Progress and Outlooks in a Genetic Absence Epilepsy Model (WAG/Rij)

Luijtelaar, E.L.J.M. van; Zobeiri, Mehrnoush

doi:10.2174/0929867320666131119152913

Cited by 69 publications

(55 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…GSWDs appeared simultaneously in bilateral primary motor (M1) and sensory cortices (S1) at 7.6 ± 0.6Hz with an average duration of 3.6 ± 1.4 seconds (n = 17 mice). The GSWD frequency and appearance were comparable to earlier reports of awake tg and other rodent models of absence epilepsy 30, 32, 34, 45. During these GSWDs, action potential firing of a subset of CN neurons was phase‐locked to GSWDs.…”

Section: Resultssupporting

confidence: 86%

Cerebellar output controls generalized spike‐and‐wave discharge occurrence

Kros

Rooda

Spanke

et al. 2015

Annals of Neurology

122

138

View full text Add to dashboard Cite

ObjectiveDisrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike‐and‐wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures.MethodsTwo unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short‐lasting, on‐demand CN stimulation could disrupt epileptic seizures.ResultsWe found that a subset of CN neurons show phase‐locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ‐aminobutyric acid type A (GABA‐A) agonist muscimol increased GSWD occurrence up to 37‐fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA‐A antagonist gabazine decimated its occurrence. A single short‐lasting (30–300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed‐loop system, GSWDs were detected and stopped within 500 milliseconds.InterpretationCN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated. Ann Neurol 2015;77:1027–1049

show abstract

Section: Resultssupporting

confidence: 86%

Cerebellar output controls generalized spike‐and‐wave discharge occurrence

Kros

Rooda

Spanke

et al. 2015

Annals of Neurology

122

138

View full text Add to dashboard Cite

show abstract

“…In addition, the cortical discharges are rapidly abolished by ethosuximide. Where they have been developmentally studied, the seizures arise after the second postnatal week, roughly comparable to the earliest presentation in humans (Caraballo et al, 2011) and not in adulthood as seen in inbred rat strains (Danober et al, 1998;van Luijtelaar and Zobeiri, 2014); however, in all rodent models, they typically persist in the adult animals. In general, this electroclinical syndrome only loosely resembles that of classical descriptions of childhood absence epilepsy, with the salient distinctions being that human spike-wave seizure frequency is almost always slower at 3-4 Hz, often subside in adulthood, and approximately 15-30% of patients with the diagnosis of absence epilepsy are not responsive to ethosuximide (Tenney and Glauser, 2013).…”

Section: Monogenic Mutations Of Diverse Genes Converge On the Absencementioning

confidence: 95%

“…This explains the great appeal of genetic models of this disorder, even though important information on the excitability and synchronization of this network has been steadily revealed using pharmacological phenocopies of the seizure discharge itself (Avoli, 1995;Smith and Fisher, 1996;Snead, 1992). Genetically undefined inbred rat strains have also contributed importantly to the understanding of abnormal oscillatory discharges in the thalamocortical system (Danober et al, 1998;de Curtis and Avanzini, 1994;van Luijtelaar and Zobeiri, 2014).…”

Section: Introductionmentioning

confidence: 99%

Monogenic models of absence epilepsy

Maheshwari

Noebels

2014

Progress in Brain Research

View full text Add to dashboard Cite

“…Indeed, WAG/Rij rats have long been known and studied as an animal model of absence epilepsy and from this point of view much is known (van Luijtelaar, 2011;van Luijtelaar and Zobeiri, 2014) even though, as evidenced in this review, most of these data are not helpful to understand the process of epileptogenesis in this strain. 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.…”

Section: Current Limitations and Future Directionsmentioning

confidence: 97%

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

View full text Add to dashboard Cite

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.

show abstract

Progress and Outlooks in a Genetic Absence Epilepsy Model (WAG/Rij)

Cited by 69 publications

References 0 publications

Cerebellar output controls generalized spike‐and‐wave discharge occurrence

Cerebellar output controls generalized spike‐and‐wave discharge occurrence

Monogenic models of absence epilepsy

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

Contact Info

Product

Resources

About