Summary: When dysfunctional, somatostatin interneurons drive brain activity and provoke seizures.
Source: University of Virginia
Researchers at the University of Virginia School of Medicine have uncovered how problems in cortical microcircuits in the brain can trigger epileptic seizures. The researchers say that targeting the problem could lead to new treatments for a devastating form of the disease.
UVA epilepsy researchers Eric R. Wengert, PhD, and Manoj K. Patel, PhD, and their team determined that a particular type of brain cell called somatostatin interneurons can cause seizures when they go haywire. These interneurons are typically thought to function as a built-in brake system to safeguard against excessive activity in the brain and prevent seizures, but Wengert and colleagues found that, when dysfunctional, somatostatin interneurons actually drive excessive brain activity and seizures.
These malfunctions are triggered by mutations in a particular gene known to cause a rare epilepsy syndrome in human patients. These mutations are not inherited from the child’s parents but instead occur shortly after conception.
“Identifying the particular nerve cells that contribute to seizures is important because it helps direct the ways researchers go about developing novel therapies,” said Patel, of UVA’s Department of Anesthesiology. “Based on this research, we now have a new cellular target to try to restore balance to the brain and prevent seizures.”
Understanding the Cause of Epileptic Seizures
The researchers examined the role of somatostatin interneurons as part of their investigation of a rare neurological condition called SCN8A epilepticencephalopathy. SCN8A refers to a mutation in the SCN8A gene that causes the condition. Children with SCN8A epilepsy often suffer from recurrent seizures that do not respond to medication as well as severe developmental delays and movement disorders. They are also at significant risk of Sudden Unexpected Death in Epilepsy, the No. 1 cause of epilepsy-related death.
To better understand what occurs in SCN8A epilepticencephalopathy, the researchers developed mouse models of twoSCN8A mutations discovered in patients. These models allowed them to determine which neurons are responsible for driving the neurological dysfunction. The researchers found that both SCN8A mutations caused harmful changes to sodium channels in a way that made somatostatin interneurons fizzle out and stop functioning when they normally would be highly active.
“It’s similar to a speeding car with a broken brake system that cannot slow it down,” Wengert said. “A brain without properly functioning somatostatin interneurons to dampen brain activity ends up with runaway excitation which can result in a seizure.”
Based on their findings, the scientists believe that it may be possible to treat SCN8A epilepticencephalopathy by developing ways to fix the agitated interneurons. The results, they say, also help us better understand epilepsy more broadly.
“Although this work focused on SCN8A epilepsy, our results identify somatostatin interneurons as a general contributor to epileptic seizures,” Wengert said. “If we can identify ways to restore proper functioning in these cells, these approaches may be useful in providing better anti-seizure treatments to patients with various types of epilepsy.”
Funding: The research was funded by the National Institutes of Health, grants R01NS103090, R01NS120702 and 1F31NS115451-01.
Somatostatin-positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy
SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A which encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures.
Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of wild-type SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments.
These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A encephalopathy, but epilepsy in general.
SCN8A encephalopathy is a devastating neurological disorder that results from de novo mutations in the Na channel Nav1.6. Inhibitory neurons express NaV1.6, yet their contribution to seizure generation in SCN8A epileptic encephalopathy has not been determined.
We show that mice expressing a human derived SCN8A variant (R1872W) selectively in SST interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that SCN8A mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure due to depolarization block. Furthermore, chemogenetic activation of wild-type SST interneurons leads to audiogenic seizure activity.
These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in SCN8A encephalopathy, but for epilepsy broadly.