Genetic factors are known to contribute to seizure susceptibility, although the long-term effects of these predisposing factors on neuronal viability remain unclear. To examine the consequences of genetic factors conferring increased seizure susceptibility, we surveyed a class of Drosophila mutants that exhibit seizures and paralysis following mechanical stimulation. These bang-sensitive seizure mutants exhibit shortened life spans and age-dependent neurodegeneration. Because the increased seizure susceptibility in these mutants likely results from altered metabolism and since the Na 1 /K1 ATPase consumes the majority of ATP in neurons, we examined the effect of ATPa mutations in combination with bang-sensitive mutations. We found that double mutants exhibit strikingly reduced life spans and age-dependent uncoordination and inactivity. These results emphasize the importance of proper cellular metabolism in maintaining both the activity and viability of neurons. (Bittigau et al. 2002). Such links suggest that among the genetic components underlying epilepsy and neurodegeneration, certain risk factors may be shared.These neurological diseases have been extensively modeled and studied in the genetically tractable system of Drosophila. In addition to the availability of numerous seizure mutants, many mutants have been isolated, exhibiting pronounced age-dependent neurodegeneration (reviewed by Bilen and Bonini 2005;Celotto and Palladino 2005;Kretzschmar 2005). Bang-sensitive mutants exhibit behavioral seizures and paralysis following mechanical stimulation that usually become more severe with age. It was proposed that these mutants were associated with defects leading to increased membrane excitability (Benzer 1971;Ganetzky and Wu 1982). This idea is further supported by the reduced threshold for electrically induced seizures in these mutants (Kuebler and Tanouye 2000). Molecular identification of several of these mutants has suggested that they result from defects in mitochondrial metabolism (Royden et al. 1987;Zhang et al. 1999;Fergestad et al. 2006a To examine the long-term effects of genetic perturbations conferring increased seizure susceptibility, we performed aging and histological analyses on these seizure mutants alone and in combination with ATPa mutations. Our studies of bang-sensitive seizure mutants revealed reduced life spans and appearance of age-dependent spongiform-like degeneration in the nervous system. Strong genetic interactions were identified between bang-sensitive mutations and dominant mutations affecting ATPa, the Na 1 /K 1 ATPase a-subunit, known to cause conditional seizures, neurodegeneration, and early death, supporting a model in which metabolic perturbations result in both altered neuronal activity and neurodegeneration. MATERIALS AND METHODSFly strains: Fly stocks were cultured on cornmeal-molasses agar medium at 22-25°. Strains used in this study include tko 25t , We dedicate this article to the memory of Seymour Benzer, mentor, friend, and father of our field.