Dataset Information

Shortened Lifespan and Other Age-Related Defects in Bang Sensitive Mutants of Drosophila melanogaster.

ABSTRACT: Mitochondrial diseases are complex disorders that exhibit their primary effects in energetically active tissues. Damage generated by mitochondria is also thought to be a key component of aging and age-related disease. An important model for mitochondrial dysfunction is the bang sensitive (bs) mutants in Drosophila melanogaster Although these mutants all show a striking seizure phenotype, several bs mutants have gene products that are involved with mitochondrial function, while others affect excitability another way. All of the bs mutants (parabss , eas, jus, ses B, tko are examined here) paralyze and seize upon challenge with a sensory stimulus, most notably mechanical stimulation. These and other excitability mutants have been linked to neurodegeneration with age. In addition to these phenotypes, we have found age-related defects for several of the bs strains. The mutants eas, ses B, and tko display shortened lifespan, an increased mean recovery time from seizure with age, and decreased climbing ability over lifespan as compared to isogenic CS or w1118 lines. Other mutants show a subset of these defects. The age-related phenotypes can be rescued by feeding melatonin, an antioxidant, in all the mutants except ses B The age-related defects do not appear to be correlated with the seizure phenotype. Inducing seizures on a daily basis did not exacerbate the phenotypes and treatment with antiepileptic drugs did not increase lifespan. The results suggest that the excitability phenotypes and the age-related phenotypes may be somewhat independent and that these phenotypes mutants may arise from impacts on different pathways.

SUBMITTER: Reynolds ER

PROVIDER: S-EPMC6288826 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Publications

Shortened Lifespan and Other Age-Related Defects in Bang Sensitive Mutants of <i>Drosophila melanogaster</i>.

Reynolds Elaine R ER

G3 (Bethesda, Md.) 20181210 12

Mitochondrial diseases are complex disorders that exhibit their primary effects in energetically active tissues. Damage generated by mitochondria is also thought to be a key component of aging and age-related disease. An important model for mitochondrial dysfunction is the bang sensitive (bs) mutants in <i>Drosophila melanogaster</i> Although these mutants all show a striking seizure phenotype, several bs mutants have gene products that are involved with mitochondrial function, while others affe ...[more]

PMID: 30355763

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Project description:There is clinical need to extend the understanding of epilepsy and to find novel approaches to treat this condition. Bang-sensitive (bs) Drosophila mutants, which exhibit reduced thresholds for seizure, offer an attractive possibility to combine tractable genetics, electrophysiology, and high-throughput screening. However, despite these advantages, the precise electrophysiological aberrations that contribute to seizure have not been identified in any bs mutant. Because of this, the applicability of Drosophila as a preclinical model has not yet been established. In this study, we show that electroshock of bs slamdance (sda) larvae was sufficient to induce extended seizure-like episodes. Whole cell voltage-clamp recordings from identified motoneurons (termed aCC and RP2) showed synaptic currents that were greatly increased in both amplitude and duration. Current-clamp recordings indicated that these inputs produced longer-lived plateau depolarizations and increased action potential firing in these cells. An analysis of voltage-gated currents in these motoneurons, in both first and third instar larvae, revealed a consistently increased persistent Na(+) current (I(Nap)) and a reduced Ca(2+) current in first instar larvae, which appeared normal in older third instar larvae. That increased I(Nap) may contribute to seizure-like activity is indicated by the observation that feeding sda larvae the antiepileptic drug phenytoin, which was sufficient to reduce I(Nap), rescued both seizure-like episode duration and synaptic excitation of motoneurons. In contrast, feeding of either anemone toxin, a drug that preferentially increases I(Nap), or phenytoin to wild-type larvae was sufficient to induce a bs behavioral phenotype. Finally, we show that feeding of phenytoin to gravid sda females was sufficient to both reduce I(Nap) and synaptic currents and rescue the bs phenotype in their larval progeny, indicating that a heightened predisposition to seizure may arise as a consequence of abnormal embryonic neural development.

Dataset Information

Shortened Lifespan and Other Age-Related Defects in Bang Sensitive Mutants of Drosophila melanogaster.

Publications

Shortened Lifespan and Other Age-Related Defects in Bang Sensitive Mutants of <i>Drosophila melanogaster</i>.

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