According to the World Health Organization (WHO), more than 50 million people worldwide suffer from epilepsy. About a third of these people do not respond to current antiepileptic treatments. It's a century-old mystery of neuroscience that these Virginia Tech scientists solve here: the research team indeed identifies mysterious brain structures called perineuronal networks, which help modulate the activity of electrical impulses in the brain. New findings, presented in the journal Nature Communications, that may lead to the treatment of epileptic disease, far beyond just managing its main symptoms, seizures.
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In 1893, the Virginia researchers explain, scientists discovered the existence of enigmatic structures called perineuronal networks wrapped around neurons, but their function remained misunderstood. The team figured out that these networks modulate electrical impulses in the brain. And if by misfortune these networks are eliminated or malfunction, crises can then occur.
The implications relate to the different forms of acquired epilepsy, resulting from brain damage caused by trauma, infection, or brain tumors. The researchers began by studying tumor-associated epilepsy in a mouse model of glioblastoma-induced epilepsy. As the skull prevents the glioblastoma from spreading outward, the tumor produces an excitatory neurotransmitter called glutamate, in excessive amounts, which kills nearby healthy cells to allow its growth. And, in addition to glutamate, the tumor secretes an enzyme aimed at destroying the surrounding extracellular matrix, a gel-like substance that holds brain cells in place. This enzyme, explains the author, “is the knife that cuts the links of the tumor and lets it migrate freely”. The researchers find, surprisingly, that the enzyme attacks the perineuronal networks wrapped around inhibitory neurons secreting GABA, which normally helps prevent seizures. Once the neurons are stripped of these networks, a “crisis” effect develops.
An enzyme that can devour a perineuronal network in less than 30 minutes: neurons covered in perineuronal networks have reduced membrane capacity or electrical charge storage capacity, which means they can trigger an impulse and recharge twice as much faster than neurons without perineuronal networks. When inhibitory neurons lose their perineuronal networks, the results can be catastrophic. So when researchers apply the enzyme to tumor-free brains, they find that enzymatic degradation of perineuronal networks is sufficient to induce seizures. Thus, without the perineuronal networks, the inhibition becomes too weak and the seizure occurs.
The discovered enzyme as well as the perineuronal networks appear here as possible targets in different forms of acquired epilepsy and could allow the development of new pharmacological solutions aimed at controlling tumor-associated seizures or other causes of acquired epilepsy.
Thus, while controlling the symptoms of the disease is important in the management of epilepsy, this study opens a new avenue for treating the causes and progression of the disease.
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