Accidental Discovery Solves 125-Year-Old Neuroscience Mystery – May Help Treat Acquired Epilepsy

Science is rarely eureka moments and instead hard work for slender strands of revelation. However, a team of scientists from the Virginia Tech Carilion Research Institute have done what many scientists envy: they’ve made a serendipitous discovery of what they claim “solves” a century-old mystery around a web-like structure in the brain.



This puzzling matrix of molecules, known as perineuronal nets, wrap around certain neurons and dendrites. They have been implicated in plasticity, disease, and aging, but their precise function remains unclear.

Now, the team led by Harald Sontheimer have discovered that the nets – at least in one capacity – are involved in modulating electrical impulses in the brain. Even more compelling is what happened when the scientists dissolved these nets: brain seizures.

"It was a surprise to see this bystander effect of seizure activity once the neurons were stripped of their nets,” said Sontheimer, executive director of the School of Neuroscience, in a statement.

The scientists were not initially investigating these matrixes, but instead studying epilepsy in mouse models brought on by terminal brain cancer known as glioblastoma.

Glioblastoma is a difficult type of cancer to treat due to the confined nature of the skull and the ability of tumor cells to spread rapidly. Since the cancerous cells are limited to our noggin’s chamber of bone, it must kill healthy cells first in order to make more room to grow and infect new tissue. The prognosis for adults with this disease is bleak, with a 5 percent survival rate five years after diagnosis.

To kill healthy cells, the tumors secrete glutamate in high amounts in order to have room to flourish. The glutamate seems to specifically target brain cells producing GABA – a neurotransmitter that inhibits neurons from getting too overexcited, without which the brain can seize.



Perineuronal nets (red) around the soma of neurons and initial dendrite segments. Stain procedures were made by Arnst Nikita. Confocal imaging procedures were made by Kuznetsova Svetlana, Melnikova Anastasiya, Arnst Nikita.


"Unexpectedly, we also saw the enzyme attacking the perineuronal nets,” said Sontheimer, adding that the nets are usually found around GABA-secreting inhibitory neurons.

To test this finding further, the team injected the enzyme into brain slices without tumors. Rather disturbingly, they found that the enzyme can devour a perineuronal net in around 30 minutes and induce seizures.

“No one thought that these structures would have such a profound effect on how normal processes operate,” said Sontheimer.

"Without the perineuronal nets, inhibitory neurons would fire too slowly and therefore inhibition becomes too little, too late, and a seizure will occur – even in otherwise healthy brains."

The results published in Nature Communications are preliminary, but the team say the discovery could lead to pharmacological solutions to help epilepsy patients.

Around 50 million people worldwide have epilepsy, according to the World Health Organization. This makes it one of the most common neurological diseases globally.

“We propose that blocking matrix degrading enzymes using already approved drugs that pass the blood-brain barrier may be effective in slowing cell invasion and tumor angiogenesis," wrote the authors.

The team are now studying whether or not perineuronal nets play a role in epilepsy brought on by other triggers, such as head injury or brain infection.

"We need new approaches to treat epilepsy. I think this could be an effective way to control seizures," Sontheimer said. "And we solved a 125-year-old neuroscience mystery! This is what basic science is all about – keeping an open and observant mind to answer questions old and new.”

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