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An elusive link between seizures, the identifier of a cell signaling protein in zebrafish

The Fralin Biomedical Research Institute of VTC says a lack of brain protein increases susceptibility to seizures

For the brain to learn, retain memories, process sensory information, and coordinate body movements, groups of neurons must generate coordinated electrical signals. Disruption of simultaneous shooting can impair these processes and, in extreme cases, lead to epileptic seizures.

Synchronization between adjacent neurons relies on the connexin 36 protein, which is an essential component of certain types of synaptic connections that, unlike conventional chemical synapses, pass signals between neurons through direct electrical connections. For more than 15 years, scientists have discussed the relationship between Konixin 36 and epilepsy.

Now, a team of Virginia Tech scientists led by Yoshin Albert Pan, associate professor at the Fralin Biomedical Research Institute at VTC, has identified a new link between seizures and a 36 konixin deficiency. The discovery was published today (Jan 11, 2021) at Frontiers in Molecular Neuroscience,, It was found that this interaction may make the brain more likely to have seizures.

Alyssa Brunal, who recently graduated from the PhD program in Biology, Medicine, and Health at Virginia Tech, in collaboration with her mentor Pan, has developed new models to study the relationship between connexin 36 and seizures and confirm the relationship.

Zebrafish act as a powerful animal model, allowing researchers to evaluate the effects of connexin 36 on the whole brain in a healthy living system during neural hyperactivity.

As a primary component of the electrically coupled synapses between neurons, connexin 36 plays an important role in the rapid and simultaneous activation of interconnecting neurons within the brain, which is essential for normal brain processes.

“In previous studies, people weren’t using the same patterns of organisms. They weren’t looking at the same areas of the brain. They weren’t using the same techniques to induce seizures.” I thought, since zebrafish is a versatile model organism, we can use it to try to differentiate What is really happening. “

Pan, who uses zebrafish larvae frequently in studies, said the fish are ideal because they grow outside the womb, are transparent, and their entire brains are small enough to fit perfectly under a microscope.

“Using modern microscopy techniques, we can see in a healthy animal what is happening inside the brain,” said Pan, who is also a senior research fellow at the Commonwealth Center for Innovative Technology in Developmental Neuroscience and Associate Professor in the Department of Biomedical Sciences and Pathobiology of Virginia Maryland College of Veterinary Medicine. .

Brunal created dozens of full-fledged zebrafish brain maps for study.

Researchers used varying doses of a drug that causes seizures, which causes nerve cells to become overactive and is one of the main factors causing seizures. By comparing common wild-type zebrafish and mutated zebrafish with deficiencies of connexin 36, they found that connexin 36 deficiency altered susceptibility to neural hyperactivity in the brain region in a dose-dependent manner.

After they demonstrated that connexin protein deficiency altered seizure susceptibility, they questioned whether seizure-related hyperactivity in turn affected protein expression. To test this, they applied the drug that causes seizures only to wild zebrafish, but this time, instead of looking for hyperactivity in the brain, they looked for expression of connexin 36. The results were startling.

The drug-induced hyperactivity caused a sharp drop in the levels of konexin 36 across the brain, which recovered over time.

“I was like, holy cow, there’s really something going on with the protein. So not only does the protein affect the hyperactivity, we also have some effect on the protein itself,” Pronal said. “I think that’s what really opened the project so wide.”

Pan said the results were impressive.

“A lot of times in science, you don’t know what’s going on until you’ve pinpointed microscope images and see something emerging from statistical analysis to the level of significance, but in one case in this study, connexin 36 was visible gone,” Pan said. “We thought there had to be something important.”

They applied connexin 36-blocking to wild-type zebrafish before using the drug that causes seizures. They compared the results to a control group of wild zebrafish that received nothing but the drug that causes seizures. The first group had significantly more neuropathy, indicating that acute loss of connexin 36 may lead to more seizures.

While it is known that having a single seizure increases the likelihood of later events, the mechanisms underlying this clinical phenomenon are not well understood. This study describes a new mechanism: seizures reduce levels of konixin 36 in zebrafish models, and may contribute to the emergence of later seizures.

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Pan, the principal investigator, and Brunal, who defended her doctoral thesis based on the study findings, joined as authors on the paper by postdoctoral fellow Karim Clark, research assistant Mancio Ma of the Fralin Biomedical Research Institute, and Ian Woods, associate professor in the department Neighborhoods of Ithaca College.

This study was funded by the Commonwealth Research Marketing Fund and the Fralin Biomedical Reserch Institute.

They showed that a chronic deficiency of connexin 36 in mutant zebrafish made them more susceptible to brain overactivity, which in turn led to reduced expression of connexin 36. Next, they wanted to see if a sharp decrease in connexin 36 could predict the likelihood of future seizures.

Written by Matt Chetum, Virginia Tech

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