Solving a century-old neuroscience puzzle may lead to epilepsy therapy

Migraine headache/epilepsy brain image
Virginia Tech scientists suggest their new research on perineuronal nets could lead to new approach against epilepsy. (CC0 Creative Commons)

Perineuronal nets, a type of matrix structures surrounding neurons, were first identified in 1893. They’re believed to provide neuroprotection, but the exact functions have yet to be fully understood. Now, scientists at Virginia Tech have cast some light on the nets’ role in brain seizures, a discovery they believe could lead to potential treatment for acquired epilepsy.

When Italian neurobiologist Camillo Golgi first uncovered perineuronal nets, he assumed they likely impeded communication between neurons. But a team led by Harald Sontheimer at Virginia Tech Carilion Research Institute now suggests otherwise—the nets promote messaging, according to their recent study published in Nature Communications.

Seizure is a common symptom in people with brain tumors. The researchers first tested on a mouse model with epilepsy caused by glioblastoma.

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The brain cancer cells produce glutamate—a chemical that nerve cells use to transmit signals—in excessive amounts that kill nearby heathy cells to grow. In the process, the so-called GABAergic neurons, which produce another neurotransmitter called GABA, were targeted, the team observed. GABA’s key function is preventing neurons from sending electrical impulses nonstop; without it, the brain can become too excited and cause seizure.

Besides glutamate, the tumor also produces a type of enzyme called MMP that degrades its surrounding extracellular matrix to flee to other sites. As it turned out, the enzyme also seemed to attack the perineuronal nets, which are mostly found around GABA-secreting neurons, according to the team. How does that contribute to seizures?

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Contrary to previous knowledge that perineuronal nets stem neuronal messaging, the Virginia Tech researchers found they actually do the opposite. GABAergic neurons with those covers can send inhibitory impulses much faster due to a reduced ability to store electrical charge.

“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,” said Sontheimer in a statement.

After applying MMPs to noncancerous brains, Sontheimer and his colleagues saw that, even without the cancer cells’ harm on neurons, destruction of the surrounding perineuronal nets alone was able to induce seizures.

Neurotransmitters GABA and glutamate are often targeted by scientists to fight CNS disorders. Research at the University of California, Los Angeles, recently linked ketogenic diet to bacteria that fuel GABA production. A startup called Bloom Science has licensed the technology to develop bacterial treatments for epilepsy. Another company, Appello Pharmaceuticals, has opted to license discovery from Vanderbilt University that uses modulators of metabotropic glutamate receptor subtype 4 to treat Parkinson’s.

Sontheimer’s team are now studying how perineuronal nets might affect other types of epilepsy, for example, from head injury or brain infection rather than brain tumor.

“If we confirm our hypothesis that digested perineuronal nets are responsible for other forms of acquired epilepsy, then a potential treatment could be an enzyme inhibitor,” Sontheimer said, noting that there’s already an FDA-approved therapy with that mechanism for other uses.