02.07>> EPILEPSY    
Too Much Brain Excitement
Could Be Harmful To Your Health

Sometimes when you turn off a car engine it will continue to run for a while on its own. The cylinders keep firing even though they shouldn’t. This condition is called dieseling and indicates a problem with the motor that needs to be fixed. Something similar happens in the brain of a person with epilepsy.

Have you ever seen somebody stop doing something and just shake, or stare into space? If you have, it can be pretty scary. That person may be having a seizure. Seizures are one symptom of epilepsy. Epilepsy is characterized by frequent seizures. One important fact to remember: there are many types of epilepsy that may affect muscle control, mental focus, speech, even consciousness.

Epilepsy affects more than 2 million Americans. The illness can start in infancy, childhood, teen years, maturity or old age. But once it starts, it becomes a lasting condition of the patient.

Epilepsy may arise from conditions in the patient’s brain at birth. Or, it may be caused by an injury such as head trauma, or what doctors call an insult, such as a drug overdose, viral or bacterial infection, inflammation or fever. One type of epilepsy called temporal lobe epilepsy does not necessarily occur immediately. It may take years or even decades before the symptoms of temporal lobe epilepsy appear.

Patients and physicians need new treatments for epilepsy. Why? The current treatments are far less than perfect. Drugs that reduce the occurrence of seizures can have severe side effects even if they control the seizures. Epileptics whose seizures are not effectively controlled by drug therapy will often have brain surgery to remove large parts of the hippocampus where the seizure is thought to begin. But taking out parts of the brain always has a consequence: in this case it can result in severe short-term memory loss and learning disabilities.

“These surgical options don’t work well for many epileptics, and cause awful side effects even if they do,” says Dr. Shelley Russek, who studies epilepsy at the Boston University School of Medicine. She and her research team are trying to understand the basic mechanisms of temporal lobe epilepsy. That is the only foundation on which better future treatments for epilepsy may be constructed.

Her work has led to a discovery: a change in the molecular structure of a receptor (part of a nerve in the brain) has been shown to cause a form of epilepsy. This is the first time a change in such a molecular structure has been conclusively shown to cause a disease. It is often true that a tiny, minuscule change in your body can have enormous consequences.

Here is the story behind the Boston University breakthrough.

The human brain includes almost 100 billion nerve cells (www.epilepsy.com). For those of you with a mathematical bent, that’s 10¹¹. These nerve cells (officially called neurons) send messages to each other using electrical impulses. How do neurons send messages?

Neurons are separated by a space called a synapse. When a neuron wants to communicate with another neuron, it releases chemicals known as neurotransmitters that travel across the synapse to the next neuron . The neurotransmitters stimulate the next neuron to fire. All this happens pretty fast. Why do neurons need to communicate? To start muscles, create memories, recall facts, hold your breath, react to danger; in fact, anything the brain controls requires electrical impulses traveling along neurons.

Not too much. Not too little.

The firing of a neuron is a delicate balance: first, starting the release of neurotransmitters and then, when necessary, stopping it. Vocabulary to know: when a neuron is releasing neurotransmitters it is excited; to stop it, the neuron must be inhibited. In normal circumstances, this happens automatically in your brain.

If a neuron is not stopped (inhibited), it will continue to fire like the dieseling auto engine and will continue to send messages to other neurons, causing them to fire too. In the normal brain, a neuron may fire 80 times per second, but during an epileptic seizure, a neuron may fire up to 500 times per second (www.epilepsy.com). The current theory on the cause of an epileptic seizure is that certain neurons are not inhibited, so they continue to fire, in a cascade of over-excitation.

So, fully understanding inhibition – stopping – of this firing is critical to understanding epilepsy. “The pauses between excitation are just as important as the excitation itself”
says Dr. Russek.

Here’s where it gets a little complicated, but also very interesting: Inhibition is controlled by a specific neurotransmitter called gamma-amino butyric acid (thankfully, shortened to GABA).

GABA works by attaching to little structures in the cells called receptors. Once the GABA attaches to a receptor, a specific chemical reaction takes place. In neurons, the important receptors are called GABA(A) receptors: they are crucial to inhibition.

1. When a neuron fires, GABA binds to the GABA(A) receptor in the neuron.
2.   The GABA(A) receptor opens a hole in the neuron’s membrane. The hole is specific for the negatively charged chloride ion (Cl-).
3.   Cl- will go into the neuron, and inhibit it.
4.   However, if the GABA(A) receptor is not functioning properly, the neuron will remain in an excited, firing state.

Dr. Russek and her research colleagues study the behavior of GABA(A) receptors as a cause of Temporal Lobe Epilepsy (TLE). Dr. Russek and her collaborator at the Children’s Hospital of Philadelphia, Amy Brooks-Kayal, use an animal model that simulates the initial injury, which is followed by the development of chronic seizures or epilepsy in rats.

