This is an image from the research is featured on the cover of volume 346 (pages 409-422) of the journal <i>Neuroscience</i>. CREDIT Elsevier.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects nearly 2.3 million people worldwide. MS is triggered when the immune system attacks the protective covering around nerve fibers, called the myelin sheath. The resulting “demyelination” damages nerve cells and impairs the exchange of information between the brain and body and within the brain itself.
When the protective covering around nerve fibers wears off, nerve signals can slow down or stop. Depending on where the damage occurs, this can lead to impaired vision, sensation, and use of limbs. If the disease destroys nerve fibers, it can lead to permanent paralysis.
“In addition to this, individuals with multiple sclerosis (MS) are three to six times more likely to develop seizures—abnormal hyperactivity of nerve cells—compared to the rest of the population. Despite this increased occurrence, little research has been conducted to explore the reasons behind these seizures in MS patients.”
In a mouse model, a team of scientists at the University of California, Riverside, has discovered that chronic demyelination is closely linked to, and likely the cause of, seizures. The researchers reported their findings in the journal Neuroscience. They also observed that specific neurons in the brain, known as “parvalbumin interneurons,” which are crucial for controlling hyperactivity, undergo changes and are lost when extensive demyelination occurs in the brain’s cortex and hippocampus.
“Demyelination causes damage to axons and neuronal loss. Specifically, parvalbumin interneurons are lost in mice, resulting in a shift from reduced activity to increased activity, which could be a cause of seizures,” explained Seema Tiwari-Woodruff, an associate professor of biomedical sciences in the UC Riverside School of Medicine, whose laboratory conducted the research. “It’s highly likely that this is also happening in MS patients who experience seizures.”
Tiwari-Woodruff and her team induced demyelination in mice in the lab by feeding them a diet containing cuprizone, a copper-binding substance that causes damage to oligodendrocytes, the brain cells that produce myelin. After nine weeks of being fed cuprizone, the majority of the mice started having seizures.
“Without myelin, axons are vulnerable,” said Tiwari-Woodruff. “They develop blebs – ball-like structures that hinder the transport of important proteins and conduction of electrical signals. In some instances, significant axon damage can lead to neuronal loss. In both MS and our mouse model, parvalbumin interneurons are more vulnerable and likely to die. This causes the inhibition to be removed and induce seizures. Thus, axonal and neuronal survival may be directly tied to the trophic support provided by myelin.”
In another study, after nine or twelve weeks, the researchers stopped feeding the mice the cuprizone diet. Oligodendrocytes began to repopulate the demyelinated areas and remyelinate the intact but myelin-stripped axons. Future studies will assess seizure activity with remyelination.
“Does remyelination affect seizure activity? Can we accelerate remyelination with drugs to provide relief for MS patients? We are interested in addressing these questions,” Tiwari-Woodruff said.
Her team recently received a pilot grant from the National Multiple Sclerosis Society. They will be comparing postmortem brain tissue from MS patients with seizures to those without in order to understand the cellular basis of seizures in MS. Additionally, they will use their findings to assess how accurately the cuprizone mouse model replicates the changes observed in humans.
“We want to know if the tissues exhibit the same characteristics as those in our mouse model,” said Tiwari-Woodruff. “Our initial findings in postmortem tissue indicate significant similarities between the two. We now have a mouse model that we can utilize to test and propose potential therapeutic treatments. Once developed, these drugs, designed to reduce hyperactivity and decrease the occurrence of seizures, could also benefit patients with epilepsy.”