From left, Wangzhen Shen, M.D., Jingqiong Kang, M.D., Ph.D., and Robert Macdonald, M.D., Ph.D.
Photo by Dana Johnson
Seizure research heats up with new molecular clues
It's one of those unavoidable facts of life — kids get sick and have fevers. Usually, those elevated internal temperatures cause only temporary discomfort, but in some small children they spark convulsions called “febrile seizures.”
These convulsions are “scary and very upsetting to parents,” said Robert L. Macdonald, M.D., Ph.D., professor and chair of Neurology.
They've also been something of an enigma, he said. The epilepsy research community has struggled to understand how fever ignites convulsions and how to treat them.
Macdonald and colleagues including Jing-Qiong Kang, M.D., Ph.D., research assistant professor of Neurology, have now discovered a molecular mechanism that could explain febrile seizures. The research, published last week in The Journal of Neuroscience, may lead to new approaches for preventing recurrent febrile seizures in vulnerable children.
Febrile seizures affect as many as one in 15 children worldwide, generally between the ages of 6 months and 6 years. Most children will suffer no long-term consequences from the convulsions, which tend to be generalized — involving the whole body — but some will go on to develop epilepsy.
“It has been very controversial through the years: do you treat febrile seizures or not?” Macdonald said. Several studies have investigated treating children with anti-seizure medications such as phenobarbital or sodium valproate to prevent recurrent febrile seizures, but the studies showed only limited benefit to the approach, Macdonald said.
“That idea has gone by the wayside, and it has not been replaced with any rational strategy for preventing or avoiding subsequent febrile seizures,” he said. “The promise of knowing what causes the febrile seizures is part of the excitement about this work.”
Kang got interested in febrile seizures when she was working as a neurologist and epilepsy specialist in her native China.
“I was always impressed by how quickly fevers can trigger convulsions in children,” she said. “I have been curious about this mystery for years.”
Kang came to Vanderbilt to work with Macdonald, internationally renowned for his research on epilepsy and GABA-A receptors, proteins on the surfaces of nerve cells that normally quiet the brain's excited chatter.
GABA-A receptors were long suspected to play a role in epilepsy because they are the major inhibitory receptors in the brain and might therefore dampen the hyperexcitability that characterizes seizures. Phenobarbital and other barbiturate drugs and anti-anxiety drugs like Valium exert their calming effects by enhancing the activity of GABA-A receptors.
Indeed, mutations in GABA-A receptors were linked to inherited forms of epilepsy beginning in 2001. Macdonald's group has been characterizing the functional defects of the mutant GABA-A receptors, offering insight into the mechanisms underlying those epilepsies.
One of the common features in the families with mutations in the GABA-A receptor gamma subunit — one of several protein “parts” that come together to make a functional receptor — is a history of febrile seizures.
Kang and Macdonald had already discovered that GABA-A receptors containing mutant gamma subunits were not as good at getting to the neuronal cell surface, and Kang wondered what would happen to these receptors when they were exposed to high temperatures. She raised the temperature of cells expressing the mutant receptors to 40 degrees Celsius, simulating a “fever” of 104 degrees Fahrenheit, and she found that the receptors disappeared from the cell surface.
Fewer inhibitory GABA-A receptors on the cell membrane could leave a neuron open to the excitation and repetitive firing that characterizes seizures. The investigators are currently studying where the receptors go when the temperature is raised — are they taken inside the cell more quickly, are they degraded, is their forward insertion into the cell membrane slowed?
“Trying to get at why the surface receptor levels are reduced requires a whole set of complicated approaches,” Macdonald said. “It's like looking out the window and counting the cars on the street: it's easy to count how many are there at any time, but if we want to know where they all came from and where they're all going, that's a whole different problem.”
The team's discovery that high temperature reduces cell surface GABA-A receptor levels “raises the idea that one could develop a treatment for vulnerable patients that would prevent them from developing febrile seizures and possibly epilepsy,” Macdonald said.
Vulnerable patients include children who suffer recurrent febrile seizures, febrile seizures that involve only part of the body (partial instead of generalized), and long-lasting febrile seizures, as well as children with genetic mutations linked to inherited epilepsies. These patients have a higher incidence of developing epilepsy.
“There's a huge incidence of febrile seizures, so even though only a small percentage — 2 to 4 percent — progress to epilepsy, it represents a large burden of epilepsy in the world,” Macdonald said. “Our findings are attracting attention because they show a novel mechanism for febrile seizures, and now that we know a vulnerable step, we can in principle design therapeutic strategies to overcome it.”
Wangzhen Shen, M.D., also contributed to the research, which was supported by the National Institutes of Health.