The researchers knew that there were many subunits of GABA(A) receptors and that there was a specific gene for turning each subunit ON or OFF. They discovered that just before a seizure, changes occurred in the levels of specific parts of two subunits. Specifically, the mRNAs of the α4 subunit gene receptor increased (turned ON) and the mRNAs of the α1 subunit gene decreased (turned OFF). (Scientists like to use Greek letters: in this case, the letter α, pronounced alpha.) Somehow the subsequent change in the molecular composition of the GABA(A) receptors was resulting in a seizure.

To study this change in gene expression, Dr. Russek and her collaborator Dr. Brooks-Kayal created a virus that would use the genetic switches in the α4 subunit gene to deliver the α1 gene product. This process is called viral vector gene transfer. “The viral model is perfect for this kind of work,” says Dr. Russek, “because viruses are experts at getting into the cells and we can put them exactly where they are needed.” The researchers injected the virus into a part of the brain that is the site of most seizure activity.

Two weeks after injection Dr. Russek and her colleagues found that the injected virus increased the levels of the α1 GABA(A) receptor subunit in the rat brains. When rats were injected with the virus before developing continued seizures, the rats did not develop spontaneous epilepsy. “We demonstrated that expression of GABA(A) receptor subunits is important in inducing a seizure,” says Dr. Russek.

These researchers also demonstrated that the α1 subunit is important in maintaining inhibition in the brain and may be one of the keys to determine if epilepsy occurs after an injury. This is the first time a change in the expression of one subunit of a multi-subunit receptor has been associated with a disease like epilepsy.

These results are exciting, but the team has not yet determined whether the virus acted to suppress the seizures or whether it actually prevented the development of the epileptic condition. This is an important distinction to determine how the findings can best be translated into a treatment.

Dr. Russek and Dr. Brooks-Kayal would like to see something done about the plight of people with epilepsy in this country. One option is gene therapy. A virus similar to the one used in rats could be injected into the brain of an epileptic to suppress seizures. “Gene therapy,” says Dr. Russek, “has a promise for being used in the near future (10 years) by neurosurgeons as a treatment for epilepsy and much work is going into making more stable viruses with less toxicity.”

People with epilepsy. Can you identify them?
1. Actor Danny Glover
2.   Russian revolutionary
Vladimir Lenin
3.   Singer/actor/musician
Adam Horovitz
4.   Runner Florence Griffith Joyner (Flo-Jo)

Student Worksheet
Feburary 2007
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Feburary 2007

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What A Year! is a project of the Massachusetts Society for Medical Research.

And it is funded by a grant from The William Townsend Porter Foundation

  Dr. Shelley Russek is a molecular neurobiologist/pharmacologist who is an Associate Professor in the Department of Pharmacology and Experimental Therapeutics at Boston University School of Medicine. She began her career as a singer and musician, with several Broadway appearances in Hair and The Me Nobody Knows. She played the piano, wrote and sang rock music, made many records, and was even on the Merv Griffin Show. “After being out of college for 8 years,” says Russek, “I wasn’t happy with the way my life was going.” So she went back to graduate school to study pharmacology and the brain with a leader in the field of neuropharmacology and GABA, Dr. David Farb. Along the way she met wonderful people who shared a passion about science and curing disease. Her current collaboration with Dr. Amy Brooks-Kayal, a clinician/researcher with a specialty in pediatric epilepsy has been especially rewarding. “This is the perfect collaboration,” Dr. Russek explains “We are like two sisters whose efforts come together to build a whole that is so much more than the sum of its parts.” Together they hope to find better treatments, and, hopefully, a cure for epilepsy.

To Learn More:

  • Raol Y, Lund I, Bandyopadhyay S, Zhang G, Roberts D, Wolfe J, Russek S, Brooks-Kayal A. Enhancing GABAa receptor ?1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. Journal of Neuroscience, 26(44): 11342-11346, 2006.
  • Roberts DS, Hu Y, Lund IV, Brooks-Kayal AR, Russek SJ. Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor ?4 subunits in hippocampal neurons. Journal of Biological Chemistry, 281(40): 29431-29435, 2006.
  • Roberts DS, Raol, YH, Bandyopadhyay S, Lund IV, Budreck EC, Passini MA, Wolfe JH, Brooks-Kayal AR, Russek SJ. Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA (A) receptor alpha4 subunit expression. Proceedings of the National Academy of Science 102(33): 11894-11899, 2005.

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Written by Rebecca Kranz with Andrea R. Gwosdow, PhD

Gwosdow Associates



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