Targeting Specific Brain Region May Be Key in Treating Non-convulsive Seizures, Mouse Study Shows
The study, “Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome,” was published in the journal Cell Reports.
Non-convulsive seizures in toddlers with Dravet may occur more than 50 times a day and disrupt their consciousness. These difficult-to-treat seizures often go undetected and may be responsible for the cognitive decline, behavioral disorders, and socialization problems in children with Dravet.
“If we could successfully eliminate non-convulsive seizures in children with Dravet syndrome, we could significantly improve their quality of life,” Maria Roberta Cilio, MD, PhD, study co-author and director of research at the University of California, San Francisco, Pediatric Epilepsy Center, said in a press release.
SCN1A is one of the most frequently mutated genes associated with Dravet. This gene provides instructions for the production of the alpha subunit of the voltage-gated sodium channel Nav1.1, widely expressed in the brain and heart.
In mouse models of Dravet, reduced SCN1A function in GABAergic neurons of the cerebral cortex and the hippocampus in the brain is associated with convulsive seizures.
Excitatory and inhibitory signals are the basis of communication between the brain’s nerve cells. Excitatory signaling from one cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling, such as that sent by GABAergic neurons, limits the firing signal. Like the exaggerated function of excitatory cells, impaired activity of the inhibitory neurons may lead to seizures.
The reticular thalamic nucleus (nRT), which modulates interactions between the thalamus and the cerebral cortex, contains significant levels of SCN1A-expressing inhibitory neurons. The nRT is part of the thalamus, which plays a key role in cognition, sleep, attention, and consciousness, all affected in Dravet patients.
Based on the correlation between disruptions in the nRT and neurological and psychiatric disorders, researchers evaluated whether SCN1A deficiency results in nRT alterations, and is connected to non-convulsive seizures.
“We wanted to see what happens in this brain region and how its cells might be altered in the context of this syndrome,” said Jeanne Paz, PhD, the study’s senior author and an investigator at the Gladstone Institutes in San Francisco.
Unlike the decreased activity of inhibitory cells in the thalamus, the researchers found that nRT neurons in mice with a loss of function in the SCN1A gene had increased excitability.
Using electroencephalography (EEG) to record brain waves and detect brain activity, the team found that nRT neurons had abnormally long bursts of firing (activity), caused by a dysfunction of calcium-activated potassium small conductance (SK) channels.
“We were able to pinpoint the exact spot in the brain that causes the seizures,” Paz said.
“Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in [Dravet],” the researchers wrote in the study.
They observed that non-convulsive seizures were much more frequent than convulsive ones. When they compared human and mouse EEG recordings, the investigators found they closely matched.
“We were encouraged that our work could translate to real people, so we went on to look for ways to stop the seizures,” Paz said.
For this purpose, the team developed ways to detect seizures by manipulating the activity of specific nRT neurons with a technique called optogenetics that uses light from lasers.
“This approach allowed us to identify the specific cells and brain activity required for initiating and aborting non-convulsive seizures in models of Dravet,” Paz said. Such discoveries had not been possible in the past, “because seizures involve a very large network of cells that ping-pong signals all around the brain within milliseconds.”
As optogenetics cannot be used in humans yet, the scientists explored pharmacological options with similar results. They found that EBIO1, an activator of SK channels, reduced the activity of inhibitory neurons in the nRT and significantly reduced or even stopped seizures in mice.
“It is very exciting that [a U.S. Food and Drug Administration]-approved drug already exists that targets the very brain activity we found to cause non-convulsive seizures,” Paz said, adding that EBIO1, although not presently used in epilepsy, was not associated with side effects in clinical trials of movement disorders.
“When I presented my findings recently at the American Epilepsy Society, some physicians expressed keen interest in testing this FDA-approved drug in the clinic. Hopefully, this will be life-changing for these children,” she said.