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The Journal of Neurophysiology Vol. 86 No. 3 September 2001, pp. 1211-1225
Copyright ©2001 by the American Physiological Society
1Department of Environmental Science, Policy and Management, Division of Insect Biology and 2Department of Molecular and Cell Biology, Division of Neurobiology, University of California, Berkeley, California 94720
Kuebler, Daniel,
Haiguang Zhang,
Xiaoyun Ren, and
Mark A. Tanouye.
Genetic Suppression of Seizure Susceptibility in
Drosophila. J. Neurophysiol. 86: 1211-1225, 2001. Despite the frequency of seizure disorders in the human
population, the genetic and physiological basis for these defects has
been difficult to resolve. Although many genetic defects that cause
seizure susceptibility have been identified, the defects involve
disparate biological processes, many of which are not neural specific.
The large number and heterogeneous nature of the genes involved makes
it difficult to understand the complex factors underlying the etiology
of seizure disorders. Examining the effect known genetic mutations have
on seizure susceptibility is one approach that may prove fruitful. This
approach may be helpful both in understanding how different
physiological processes affect seizure susceptibility and in
identifying novel therapeutic treatments. In this study, we have taken
advantage of Drosophila, a genetically tractable system, to
identify factors that suppress seizure susceptibility. Of particular
interest has been a group of Drosophila mutants, the
bang-sensitive (BS) mutants, which are much more susceptible to
seizures than wild type. The BS phenotypic class includes at least
eight genes, including three examined in this study, bss,
eas, and sda. Through the generation of double-mutant combinations with other well-characterized Drosophila
mutants, the BS mutants are particularly useful for identifying genetic factors that suppress susceptibility to seizures. We have found that
mutants affecting Na+ channels,
mlenapts and para,
K+ channels, Sh, and electrical
synapses, shak-B2, can suppress seizures
in the BS mutants. This is the first demonstration that these types of
mutations can suppress the development of seizures in any organism.
Reduced neuronal excitability may contribute to seizure suppression.
The best suppressor, mlenapts, causes an
increased stimulation threshold for the giant fiber (GF) consistent
with a reduction in single neuron excitability that could underlie
suppression of seizures. For some other double mutants with
para and ShKS133, there are no
GF threshold changes, but reduced excitability may also be indicated by
a reduction in GF following frequency. These results demonstrate the
utility of Drosophila as a model system for studying seizure
susceptibility and identify physiological processes that modify seizure susceptibility.
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