Mutations of the Calcium Channel Gene cacophony Suppress Seizures in Drosophila

Bang sensitive (BS) Drosophila mutants display characteristic seizure-like phenotypes resembling, in some aspects, those of human seizure disorders such as epilepsy. The BS mutant parabss1, caused by a gain-of-function mutation of the voltage-gated Na+ channel gene, is extremely seizure-sensitive with phenotypes that have proven difficult to ameliorate by anti-epileptic drug feeding or by seizure-suppressor mutation. It has been presented as a model for intractable human epilepsy. Here we show that cacophony (cacTS2), a mutation of the Drosophila presynaptic Ca++ channel α1 subunit gene, is a particularly potent seizure-suppressor mutation, reverting seizure-like phenotypes for parabss1 and other BS mutants. Seizure-like phenotypes for parabss1 may be suppressed by as much as 90% in double mutant combinations with cacTS2. Unexpectedly, we find that parabss1 also reciprocally suppresses cacTS2 seizure-like phenotypes. The cacTS2 mutant displays these seizure-like behaviors and spontaneous high-frequency action potential firing transiently after exposure to high temperature. We find that this seizure-like behavior in cacTS2 is ameliorated by 85% in double mutant combinations with parabss1.Author Summary: Seizure disorders, such as epilepsy, are a serious health concern because of the large number of patients affected and a limited availability of treatment options. About 10% of the population will have at least one seizure during their lifetime, and 1% will experience persistent, recurrent epileptic seizures. Moreover, for about one-third of patients, epilepsy is intractable with seizures that are not controlled with any available drugs. Genetic seizure suppressors are modifier mutations that are capable of reverting seizure susceptibility to wild type levels when combined with seizure-prone mutants in double mutant individuals. Suppressors are valuable in providing an experimental approach that can provide insight into mechanisms underlying seizure susceptibility. Also, they identify novel gene products that may be targets for therapeutic drug development. In the present study we show that a severe seizure phenotype of the Drosophila paralyticbss1 (parabss1) mutant is 90% suppressed by the N-type calcium channel mutation cacophonyTS2 (cacTS2). The effect of suppression is not restricted to parabss1, but cacTS2 can also revert seizure-like phenotypes of other Drosophila mutants like easily-shocked (eas) and slamdance (sda). Thus, cacTS2 acts as a highly potent, general seizure suppressor mutation. A surprising finding in this study is co-suppression: parabss1 also suppresses a seizure phenotype in cacTS2 mutants induced by elevated temperature. A current view of complex diseases such as epilepsy, is that multiple genes and environmental factors can each contribute small, additive effects that can summate to produce a disease state when some threshold value is exceeded. Our findings indicate that different pathogenic ion channel mutations can sometimes form therapeutic combinations with effects that mask one another.