Genetic Suppression of Seizure Susceptibility in Drosophila Kuebler D, Zhang H, Ren X, Tanouye MA J Neurophysiol 2001;86:1211–1225 Purpose Despite the frequency of seizure disorders in the human population, the genetic and physiologic basis for these defects has been difficult to resolve. Although many genetic defects that cause seizure susceptibility have been identified, the defects involve disparate biologic processes, many of which are not neural specific. The large number and heterogeneous nature of the genes involved make it difficult to understand the complex factors underlying the etiology of seizure disorders. Examining the effect known genetic mutations have on seizure susceptibility is one approach that may prove fruitful. This approach may be helpful both in understanding how different physiologic processes affect seizure susceptibility and in identifying novel therapeutic treatments. Methods In this study, we have taken advantage of Drosophila, a genetically tractable system, to identify factors that suppress seizure susceptibility. Of particular interest has been a group of Drosophila mutants, the bang-sensitive (BS) mutants, which are much more susceptible to seizures than are wild type. The BS phenotypic class includes at least eight genes, including three examined in this study, bss, eas, and sda. Through the generation of double-mutant combinations with other well-characterized Drosophila mutants, the BS mutants are particularly useful for identifying genetic factors that suppress susceptibility to seizures. Results We found that mutants affecting Na+ channels, mlenapts and para, K+ channels, Sh, and electrical synapses, shak-B2, can suppress seizures in the BS mutants. This is the first demonstration that these types of mutations can suppress the development of seizures in any organism. Reduced neuronal excitability may contribute to seizure suppression. The best suppressor, mlenapts, causes an increased stimulation threshold for the giant fiber (GF), consistent with a reduction in single-neuron excitability that could underlie suppression of seizures. For some other double mutants with para and ShKS133, there are no GF threshold changes, but reduced excitability also may be indicated by a reduction in GF following frequency. Conclusions These results demonstrate the utility of Drosophila as a model system for studying seizure susceptibility and identify physiologic processes that modify seizure susceptibility.