UCI, Brown work advances quest for novel treatments for inherited disorder
UC Irvine and Brown University researchers have created a new fruit fly model of inherited epilepsy that's providing insights into the mechanisms underlying temperature-dependent seizures while establishing a platform from which to develop therapies for these disorders.
In the Oct. 10 issue of The Journal of Neuroscience, Diane O'Dowd of UCI, Robert Reenan of Brown and colleagues report their method for placing a gene mutation that causes human fever-induced seizures into drosophila fruit flies. As a result, the mutant flies experience heat-induced seizures.
This represents the first time a human genetic disease mutation has been "knocked in" to the equivalent location in the fruit fly genome. The drosophila knock-in model provides a rapid and low-cost basis for defining the neural mechanisms contributing to inherited seizure disorders.
"We can also use this genetic model of human epilepsy in fruit flies to look for new treatments for the disease," said O'Dowd, professor and chair of developmental & cell biology at UCI.
Fever-induced, or febrile, seizures are most commonly seen in children. Only about one in 100 children with febrile seizures develops epilepsy, and most outgrow them by age 5. In contrast, individuals who have the inherited disorder - termed GEFS+ - have febrile seizures that persist beyond childhood and also often develop seizures in the absence of fever.
Reenan, a biology professor at Brown, and Brown undergraduate Jeff Gilligan used a genetic-exchange research method called "homologous recombination" to insert a mutation into the gene in fruit flies that's a direct parallel of the GEFS+ mutation in the human SCN1A sodium channel gene that causes febrile seizures in people.
When placed in tubes that were put in warm water, most of the mutant fruit flies began to experience seizures within 20 to 30 seconds. They would fall over, and their wings would flap and their legs twitch for about two minutes while the flies were kept at a high temperature. The researchers found that seizure susceptibility was dose-dependent: Ninety-five percent of the flies with two copies of the mutant gene had seizures, as opposed to 60 percent of those with just one copy. Unaltered control flies did not have temperature-dependent seizures.
To determine the neurological causes of the seizures, O'Dowd, her postdoctoral fellow and lead study author Lei Sun, and UCI colleagues examined neurons in the brains of both mutant and control flies to monitor activity and see how they behaved as the brains were heated. In the mutant flies, they discovered flaws in the functioning of sodium channels.
"What happens is the mutant channels don't open and close properly," O'Dowd said. "This effect is amplified at high temperature, and this changes the ability of neurons to generate the appropriate electrical signals, leading to hyperactivity in the brain circuits."
"With this knowledge, the next step is to use this model to look for drugs that might reduce or eliminate heat-induced seizures," she added.
In addition to providing insight into the neurology of febrile seizures, the study establishes a new fruit fly model as a viable genetic platform for the study of epilepsy and validates the use of homologous recombination in flies to explore mechanisms underlying other genetically linked diseases.