Epilepsy was known in ancient times, when the Greek physician Hippocrates disparaged the popular notion that seizures arose from divine intervention. The disease has remained stubbornly mysterious, but new scientific tactics finally are helping researchers pick up the pace in solving its mysteries. New treatment ideas also are emerging.
In fact, UCSF researchers now believe it might one day be possible to prevent seizures by transplanting cells into the brain.
Aggressive forms of the disease may warrant such aggressive new treatment approaches. Uncontrolled seizures, especially in young children, cause great misery and over time may even cause brain damage. In many cases, epilepsy is not controlled by antiseizure medications. The available drugs also have significant side effects.
Surgeons already remove bits of a part of the brain called the hippocampus in some patients with uncontrolled cases of epilepsy that arise in the brain’s temporal lobe. Children who have uncontrolled seizures may undergo a more invasive form of surgery to remove larger portions of the brain – sometimes even an entire brain hemisphere – with serious consequences for development.
Scott C. Baraban, PhD, is a key bench scientist among the UCSF scientific collaborators investigating cell transplantation as an alternative to removing brain tissue in epilepsy.
“The forms of intractable epilepsy seen in children tend to be widespread throughout the brain,” Baraban says. “If transplanted cells integrate rapidly and in a widespread fashion, then transplantation might be very useful as a potential alternative to removing large regions of the brain.”
Inhibition and Excitation
Baraban, the William K. Bowes, Jr., Endowed Chair in Neuroscience Research, studies the physiology of electrical signaling in the brain – especially the damper put on signaling by inhibitory nerve cells called interneurons.
Epileptic seizures result from uncontrolled and widespread electrical signaling. During a seizure, large networks of neurons fire at the same time.
An electrical imbalance triggers seizures. Research from Baraban’s lab and other labs suggests that the failure of interneurons to effectively inhibit excitatory circuits within the brain plays a key role in epilepsy. Too few inhibitory signals are transmitted, and excitatory inputs win the day. The result is a chain reaction, an inferno of firing neurons.
The stem cells used in the UCSF cell transplantation experiments consist of a specific set of embryonic brain cells, most of which mature to become inhibitory interneurons. In mice, Baraban and colleagues recently have shown that these progenitors integrate within the host brain, making new connections with other host neurons. The inhibitory input provided by the transplanted cells, as they become incorporated into nerve networks, helps to dampen excessive signaling and to prevent seizures.
“The cells actually make new synapses,” Baraban says. “That’s the key feature. By making a new synapse with host cells, a transplanted cell acts more like a native cell. We’re basically rewiring the brain.”
It takes about a month for transplanted cells to spread out from the site of transplantation, settle down at their new neural addresses, grow up and connect with their neighbors.
“Interneurons only comprise about 20 percent of neurons in the cerebral cortex, but one interneuron can make up to 1,000 connections to other neurons,” Baraban says. “These cells might only go to certain places, but they are going to talk to a lot of cells when they get there.”
The transplanted interneurons appear to inhibit signaling enough to quell seizures in mice, but do not otherwise appear to affect their behavior. If these progenitor cells also had given rise to other types of brain cells, the results might not have been so promising, Baraban says.
Cells like these don’t grow on trees. Painstaking research by UCSF colleagues Arturo Alvarez-Buylla, PhD, a world-renowned brain stem cell scientist, and John Rubenstein, MD, PhD, an expert on the origins and molecular characteristics of interneurons, was key.
Their work led to the availability of embryonic cells fated to mature and become these specialized inhibitory cells. Lab tricks make the cells give off fluorescent green light, allowing the neurons to be tracked as they move and settle down within the brains of lab mice.
“About five years ago, Arturo and John just showed up at my office one morning,” Baraban says. “I had never met them. They had this picture of the hippocampus, showing newly born green cells. They told me they had a new technique for making interneurons, and asked me if I wanted to collaborate. It was an obvious fit, and I couldn’t pass it up.”
Treating Children Is a Major Goal
In about 50 percent to 70 percent of epilepsy cases, an underlying cause of seizures cannot be determined. But in recent years, advances in genetics, biochemistry and functional imaging have helped researchers identify the biological basis of some forms of the disease. The Baraban lab team is working with mice that possess the same genetic, biochemical and anatomical defects that are seen in specific types of human epilepsy.
Baraban, Alvarez-Buylla and Rubenstein, along with Arnold Kriegstein, MD, PhD, director of the UCSF Institute for Regeneration Medicine, also have begun working with human stem cells in a project funded by the California Institute for Regenerative Medicine.
The aim is to develop a treatment based on using cell transplantation to boost inhibitory circuits in the brain. While the strategy appears quite promising so far, there is plenty of additional preclinical work to do before any human clinical trials begin.