Modifications of Seizure Susceptibility in<i>Drosophila</i>

Kuebler, Daniel; Tanouye, Mark A.

doi:10.1152/jn.2000.83.2.998

Cited by 107 publications

(164 citation statements)

References 36 publications

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“…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.…”

Section: /Kmentioning

confidence: 99%

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

et al. 2008

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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.

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Section: /Kmentioning

confidence: 99%

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

et al. 2008

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“…This phenotype has been associated with mutations in genes involved in neuronal function as well as mitochondrial integrity (33)(34)(35)(36)(37)(38). Two stress-sensitive mutants have been identified as nuclear-encoded mitochondrial genes: stress sensitive B (sesB), encoding the fly ortholog of the adenine nucleotide translocase (39), and technical knock-out (tko), encoding a subunit of the mitochondrial ribosome (40).…”

Section: Mutants Exhibit Partial Lethality and Reduced Viability-porinmentioning

confidence: 99%

Neurologic Dysfunction and Male Infertility in Drosophila porin Mutants

Graham¹,

Li²,

Alesii³

et al. 2010

Journal of Biological Chemistry

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Voltage-dependent anion channels (VDACs) are a family of small pore-forming proteins of the mitochondrial outer membrane found in all eukaryotes. VDACs play an important role in the regulated flux of metabolites between the cytosolic and mitochondrial compartments, and three distinct mammalian isoforms have been identified. Animal and cell culture experiments suggest that the various isoforms act in disparate roles such as apoptosis, synaptic plasticity, learning, muscle bioenergetics, and reproduction. In Drosophila melanogaster, porin is the ubiquitously expressed VDAC isoform. Through imprecise excision of a P element insertion in the porin locus, a series of hypomorphic alleles have been isolated, and analyses of flies homozygous for these mutant alleles reveal phenotypes remarkably reminiscent of mouse VDAC mutants. These include partial lethality, defects of mitochondrial respiration, abnormal muscle mitochondrial morphology, synaptic dysfunction, and male infertility, which are features often observed in human mitochondrial disorders. Furthermore, the observed synaptic dysfunction at the neuromuscular junction in porin mutants is associated with a paucity of mitochondria in presynaptic termini. The similarity of VDAC mutant phenotypes in the fly and mouse clearly indicate a fundamental conservation of VDAC function. The establishment and validation of a new in vivo model for VDAC function in Drosophila should provide a valuable tool for further genetic dissection of VDAC role(s) in mitochondrial biology and disease, and as a model of mitochondrial disorders potentially amenable to the development of treatment strategies.

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“…Single-pulse stimuli (0.5 ms duration, 0.8 Hz) were used to drive the GF, and the GF-driven muscle potentials were recorded from the dorsal longitudinal muscle (DLM) using a tungsten recording electrode. Seizure-like spiking is observed in at least seven different muscle groups and over 30 muscle fibers in the thorax that reflect the HF firing of the innervating motoneurons (Kuebler and Tanouye 2000). Seizure-like activity was evoked by delivering short wave trains of HF electrical stimuli (0.5-ms pulses delivered at 200 Hz for 300 ms) to the fly's brain.…”

Section: Molecular Biologymentioning

confidence: 99%

Seizure Sensitivity Is Ameliorated by Targeted Expression of K+–Cl− Cotransporter Function in the Mushroom Body of the Drosophila Brain

Hekmat-Scafe

Mercado

Fajilan³

et al. 2010

Genetics

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The kcc DHS1 allele of kazachoc (kcc) was identified as a seizure-enhancer mutation exacerbating the bangsensitive (BS) paralytic behavioral phenotypes of several seizure-sensitive Drosophila mutants. On their own, young kcc DHS1 flies also display seizure-like behavior and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. The product of kcc shows substantial homology to KCC2, the mammalian neuronal K transgene was used to determine where cotransporter function is required in order to rescue the kcc DHS1 BS paralytic phenotype. Interestingly, phenotypic rescue is largely accounted for by targeted, circumscribed expression in the mushroom bodies (MBs) and the ellipsoid body (EB) of the central complex. Intriguingly, we observed that MB induction of kcc 1 functioned as a general seizure suppressor in Drosophila. Drosophila MBs have generated considerable interest especially for their role as the neural substrate for olfactory learning and memory; they have not been previously implicated in seizure susceptibility. We show that kcc DHS1 seizure sensitivity in MB neurons acts via a weakening of chemical synaptic inhibition by GABAergic transmission and suggest that this is due to disruption of intracellular Cl À gradients in MB neurons.

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Modifications of Seizure Susceptibility inDrosophila

Cited by 107 publications

References 36 publications

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

Neurologic Dysfunction and Male Infertility in Drosophila porin Mutants

Seizure Sensitivity Is Ameliorated by Targeted Expression of K+–Cl− Cotransporter Function in the Mushroom Body of the Drosophila Brain

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