From Insult to Inquiry: Research Yields Hope for Seizures
Despite our advances in understanding disease, the underlying causes of some conditions continue to elude researchers’ grasp. Epilepsy is one such disorder. But new findings by Cincinnati Children’s researcher Steven Danzer, PhD, show promise of removing some of the mystery around epilepsy and could lead to new, more effective treatments.
"What actually makes the brain epileptic is still not known," says Danzer. "Even though the structural changes in the brain have been known for decades, nobody's been able to prove that any particular change is responsible for producing epilepsy." Furthering the problem, he says, is that treatments currently available for epilepsy are often ineffective and can have serious side effects.
"You’re between a rock and hard place because you have to control seizures, so you put patients on anti-convulsive drugs," Danzer says. "But we know a lot of these drugs are going to affect development in negative ways. We’d like to find something that can treat people without the side effects."
Danzer’s research focuses on temporal lobe epilepsy, which involves the hippocampus and associated regions. "One of the reasons we focus on this region is that it’s the site of one of the more common but difficult-to-treat forms of epilepsy," he says.
He explains that medications often don’t work for patients whose seizures originate in this portion of the brain, which is responsible for learning and memory. The hippocampal region is also one of the few structures in the adult brain that continues to produce new cells, says Danzer. "Up until about 10 to 20 years ago, it was dogma that, in adulthood, you had all the brain cells that you were ever going to get and you didn't grow any more."
It turned out that this was not the case.
"Only recently, it became clear that the region of the hippocampus called the dentate gyrus continually produces new cells throughout life," Danzer says.
It is believed that the generation of new cells is important for the hippocampus to function. And even though the idea that new cells are being born all the time in adults and children sounds good, Danzer cautions that this neurogenesis may be the root of the problem in epileptic development.
The Downside of New Cell Development
"What we’re finding is that in the case of epilepsy, this neurogenesis may be a bad thing," says Danzer. "We know that the developing brain is sensitive to all kinds of toxic insults. In the adult brain, most of the brain is mature but you have this one population of cells being continually generated. Because these are younger cells, they may have similar vulnerabilities to toxic insults that we see in the developing brain."
"Decades of research from many labs have previously shown that in the epileptic brain, many of the cells located in this neurogenic region of the hippocampus have excessive numbers of connections with their neighbors," explains Danzer. "Now you have a short circuit in the brain with a population of neurons connected to itself. Epilepsy is characterized by uncontrolled, rhythmic firing of populations of neurons, so if you have a lot of neurons connected to each other, we speculate that it might contribute to epilepsy."
Previous studies have also shown that there is a burst of neurogenesis in animal models that have experienced an epileptogenic insult. When this happens, the new cells are no longer being born under normal conditions.
"What was not known, however," says Danzer, "was whether the cells produced in this burst of neurogenesis were also responsible for creating the short circuit."
To test the effect of this brain insult on developing cells, Danzer and his team analyzed the cells from transgenic mice. Using a neural birth dating technique, they looked at cells of a known age to determine if immature cells responded to the insult differently than mature cells.
"What we found was, the young cells were particularly susceptible to epileptogenic insults," he says. "So we've been able to show that these young cells do indeed contribute to the creation of short circuits in the epileptic brain, and may contribute to the development of epilepsy."
What's Next?
Danzer is currently building on these discoveries with the hope that a new treatment may be on the horizon. "We’re going to use other genetic strategies to see if we can either modify these cells to prevent them from developing abnormalities or to eliminate them altogether," he says. This could lead to less invasive treatment for patients whose seizures originate in the hippocampus.
"One of the last-line treatment strategies for epilepsy is to remove the portion of the brain identified as epileptic. It's highly effective, but it often causes some loss of function," says Danzer. "If we could demonstrate that the new cells born after an insult to the brain were the cause of making the brain epileptic, then we could think about whether there was a way to go in and selectively remove just the bad cells while leaving most of the structure intact."
Danzer and his team are currently performing experiments to see what happens if they ablate the abnormal cells. "Our hope is we’ll see fewer seizures or no seizures at all. If this work pans out, we may have down the line a new treatment for epilepsy"
