“Suddenly amid the sadness, spiritual darkness and depression, his brain seemed to catch fire . . . like lightning. These glimmerings were still but a premonition of that final second (never more than a second) with which the seizure itself began. That second was, of course, unbearable.”

So wrote Fyodor Dostoevsky in his 1868 novel, The Idiot, describing the seizures suffered by his protagonist. Scientists still don’t know much about what causes these debilitating storms of unchecked electrical activity in the brain. Although many childhood neurological disorders involve seizures, “we don’t have a real handle, developmentally, on models to study them,” notes Gordon Fishell, PhD, professor of cell biology.

But that could be changing. Dr. Fishell and his team have created one such childhood epilepsy model by disrupting the development of specific types of brain cells, called interneurons, in mice. Their findings could offer valuable insights for designing drugs to treat these disorders, which afflict some 123,000 children in the United States each year. “These cells restrict electrical activity in the brain, which, when unrestricted, causes seizures,” explains Dr. Fishell, whose work is funded, in part, by the Simons Foundation. “If we could develop drugs that stimulate those particular cells, we might be able to repress seizure activity.”

Interneurons, which make up about 20 percent of all brain cells, act locally to stem the storm of electrical signals produced by ubiquitous excitatory neurons, which carry information across long distances. Each variety, notes Dr. Fishell, probably has a unique filtering function to calm the brain’s storms.

Dr. Fishell has long suspected that some brain diseases are caused by the disruption of interneurons. To test this theory, his team used a DNA chip to search for genes that act in different interneurons. They found that one gene, Sox6, is robustly expressed in two types: basket cells and Martinotti cells, both of which have been shown to dampen rampant brain activity.

Because the Sox family of genes is known to play a role in development in bone, cartilage, and excitatory brain cells, Dr. Fishell wondered if it has a similar function in interneurons. When the researchers selectively knocked it out of basket and Martinotti cells during early development, the mutant mice developed a seizure disorder during adolescence. In addition to spasmodic muscle twitching, the animals “stretch out their arms stiffly and then cross them like a pair of scissors,” explains Dr. Fishell. When the researchers measured the mutant animals’ brain rhythms, they found signature wave patterns of seizure activity. They also found that almost all of the basket cells and about half of the Martinotti cells had been lost. What’s more, the basket cells that remained had not migrated to the appropriate layer of the cerebral cortex.

In future experiments, Dr. Fishell wants to look deeper into the timing of these abnormal changes by manipulating the Sox6 gene in later stages. “What we want to know,” he says, “is how much it’s needed for maintaining the behavior of the cells once they’re all grown up.”

(Published in NYU’s News & Views)