Brain Pathway That Shuts Down Seizures Uncovered

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A multidisciplinary team of scientists from the University of Iowa and the VA Iowa City Health Care System claims that they have identified a brain pathway that shuts down seizures.

The researchers analysed different clinical observations made in the first half of the 20th century, modern genetics, and molecular biology for their research.

Their efforts showed that an acid-activated ion channel in the brain reacts to a drop in pH (increased acid) in a way that shuts down seizure activity.

According to the research team, the link between low pH in the brain and seizure termination was first hinted at nearly 80 years ago when clinical experiments showed that breathing carbon dioxide, which makes brain tissue more acidic, helps stop epileptic seizures.

The group also says that studies conducted subsequently in the 1950s found that seizures themselves reduce brain pH.

However, they add, it is the modern discovery of an acid-activated ion channel (ASIC1a) in the brain that provided key to their latest discovery.

"We found that ASIC1a does not seem to play a role in how a seizure starts, but as the seizure continues and the pH is reduced, ASIC1a appears to play a role in stopping additional seizure activity," Nature Neuroscience quoted Adam Ziemann, a student in the Medical Scientist Training Program at the UI and co-lead author of the study, as saying.

The study on mice specifically showed that animals without the ASIC1a gene had more severe and longer seizures than those with their genes intact.

It also demonstrated that chemically inactivating ASIC1a increased the severity and duration of seizures in mice with the gene, suggesting that increasing the expression of this gene could protect the mice from severe seizures.

The researchers also observed that reducing the pH in slices of brain tissue expressing ASIC1a in turn led to a reduction in the seizure activity, but acid had no effect on seizures in tissue without the protein.

Upon measuring pH in mouse brains, the researchers found that seizures lower the pH to levels that can activate ASIC1a channels.

They also observed that breathing CO2 causes an additional rapid drop in brain pH, and that breathing 10 percent carbon dioxide was sufficient to protect mice with the ASIC1a protein from lethal seizures.

"In seizures, ASIC1a appears to be activating inhibitory neurons. This is the first study to show that ASIC1a activation can have an inhibitory effect," said Dr. John Wemmie, senior study author and assistant professor of psychiatry in the UI Roy J. and Lucille A. Carver College of Medicine, and a staff physician and researcher at the VA Iowa City Health Care System.

"One of the most exciting aspects of the work is that it highlights the potent anti-epileptic effects of acid in the brain -- effects that have been recognized for nearly 100 years but until recently have been poorly understood -- and it identifies ASIC1a as a key player in mediating the anti-epileptic effect of low pH," Ziemann said.

"We don't know yet, but presumably there might be examples where the seizures don't stop because of a deficit in this pathway," Wemmie added.

Although the vast majority of seizures are self-limiting and stop by themselves, seizures that do not stop can develop into a life-threatening condition called status epilepticus with a mortality rate of up to 20 per cent.

"The discovery helps explain why breathing carbon dioxide stops seizures, which might stimulate the use of carbon dioxide for stopping seizures. However, although this work provides insight into how seizures normally stop and might help us learn more about how to terminate those seizures that don't stop, it will take more work to turn the finding into a new therapeutic approach. We will be working with colleagues in neurology and neurosurgery to try and translate the findings to treatments," Wemmie said.

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