Abstract
ABSTRACTIn most mouse models of disease, the outward manifestation of a disorder can be measured easily, can be assessed with a trivial test such as hind limb clasping, or can even be observed simply by comparing the gross morphological characteristics of mutant and wild-type littermates. But what if we are trying to model a disorder with a phenotype that appears only sporadically and briefly, like epileptic seizures? The purpose of this Review is to highlight the challenges of modelling epilepsy, in which the most obvious manifestation of the disorder, seizures, occurs only intermittently, possibly very rarely and often at times when the mice are not under direct observation. Over time, researchers have developed a number of ways in which to overcome these challenges, each with their own advantages and disadvantages. In this Review, we describe the genetics of epilepsy and the ways in which genetically altered mouse models have been used. We also discuss the use of induced models in which seizures are brought about by artificial stimulation to the brain of wild-type animals, and conclude with the ways these different approaches could be used to develop a wider range of anti-seizure medications that could benefit larger patient populations.
Highlights
Introduction: what is epilepsy? Epilepsy is one of the most common neurological conditions worldwide, with an incidence of just under one in every hundred people in the UK, and a peak in occurrence in very young and very old people (Beghi and Giussani, 2018)
Anti-seizure drugs [ASDs; known as antiepileptic drugs (AEDs); see Glossary, Box 1] can be used to treat patients, these have very variable efficacies and are palliative, as there is no cure for epilepsy
The three main categories of epilepsy, as defined by the International League Against Epilepsy (ILAE), are based on the origin of onset: seizures of generalised onset involve large bilateral brain areas, focal onset seizures arise in a specific region on one side of the brain, and the remaining category comprises seizures of unknown onset
Summary
By their seizure phenotypes (or lack thereof ). Recent advances in three-dimensional culture techniques and differentiation methods have allowed the generation of cerebral organoids from single iPSC lines These organoids comprise diverse neuronal and glial cell types, which show limited self-organisation and exhibit spontaneous, synchronised neural activity (Izsak et al, 2019; Trujillo et al, 2019; Zafeiriou et al, 2020), meaning that they could eventually model both network-level and cell-autonomous defects in epilepsy. Mammalian neurons and use conserved neurotransmitters, For example, a zebrafish model of Dravet syndrome (with mutations in the there are important physiological differences – C. elegans neurons have SCN1A homologue scn1lab) shows face validity for behavioural and ion channels but they do not have voltage-gated sodium channels electrographic seizures Drug screening using this model identified (Bargmann, 1998; Risley et al, 2016). Transgenesis and site-specific editing are feasible in rats (Ellenbroek and Youn, 2016; Guan et al, 2014; Gurumurthy and Lloyd, 2019)
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