Epilepsy Gene Can Be Switched On

Researchers at Wake Forest University School of Medicine have uncovered something that may help explain how people not genetically predisposed to epilepsy develop the disorder.

Published in the Journal of Neuroscience, the study(1) reports that a gene known to predispose people who inherit an active form of it to certain forms of epilepsy, can be “switched on” in mice that do not appear to have inherited the active form, and thus a genetic predisposition, to the condition.

The susceptibility gene codes for a calcium channel in the brain which is associated with seizures, so the discovery may disclose a mechanism by which epilepsy develops in those with no apparent genetic predisposition to it. (The gene that codes for the misplaced channel has been called a “susceptibility gene” within the research community, because it shows up in the genetic makeup of some individuals with epilepsy. In other individuals, there is no genetic clue that they are capable of making extra copies of the channel.)

On – Off Switch?

If these calcium channels can be switched on, leading to epilepsy, is it possible that the gene can be switched off somehow, and the epilepsy along with it?

We do know that certain drugs can inhibit calcium channels, so, if researchers can determine that the over-expression of this calcium channel is solely responsible for seizure activity, future studies could look into the possibility of selectively inhibiting the channel with drugs, or even nutritional changes. But switching the susceptibility gene off is a more complex proposition, since it is not clear just how the gene switches on yet.

“Epilepsy is a terrible disorder that affects millions of kids and adults all over the world,” said Dwayne W. Godwin, Ph.D, senior researcher. “There are many different forms of epilepsy with different symptoms. We don’t know why some people acquire epilepsy – the cause isn’t always clear from the person’s genetic makeup. We do know that in some forms of epilepsy, once someone has a seizure they tend to have more. Our findings from this study suggest that something about the brain changes that can lead to this increased tendency to have a seizure. Our study shows that an important change occurs in calcium channels that help to transmit this abnormal activity throughout the brain.”

Calcium Channels and Epilepsy

Calcium channels exist throughout the body; they are responsible for several important functions, dependent on their quantity and placement. In the brain, calcium channels are normally embedded in the brain cell membranes, where they allow for passage of calcium ions into the cell and for the electrical activity of the brain. Passage of calcium ions into cells determines how excitable the cells are, and how easily abnormal activity spreads throughout the brain.

In epilepsy, a particular channel shows up where it is not supposed to or appears in too many or too few numbers, and the function that channel is responsible for can become anomalous. Scientists know that during epileptic seizures, these calcium channels in the brain, responsible for generating electrical brain rhythms, become highly active.

In the Wake Forest study, researchers employed a mouse pilocarpine model(2) to watch changes in tissue from regions of the brain involved in seizures- the hippocampus and the thalamus. They measured the changes at different intervals as the mice developed epilepsy. The researchers found that after an initial seizure, more of a specific type of calcium channel starts to be expressed where it wasn’t before, and the presence of the channel is linked to brain activity that became increasingly abnormal and epileptic.

Thalamus and Hippocampus Activity

Usually the hippocampus is looked in studies of epilepsy, but the new channels were being made in a region of the brain known as the thalamus, which is connected to the hippocampus and involved in the spread of seizures through the brain.

“Certain kinds of channels are normal and expected in the thalamus, but after an initial seizure more copies of a channel that isn’t normally found in this brain region begin to appear,” says John Graef, first author on the study. “The brain activity then becomes dominated by the new copies of this channel. It helps explain how seizures can develop and spread.” According to Godwin, the study provides vital information but further work needs to be done to apply the findings to human patients.

“What we’ve shown is that this gene can be switched on in individuals who don’t appear to have inherited the susceptibility,” Godwin said.

References

1. John D. Graef, Brian K. Nordskog, Walter F. Wiggins, and Dwayne W. Godwin – An Acquired Channelopathy Involving Thalamic T-Type Ca2+ Channels after Status Epilepticus – J. Neurosci., Apr 2009; 29: 4430 – 4441 ; doi:10.1523/JNEUROSCI.0198-09.2009

2. E. A. Cavalheiro , N. F. Santos, M. R. Priel – The Pilocarpine Model of Epilepsy in Mice – Epilepsia Volume 37 Issue 10, Pages 1015 – 1019

Image by Natalie M. Zahr, Ph.D., and Edith V. Sullivan, Ph.D.