogenesis demands in vivo investigation. Genetic epilepsies provide a framework on which to investigate the consequences of causative mutations at a range of organizational levels within the brain, creating a chain of understanding from molecules to behavior. Linking this chain is impossible in humans because of the highly invasive methodology required and is severely limited in heterologous expression systems that lack necessary complexity. Mice mod...

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“…for genetic analyses of absence epilepsy Vadász et al, 1995;Gauguier et al, 2004). These long lasting recordings are also necessary for the study of long term drug effects and epileptogenesis , for chronic drug studies (D'Amore et al, 2014), for the study of circadian rhythms of SWDs and the consequences of their shifts (Smyk et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Methods of automated absence seizure detection, interference by stimulation, and possibilities for prediction in genetic absence models

Luijtelaar

Lüttjohann

Макаров

et al. 2016

Journal of Neuroscience Methods

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Chromosomal Mapping of Genetic Loci Controlling Absence Epilepsy Phenotypes in the WAG/Rij Rat

Cited by 49 publications

References 47 publications

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

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

Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

Methods of automated absence seizure detection, interference by stimulation, and possibilities for prediction in genetic absence models

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