Development of aDrosophilaseizure model forin vivohigh‐throughput drug screening

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Abstract
An important application of model organisms in neurological research has been to identify and characterise therapeutic approaches for epilepsy, a recurrent seizure disorder that affects > 1% of the human population. Proconvulsant‐treated rodent models have been widely used for antiepileptic drug discovery and development, but are not suitable for high‐throughput screening. To generate a genetically tractable model that would be suitable for large‐scale, high‐throughput screening for antiepileptic drug candidates, we characterized aDrosophilachemical treatment model using the GABAAreceptor antagonist picrotoxin. This proconvulsant, delivered toDrosophilalarvae via simple feeding methods suitable for automated screening, generated robust generalised seizures with lethality occurring at doses between 0.3 and 0.5 mg/mL. Electrophysiological analysis of CNS motor neuron output in picrotoxin‐treated larvae revealed generalised seizures within minutes of drug exposure. At subthreshold doses for seizure induction, picrotoxin produced an increased frequency of motor neuron action potential bursting, indicating that CNS GABAergic transmission regulates patterned activity. Mutants in theDrosophila RdlGABAAreceptor are resistant to picrotoxin, confirming that seizure induction occurs via a conserved GABAAreceptor pathway. To validate the usefulness of this model forin vivodrug screening, we identified several classes of neuroactive antiepileptic compounds in a pilot screen, including phenytoin and nifedipine, which can rescue the seizures and lethal neurotoxicity induced by picrotoxin. The well‐defined actions of picrotoxin inDrosophilaand the ease with which compounds can be assayed for antiseizure activity makes this genetically tractable model attractive for high‐throughputin vivoscreens to identify novel anticonvulsants and seizure susceptibility loci.