Metabolic Disruption in Drosophila Bang-Sensitive Seizure Mutants

Abstract

We examined a number of Drosophila mutants with increased susceptibility to seizures following mechanical or electrical stimulation to better understand the underlying factors that predispose neurons to aberrant activity. Several mutations in this class have been molecularly identified and suggest metabolic disruption as a possible source for increased seizure susceptibility. We mapped the bang-sensitive seizure mutation knockdown (kdn) to cytological position 5F3 and identified citrate synthase as the affected gene. These results further support a role for mitochondrial metabolism in controlling neuronal activity and seizure susceptibility. Biochemical analysis in bang-sensitive mutants revealed reductions in ATP levels consistent with disruption of mitochondrial energy production in these mutants. Electrophysiological analysis of mutants affecting mitochondrial proteins revealed an increased likelihood for a specific pattern of seizure activity. Our data implicate cellular metabolism in regulating seizure susceptibility and suggest that differential sensitivity of neuronal subtypes to metabolic changes underlies distinct types of seizure activity.

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction

“…Although the effects of NDI1 expression on flies were subtle, and did not compromise mitochondrial ATP production to the point of affecting viability or inducing other phenotypes seen in OXPHOS mutants (17)(18)(19), several lines of evidence indicate that the enzyme was constitutively active in vivo, and able functionally to replace complex I, as seen earlier in nematodes, human cultured cells and fungi (8-10, 14, 16). NDI1 expression produced a clear shift in the steady-state ratio of the reduced and oxidized forms of NAD, which provides a possible explanation for its ability to confer significant resistance against paraquat in vivo, as shown earlier in cultured cells (20).…”

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

“…On the basis of evoked electrical seizure activity in the giant fiber pathway, two loosely defined classes of bang-sensitive mutants have been distinguished (Pavlidis and Tanouye 1995;Fergestad et al 2006a). Type I seizures, which are thought to originate upstream of flight muscle motor neurons, are characterized by 10-to 30-Hz spike trains that lack any clear pattern and terminate abruptly.…”

“…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), similar to metabolically linked seizures in humans (reviewed in Simon and Johns 1999;De Vivo 2002;Van Gelder and Sherwin 2003;Patel 2004). Seizures exhibited by these mutants respond to anticonvulsant drugs used in vertebrates (Kuebler and Tanouye 2002;Reynolds et al 2004;Tan et al 2004), further demonstrating that many of the molecular mechanisms mediating neuronal activity are conserved.…”

“…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.…”

A Drosophila behavioral mutant, down and out ( dao ), is defective in an essential regulator of Erg potassium channels

“…Recordings from the giant-fiber (GF) escape circuit were performed as previously described (33)(34)(35). Briefly, the animals were etherized, mounted in clay with the head and thorax exposed, and then placed in a humidified chamber for at least 20 minutes to allow recovery.…”