Pediatric epilepsy models are confined primarily to rodents. Although using a rodent model of a human neurologic disorder has distinct advantages, there is no rationale to support our almost exclusive reliance on this species. Indeed research questions related to genetic modifiers of pediatric epilepsy syndromes, high-throughput anticonvul-sant drug screening, and "rapid" genetic manipulations aimed at analysis of basic cellular mechanisms of epilepto-genesis could be better suited to a simple vertebrate system. Exciting new discoveries in the general field of neurobiol-ogy exploit the experimental advantages of simpler organisms such as Caenorhabditis elegans (worms), Drosophila melanogaster (fruit flies), and Danio rerio (zebrafish). Analysis of Parkinson (parkin) gene function in flies (Pesah et al., 2004) and discovery of daf genes regulating the aging process in worms (Hsin and Kenyon, 1999; Lin et al., 1997) are just two examples. Similar discoveries are possible in the epilepsy field, but there is currently little evidence that mammalian-like seizures can be induced in any of these species. For example, hyperexcitable Shaker flies featuring a potassium channel mutation are characterized by a leg-shaking behavior that most closely resembles human episodic ataxia (Tempel et al., 1987), and it is unclear whether this motor behavior represents a human seizure disorder. In a second group of Drosophila mutants termed "bang-sensitive", potential seizure suppressor genes were recently identified using a model of evoked electrical afterdischarge in the giant muscle fiber (Kuebler and Tanouye, 2000; Kuebler et al., 2001). In C. elegans a lissencephaly (LIS1) gene mutant was recently described, and these worms exhibited a rapid "head-bobbing" behavior on exposure to a convulsant agent (Williams et al., 2004); again, whether this putatively convulsive behavior resembles a clinically relevant seizure disorder is unclear. Each of these studies hints at the possibility of using simple organisms for epilepsy research. However, in none of these simple species has a systematic effort to develop and characterize a seizure model been presented. This chapter discusses a simple alternative to rodents—larval zebrafish—and describes some of the salient features of a pediatric zebrafish epilepsy model.
Our early efforts to induce seizures in zebrafish larvae were largely "trial and error." Nonetheless, we would like to recognize seminal comparative species studies done by Zdenek Servit, a Polish scientist working with turtles, frogs, and fish in the early 1970s. Using curarized adult tenches, Servit described the genesis and pattern of electrographic spikewave discharge elicited in the adult fish forebrain on topical exposure to penicillin or pentylenetetrazol (PTZ) (Servit, 1970, 1972; Servit and Strejckova, 1970). These lower vertebrate studies predate the use of zebrafish in neurobiology but are prescient in recommending that "one of the uses of an experimental model is to simplify a complex situation."
What Can One Model in Zebrafish Larvae?
In choosing zebrafish for pediatric epilepsy studies, as in any animal model choice, it is of utmost importance to consider the type(s) of experimental question one seeks to address. Our laboratory interest in zebrafish larvae stems from a desire to understand better the genetic factors that modify seizure genesis, propagation, and termination in the developing animal. For example, are there gene mutations that render an organism resistant to the generation of seizures? Does introduction of a human epilepsy gene mutation in zebrafish yield a model in which to study the basic
Models of Seizures and Epilepsy
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