PT - JOURNAL ARTICLE AU - Juan Song AU - Joyce Hu AU - Mark Tanouye TI - Seizure Suppression by <em>top1</em> Mutations in <em>Drosophila</em> AID - 10.1523/JNEUROSCI.3944-06.2007 DP - 2007 Mar 14 TA - The Journal of Neuroscience PG - 2927--2937 VI - 27 IP - 11 4099 - http://www.jneurosci.org/content/27/11/2927.short 4100 - http://www.jneurosci.org/content/27/11/2927.full SO - J. Neurosci.2007 Mar 14; 27 AB - 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, top1JS, 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 top1JS, which plays a novel role in regulating nervous system excitability. Plasmid rescue, excision, complementation, and sequencing analyses verified that top1JS 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 top1JS mutation causes reduced transcription level in the CNS, suggesting a partial loss-of-function mutation. Electrophysiological experiments revealed normal seizure thresholds in top1JS mutants, which are different from other seizure suppressors identified previously, suggesting a novel mechanism underlying seizure suppression by top1JS. The pharmacological camptothecin feeding experiment and cell death analysis suggested that the seizure suppression by top1JS may occur via increased neuronal apoptosis. Furthermore, overexpression of the DIAP1 (Drosophila inhibitor of apoptosis 1) gene rescues top1JS suppression, providing additional support for a neural apoptosis suppression mechanism. The top1JS 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.