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Increased persistent Na+ current contributes to seizure in the slamdance bang-sensitive Drosophila mutant

Affiliation

  • 1 Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
  • PMID: 21451059
  • PMCID: PMC3129721
  • DOI: 10.1152/jn.00808.2010

Free PMC article

Increased persistent Na+ current contributes to seizure in the slamdance bang-sensitive Drosophila mutant

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Authors

Affiliation

  • 1 Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
  • PMID: 21451059
  • PMCID: PMC3129721
  • DOI: 10.1152/jn.00808.2010

Abstract

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.

Figures

Both slamdance ( sda )…

Both slamdance ( sda ) adult flies and larvae display a bang-sensitive (bs)…

Endogenous synaptic drive elicits greater…

Endogenous synaptic drive elicits greater excitation in sda motoneurons. A and B :…

The persistent voltage-gated Na +…

The persistent voltage-gated Na + current ( I Nap ) is elevated in…

Phenytoin (PHY) both reduces I…

Phenytoin (PHY) both reduces I Nap in motoneurons and rescues seizure. A :…

PHY rescues the SRC amplitude…

PHY rescues the SRC amplitude and duration in sda larvae. A : SRC…

Seizure severity correlates with the…

Seizure severity correlates with the ratio of I Nap to I Nat .…

Maternal feeding of PHY reduces…

Maternal feeding of PHY reduces the ratio of I Nap to I Nat…

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-throug …