Epilepsy Can Be Triggered by Support Cells in the Brain

For release: Thursday, December 15, 2005

For decades, researchers have tried to understand what triggers clusters of neurons to begin signaling excessively in epilepsy.  A new study shows that, in many cases, the answer resides in star-shaped support cells called astrocytes.   The finding may lead to new ways of treating epilepsy.

Astrocytes are extremely common in the human brain, outnumbering neurons by a factor of 10.   Yet, until recently, no one had a good idea of how they affect brain activity.  During the last decade, studies have shown that astrocytes play a central role in brain function and even produce the nerve-signaling chemical glutamate.  They also act as "housekeepers", cleaning up pollution in the neural environment that would otherwise interfere with normal brain function.  In the new study, researchers led by Maiken Nedergaard, M.D., D.MSc., of the University of Rochester , showed that glutamate produced by astrocytes can trigger seizures.  They also showed that some of the drugs currently used to treat epilepsy interfere with this process.  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the September 2005 issue of Nature Medicine.*

In the new study, Dr. Nedergaard and her colleagues triggered seizure activity in cultured brain tissue by adding a chemical called 4-aminopyridine (4-AP).  They then treated the tissue with chemicals that prevented neurons from "firing", or releasing signals across nerve synapses.   Surprisingly, the neurons still showed "depolarization shifts," electrical changes that normally trigger neuronal firing.  Tests showed that glutamate released by astrocytes triggered these changes.  

"Even if we block all synaptic activity, we still have the triggers of a seizure," says Dr. Nedergaard.  

The researchers found that 4-AP caused astrocytes to release glutamate even when there were no neurons in the culture, showing that the drug influenced astrocytes directly and not as a result of neuronal activity.  They prompted a single astrocyte to release glutamate and other chemicals and showed that this release prompted depolarization shifts in nearby neurons.  They also tested their results in rodents that were treated with chemicals to induce seizures and found that 70 to 90 percent of the depolarizations in neurons of these animals continued to occur even when all synaptic activity was blocked.  The anti-seizure drugs valproate, gabapentin, and phenytoin significantly reduced astrocyte-triggered seizure activity when animals were given 4-AP.

This study is the first to show that astrocytes help to initiate seizure activity.   Researchers previously thought that seizures were generated by problems with the neurons themselves.  When astrocytes are healthy and act normally, they can prevent neural activity from going out of control.  If astrocytes are damaged, however, the situation changes.  "It's like the housekeeper going berserk," says Dr. Nedergaard.  Instead of cleaning up the environment around neurons, the astrocytes may start contributing to the mess.

Epilepsy and many other neurological diseases are characterized by a condition called reactive gliosis, in which astrocytes swell and stop functioning correctly.  Researchers previously thought that, in epilepsy, this swelling resulted from excessive nerve signaling.  The new finding suggests that reactive gliosis in the brain may actually be a cause of epilepsy rather than the result.  While unusual neural signals may initially trigger the astrocyte malfunction, the swollen, damaged astrocytes can then magnify the signaling and create a seizure focus in the brain, Dr. Nedergaard says.  Genetic problems that affect astrocyte function and brain damage from stroke, head injury, brain tumors, or other problems also may trigger epilepsy.  The new findings could explain why seizures often develop months after the brain is damaged, when reactive gliosis has had time to form, she adds.

The role of astrocytes and other support cells in the brain is particularly important for neurons because they are specialized and their signaling is very complicated, Dr. Nedergaard says.  If the environment around the neurons is not healthy and they do not get the support they need, problems can easily develop.  She has previously shown that astrocytes contribute to the neuronal damage that occurs after spinal cord injury, and she is now studying how these cells may contribute to Alzheimer's disease.

"Astrocytes are becoming increasingly important in our understanding of common diseases, such as brain tumor, stroke, and now epilepsy," says Tom Jacobs, Ph.D., the program director for Dr. Nedergaard's NINDS grants.  "These cells provide new targets for us to consider in developing treatments for many neurological diseases."  An emerging concept in neuroscience is that communication between the brain and the environment occurs through a "neurovascular unit" made up of neurons, astrocytes, and the endothelial cells that line blood vessels, he adds.  Astrocytes are the critical middlemen that translate signals from the blood vessels to the neurons and vice versa.  This communication is proving significant to the understanding of stroke,epilepsy, and many other neurological diseases.

Dr. Nedergaard and her colleagues are now planning studies to examine the role of astrocytes in animals with gene defects that lead to epilepsy, she says.   This will help them better understand how the disease develops naturally.  Humans have many more astrocytes than rodents, so the role of astrocytes in human disease may be even more significant than this study indicated, she adds.

Ultimately, researchers might be able to identify drugs that can treat epilepsy by changing how astrocytes function, instead of slowing neuronal activity as current drugs do, Dr. Nedergaard says.  Such treatments might prove to be more effective than current drugs, with fewer side effects.  If they could be used soon after brain damage, astrocyte-focused therapies might even be able to prevent epilepsy completely.

The NINDS is the nation’s primary funder of research on the brain and nervous system. More information about the NINDS and its mission is available at www.ninds.nih.gov.

The National Institutes of Health (NIH)—the nation's medical research agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

*Tian G-F, Azmi H, Takano T, Xu Q, Peng W, Lin J, Oberheim N, Lou N, Want X, Zielke HR, Kang J, Nedergaard M.  "An astrocytic basis of epilepsy."  Nature Medicine, September 2005, Vol.11, No. 9, pp. 973-981.

- by Natalie Frazin

 

Date Last Modified: Wednesday, January 31, 2007

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