Investigating rare and ultrarare epilepsy syndromes with Drosophila models

One in three epilepsy cases is drug resistant, and seizures often begin in infancy, when they are life-threatening and when therapeutic options are highly limited. An important tool for prioritizing and validating genes associated with epileptic conditions, which is suitable for large-scale screening, is disease modeling in Drosophila. Approximately two-thirds of disease genes are conserved in Drosophila, and gene-specific fly models exhibit behavioral changes that are related to symptoms of epilepsy. Models are based on behavior readouts, seizure-like attacks and paralysis following stimulation, and neuronal, cell-biological readouts that are in the majority based on changes in nerve cell activity or morphology. In this review, we focus on behavioral phenotypes. Importantly, Drosophila modeling is independent of, and complementary to, other approaches that are computational and based on systems analysis. The large number of known epilepsy-associated gene variants indicates a need for efficient research strategies. We will discuss the status quo of epilepsy disease modelling in Drosophila and describe promising steps towards the development of new drugs to reduce seizure rates and alleviate other epileptic symptoms.