An "electric" fish's genetics may help researchers understand epilepsy and arrhythmias

Clues to understanding human disease can turn up in the most unexpected places.

For instance, the gene responsible for the ghost knifefish's electric ‘spark’ may help researchers understand epilepsy and arrhythmias.

^{Photo by G. Troy Smith}

A new study reveals how the evolutionary modification of a sodium channel gene allows the fish to generate ultra-rapid electrical pulses that help them communicate and navigate their surroundings. While this adaptation has been highly beneficial to the fish, similar alterations to this gene can cause serious human diseases, including epilepsy, cardiac arrhythmia, and extreme pain disorder. 

“This study is a good example of how a basic science question from a field like marine evolution can help us better understand the molecular processes underpinning the function of our nervous system and the pathogenesis of related diseases,” says Danny Infield, PhD, a University of Iowa postdoctoral researcher.

He works with Chris Ahern, PhD, associate professor of molecular physiology and biophysics at the UI Carver College of Medicine and a member of the Iowa Neuroscience Institute.

Infield joins Ammon Thompson at University of Texas, Austin, as co-first authors on the study, which was published in PLOS Biology.

How the ghost knifefish got its spark

The basic science question under investigation was how do South American ghost knifefish generate the highest frequency electrical discharge in any animal?

Scientists at UT Austin, led by Harold Zakon, PhD, discovered that an unusual voltage-gated sodium channel contributes to the fish’s ability to send out rapid-fire electrical signals (often exceeding 1,000 pulses per second, or 1kHz.)

Knowing that Ahern and his Iowa team were experts on voltage-gated sodium channels, the UT Austin researchers joined forces with the UI group to analyze the gene’s sequence and investigate the function of the new sodium channel.

The role of sodium channels

Sodium channels are tiny pores that allow positively charged sodium ions in and out of cells in a tightly regulated manner, allowing the generation of electrical signals to regulate cellular functions such as muscle contraction. Voltage-gated sodium channels open and close in response to the voltage across the cell membrane.

The team found that evolutionary changes to the gene sequence over a period of 2 million years had shifted expression of the sodium channel from muscle cells to specialized nerve cells. The new gene also acquired mutations that created a molecular “glitch” causing the channel’s persistent electrical discharge ability.

“It turns out, the channel has unique mutations that cripple its ability to ‘inactivate’ or turn off,” Infield says. “While this is part of the fish’s normal physiology, in the human body this incomplete inactivation would be a very bad thing. In fact, it is a cause of many human diseases, including epilepsy, cardiac arrhythmia, and extreme pain disorder.”

The study also suggests that the gene mutations likely mediate the inactivation by creating subtle changes in how two critical parts of the sodium channel fit together.

Studies like this help the UI team better understand how voltage-gated sodium channels function as well as how disruption of these proteins might cause disease.

“Our ultimate goal is to figure out how to repair or modulate these channels to restore health,” Infield adds.

The team also included scientists at Indiana University in Bloomington and was funded in part by grants from the National Science Foundation and the National Institutes of Health.