Emerging epilepsy models: insights from mice, flies, worms and fish

Abstract

Purpose of review-Animal models provide a means to investigate fundamental mechanisms of abnormal electrical discharge (i.e., seizures). Understanding the pathogenesis of epilepsy and therapy development have greatly benefited from these models. Here we review recent mouse mutants featuring spontaneous seizures and simpler organisms.Recent findings-New genetically engineered mice provide additional insights to cellular mechanisms underlying seizure generation (BK calcium-activated potassium channels and interneuron-expressed sodium channels), genetic interactions that exacerbate seizure phenotype (Scn2a, Kcnq2 and background) and neurodevelopmental influences (Dlx transcription factors). Mutants for neuronal nicotinic acetylcholine receptors, Glut-1 deficiency and aquaporin channels highlight additional seizure phenotypes in mice. Additional models in Caenorhabditis elegans (Lis-1) and Danio rerio (pentylenetetrazole) highlight a reductionist approach. Taking further advantage of 'simple' organisms, antiepileptic drugs and genetic modifiers of seizure activity are being uncovered in Drosophila.Summary-Studies of epilepsy in mutant mice provide a framework for understanding critical features of the brain that regulate excitability. These, and as yet undiscovered, mouse mutants will continue to serve as the foundation for basic epilepsy research. Interestingly, an even greater potential for analyzing epileptic phenotypes may lie in the more widespread use of genetically tractable organisms such as worms, flies and zebrafish.

Tanshinone IIA Exhibits Anticonvulsant Activity in Zebrafish and Mouse Seizure Models

“…3,4 In a study conducted by Baraban et al, 7-days post-fertilization (dpf) zebrafish larvae display seizure-like behavior (e.g., "whirlpool" swimming, loss of posture) upon exposure to the chemoconvulsant pentylenetetrazol (PTZ). 5,6 This response to PTZ is comparable to rodent models, with similar outcomes to treatment with known antiepileptic drugs. 6−8 This similarity, as well as other factors such as ease of propagation and sample introduction and the availability of automated scoring or tracking devices, positions zebrafish as a robust model for prescreening extracts (and eventually isolated compounds) from various plant libraries or ethnopharmacopeias, such as the materia medica of traditional Chinese medicine (TCM).…”

Loss of COUP-TFI Alters the Balance between Caudal Ganglionic Eminence- and Medial Ganglionic Eminence-Derived Cortical Interneurons and Results in Resistance to Epilepsy

“…By means of a precise somatodendritic arrangement of their synaptic contacts, diverse types of interneurons specifically control excitability of principal cells and other neuronal types (Markram et al, 2004;Ascoli et al, 2008), being responsible of setting brain rhythms and local field potential oscillations (Buzsáki and Draguhn, 2004). We know that GABAergic cell dysfunction is associated primarily with epilepsy, one of the most frequent neurological disorders occurring in the young population (Cossart et al, 2005;Baraban, 2007). However, we still lack a comprehensive understanding of what determines the expression of a particular phenotype and whether interneuronal dysfunction is cause or consequence of epileptic seizures.…”

Past and Present Definitions of Epileptogenesis and Its Biomarkers

“…However, owing to the labor intensity related to these studies it would currently be impossible to utilize any of these study designs to screen the tens of thousands of compounds that might have antiepileptogenic potential. This supports the need to develop validated high-throughput, cost-effective models, for example using zebrafish, Drosophila, or slice cultures [103]. Currently, clinical trials of potential antiepileptogenic drugs would be prohibitively expensive because seizures occur only in a relatively small percentage of patients, even after the most severe TBI, and may take more than 10 years to develop.…”