A mechanism underlying most common cause of epileptic seizures revealed


Date:
August 26, 2021
Source:
The Korea Advanced Institute of Science and Technology (KAIST)
Summary:
An interdisciplinary team studying neurogenetics, neural networks,
and neurophysiology has revealed how dysfunctions in even a small
percentage of cells can cause disorder across the entire brain.



FULL STORY ========================================================================== During fetal development, cells should migrate to the outer edge of the
brain to form critical connections for information transfer and regulation
in the body. When even a few cells fail to move to the correct location,
the neurons become disorganized and this results in focal cortical
dysplasia. This condition is the most common cause of seizures that
cannot be controlled with medication in children and the second most
common cause in adults.


==========================================================================
Now, an interdisciplinary team studying neurogenetics, neural networks,
and neurophysiology at KAIST has revealed how dysfunctions in even a
small percentage of cells can cause disorder across the entire brain. They published their results on June 28 in Annals of Neurology.

The work builds on a previous finding, also by a KAIST scientists, who
found that focal cortical dysplasia was caused by mutations in the cells involved in mTOR, a pathway that regulates signaling between neurons in
the brain.

"Only 1 to 2% of neurons carrying mutations in the mTOR signaling pathway
that regulates cell signaling in the brain have been found to include
seizures in animal models of focal cortical dysplasia," said Professor
Jong-Woo Sohn from the Department of Biological Sciences. "The main
challenge of this study was to explain how nearby non-mutated neurons
are hyperexcitable." Initially, the researchers hypothesized that the
mutated cells affected the number of excitatory and inhibitory synapses
in all neurons, mutated or not.

These neural gates can trigger or halt activity, respectively, in
other neurons. Seizures are a result of extreme activity, called hyperexcitability.

If the mutated cells upend the balance and result in more excitatory
cells, the researchers thought, it made sense that the cells would be
more susceptible to hyperexcitability and, as a result, seizures.

"Contrary to our expectations, the synaptic input balance was not changed
in either the mutated or non-mutated neurons," said Professor Jeong Ho Lee
from the Graduate School of Medical Science and Engineering. "We turned
our attention to a protein overproduced by mutated neurons." The protein
is adenosine kinase, which lowers the concentration of adenosine.

This naturally occurring compound is an anticonvulsant and works to
relax vessels. In mice engineered to have focal cortical dysplasia,
the researchers injected adenosine to replace the levels lowered by the protein. It worked and the neurons became less excitable.

"We demonstrated that augmentation of adenosine signaling could attenuate
the excitability of non-mutated neurons," said Professor Se-Bum Paik
from the Department of Bio and Brain Engineering.

The effect on the non-mutated neurons was the surprising part, according
to Paik. "The seizure-triggering hyperexcitability originated not in
the mutation- carrying neurons, but instead in the nearby non-mutated
neurons," he said.

The mutated neurons excreted more adenosine kinase, reducing the adenosine levels in the local environment of all the cells. With less adenosine,
the non- mutated neurons became hyperexcitable, leading to seizures.

"While we need further investigate into the relationship between the concentration of adenosine and the increased excitation of nearby neurons,
our results support the medical use of drugs to activate adenosine
signaling as a possible treatment pathway for focal cortical dysplasia," Professor Lee said.

========================================================================== Story Source: Materials provided by The_Korea_Advanced_Institute_of_Science_and_Technology_ (KAIST). Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hyun Yong Koh, Jaeson Jang, Sang Hyeon Ju, Ryunhee Kim,
Gyu‐Bon
Cho, Dong Seok Kim, Jong‐Woo Sohn, Se‐Bum Paik, Jeong
Ho Lee.

Non-Cell Autonomous Epileptogenesis in Focal Cortical
Dysplasia. Annals of Neurology, 2021; 90 (2): 285 DOI:
10.1002/ana.26149 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210826111711.htm

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