Molecular Inner Workings Of Rare Epilepsy May Shed Light On Other Brain Disorders, According To Penn Scientists

October 20, 1997

A rare form of epilepsy, recognized only three years ago by German investigators, and often misdiagnosed as nightmares, could help neuroscientists better understand a host of nervous-system disorders. Researchers at the University of Pennsylvania Medical Center have discovered how the mutation of a common nerve-cell receptor that causes this type of epilepsy--characterized by brief, moderate seizures during light sleep--works at a molecular level.

The mutation essentially impairs signaling between nerve cells. The investigators, led by Jon Lindstrom, PhD, Trustee Professor of Neuroscience, studied how altered properties of a mutant nicotinic receptor--so-named because of its interaction with nicotine--could cause seizures in people with an inherited form of epilepsy called autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). "There are many types of nicotinic receptors, many of which are also associated with tobacco addiction, and such diseases as Alzheimer's, Parkinson's, myasthenia gravis, and possibly schizophrenia," explains Lindstrom. The researchers will present their findings at the 1997 meeting of the Society for Neuroscience in New Orleans and will publish the study in an upcoming issue of the Journal of Neuroscience.

ADNFLE is linked to a mistake in the gene that encodes a protein that forms a subunit of nicotinic receptors. These receptors respond to the neurotransmitter acetylcholine, providing a critical link in sending electrical signals between nerves and between nerves and other tissues, including muscles. Nicotinic receptors are important in mediating all sorts of physiological processes, like heart rate and hormone release, as well as signaling between nerve cells that control such phenomena as alertness, sleep, emotion, and memory.

Nerve cells release acetylcholine, which binds to a nicotinic receptor on a receiving cell. This binding opens a channel through the center of the receptor protein, allowing such positively charged ions as calcium, sodium, and potassium to pass through the cell membrane. This change in ion concentration inside the cell creates an electrical charge across the membrane, the first step in neurotransmission.

"The mutation occurs in the lining of the channels, causing several dramatic changes in its normal function," notes Lindstrom. The researchers hypothesize that two mutated amino-acid chains stick out into the middle of the channel, thereby affecting ion passage.

When the researchers continually exposed mutant receptors to acetylcholine, the channels became more desensitized than normal receptors under similar conditions, meaning acetylcholine no longer opened the channel. Mutant receptors stay open for a much shorter time, allowing fewer ions to pass, with a concomitant weaker electrical signal. The mutant receptors also completely lack the ability to conduct calcium ions, important regulators of neurotransmission.

However, there is a paradox to these findings. Epileptic seizures are actually caused by the overexcitation of nerve cells. Because nicotinic receptor channels allow positive ions to pass, they are expected to cause nerves to fire. But, how could a mutation that handicaps this type of receptor cause seizures? "We suspect that the mutation reduces the inhibition of nerve-cell excitation at critical times--for example, when a person is waking up or dozing off," says Lindstrom. "The release of this inhibition could explain the excessive excitation that leads to an epileptic seizure."

Penn neuroscientists Alexander Kuryatov, Volodymyr Gerzanich, Mark Nelson, and Felix Olale collaborated on this study, which was funded by the National Institutes of Health, the Smokeless Tobacco Research Council, Inc., and the Muscular Dystrophy Association.

Editor's Note: Dr. Lindstrom can be reached at 215-662-4392 until Oct. 24, after which time he will be at the Society for Neuroscience meeting. To find out how to reach him at the meeting call 215-662-2560.

The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1996, the medical center received $149 million. In addition, for the second consecutive year, the institution posted the highest growth rate in research activity--9.1 percent--of the top-ten U.S. academic medical centers during the same period. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's webpage ( and EurekAlert! (, a resource sponsored by the American Association for the Advancement of Science.

University of Pennsylvania School of Medicine

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