Dataset Information

Seizure suppression by top1 mutations in Drosophila.

ABSTRACT: DNA topoisomerase I is an essential nuclear enzyme involved in resolving the torsional stress associated with DNA replication, transcription, and chromatin condensation. Here we report the discovery of a seizure-suppressor mutant, top1(JS), which suppresses seizures in a Drosophila model of human epilepsy. A P-element mutagenesis screen using easily shocked seizure-sensitive mutant as a genetic background identified top1(JS), which plays a novel role in regulating nervous system excitability. Plasmid rescue, excision, complementation, and sequencing analyses verified that top1(JS) results from a P-element insertion in the 5' untranslated region. Quantitative reverse transcription analysis on wild-type and mutant fly heads showed that the top1(JS) mutation causes reduced transcription level in the CNS, suggesting a partial loss-of-function mutation. Electrophysiological experiments revealed normal seizure thresholds in top1(JS) mutants, which are different from other seizure suppressors identified previously, suggesting a novel mechanism underlying seizure suppression by top1(JS). The pharmacological camptothecin feeding experiment and cell death analysis suggested that the seizure suppression by top1(JS) may occur via increased neuronal apoptosis. Furthermore, overexpression of the DIAP1 (Drosophila inhibitor of apoptosis 1) gene rescues top1(JS) suppression, providing additional support for a neural apoptosis suppression mechanism. The top1(JS) mutation is the first viable partial loss-of-function mutation identified in higher eukaryotes, and the results presented here point to a novel function for topo I in construction and/or maintenance of circuits required for seizure propagation in vivo.

SUBMITTER: Song J

PROVIDER: S-EPMC6672588 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Seizure suppression by top1 mutations in Drosophila.

Song Juan J Hu Joyce J Tanouye Mark M

The Journal of neuroscience : the official journal of the Society for Neuroscience 20070301 11

DNA topoisomerase I is an essential nuclear enzyme involved in resolving the torsional stress associated with DNA replication, transcription, and chromatin condensation. Here we report the discovery of a seizure-suppressor mutant, top1(JS), which suppresses seizures in a Drosophila model of human epilepsy. A P-element mutagenesis screen using easily shocked seizure-sensitive mutant as a genetic background identified top1(JS), which plays a novel role in regulating nervous system excitability. Pl ...[more]

PMID: 17360915

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Project description:It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression.

Dataset Information

Seizure suppression by top1 mutations in Drosophila.

Publications

Seizure suppression by top1 mutations in Drosophila.

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