News Release: Research , School of Medicine

Mar. 26,  2010

Model of Genetic Epilepsy Shows Which Neurons are Affected

News Article ImageVideo: Dr. Andrew Escayg explains the science behind the new study.

Scientists have created a mouse model of a genetic form of human epilepsy called GEFS+ (generalized epilepsy with febrile seizures plus). In humans, GEFS+ begins with febrile seizures (seizure caused by high fever) in early childhood and progresses to seizures not linked to fever later on.

The model will allow the scientists to dissect which types of neurons are affected and precisely define the physiological changes brought about by one of the mutations that causes this form of epilepsy.

"If the goal is designing a therapy for this type of epilepsy and other related epilepsies, identifying the specific population of neurons that are most affected will be very helpful," says Andrew Escayg, PhD, assistant professor of human genetics at Emory University School of Medicine.

The results are published in the March 26 issue of the Journal of Biological Chemistry.

The first author of the paper was former graduate student Melinda Martin. The research was performed in collaboration with Alan Goldin, MD, PhD, professor of anatomy and neurobiology at University of California, Irvine.

Most types of epilepsy do not stem from mutations in a single gene. An exception to this rule, GEFS+ is caused by mutations in genes that control the excitability of neurons in the brain. Most cases involve mutations in genes encoding sodium channels, which control excitability by opening in response to changes in voltage and allowing sodium ions to rush into the cell. There are several genes encoding sodium channels in both mice and humans, so a mutation in one doesn't completely shut down this function.

Martin, Escayg and colleagues used genetic engineering techniques to create a mouse with a subtle mutation in one of the sodium channel genes SCN1A: one amino acid in the corresponding protein was changed. This matches a mutation observed in a human family with GEFS+. The mutation doesn't completely disable the gene, but it does appear to alter its activity. More severe, disabling mutations in the same gene cause Dravet syndrome, also known as SMEI (severe myoclonic epilepsy of infancy).

"The general idea about GEFS+ mutations is that they produce changes in neuron excitability, but previously, the effects were studied in frog cells or non-neuronal cells," Escayg says. "There's a clear advantage to looking at sodium channel function in the natural context."

Mice with the SCN1A mutation have occasional seizures and are more susceptible to experimentally induced febrile seizures, Escayg and colleagues found. The anticonvulsant medication, valproic acid, which is used to treat patients with epilepsy, was also effective in treating the mice.

The researchers took brain tissue from the mutant mice and dissociated it into neurons grown in culture. Broadly, neurons can be separated into two types according to their shape: pyramidal, which tend to be excitatory, and bipolar, which tend to be inhibitory. Only bipolar neurons were affected by the mutation. These neurons recovered from rapid electrical stimulation more slowly than bipolar neurons from control mice that lacked the GEFS+ mutation. This suggests that the mutation prevents inhibitory neurons from being able to control the electrical signaling patterns of groups of neurons in the brain.

"Bipolar and pyramidal neurons are made up of many different types of neurons," Escayg says. "Our next step is to narrow down which types of bipolar neurons are specifically affected by this mutation."

Escayg and his colleagues have previously observed that another mutation in a related sodium channel gene, SCN8A, dramatically reduces the severity of the seizures caused by mutations in SCN1A. This has led to them exploring the idea that knocking down the second gene in mice by a gene therapy technique called "RNA interference" could counteract the harmful effects of a mutation in SCN1A.

"One hypothesis is that these two mutations affect different kinds of neurons, and they compensate for each other," Escayg says.

The research was supported by the National Institutes of Health and the McKnight Foundation. Escayg receives research funding from Allergan, and the mouse model of GEFS+ described in this manuscript has been licensed to Allergan. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policy.


M.S. Martin et al Altered function of the SCN1A voltage-gated sodium channel leads to gabaergic interneuron abnormalities. J. Biol. Chem. 285: 9823-9834 (2010).

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Writer: Quinn Eastman


The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service.

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