Scientists watch the CLOCK gene for potential epilepsy connections

Epilepsy affects 2.2 million people in the United States, according to the Epilepsy Foundation. A new discovery by scientists has determined that the loss of a gene best known for its role in establishing circadian rhythms — the body’s innate cycles that include sleeping at night and being awake during the day — can lead to a particular type of epileptic seizures, called focal cortical epilepsy.  

The most common cause of this type of epilepsy is focal cortical dysplasia, where clusters of nerve cells in the brain’s cerebral cortex are dysfunctional or inappropriately connected to other nerve cells. This disorder is the most common cause of seizures in the U.S. pediatric population, accounting for almost half of all epilepsy surgery performed on children. 

The multi-institutional research team, including Gregorio Valdez, an assistant professor at the Virginia Tech Carilion Research Institute, said the discovery could provide insight into non-genetic causes of epilepsy. The study, published in October in the journal Neuron, was led by Judy S. Liu, an assistant professor of neurology at the Children’s National Medical Center in Washington, D.C., who recently relocated to Brown University.

“CLOCK is best known as a regulator for the sleep-wake cycle,” said Valdez, who is also an assistant professor of biological sciences in Virginia Tech’s College of Science. “However, CLOCK is now known to have other roles in the brain, including in the formation of neuronal circuits. Because we found less CLOCK in epileptogenic compared to healthy brain tissue, we became interested in its potential involvement in affecting neural circuits that cause epilepsy when disrupted.”

The Children’s National research team collected human brain tissue samples from patients at their seizures’ originating point.

“We now know that CLOCK helps maintain the excitation and inhibition in the brain, a prerequisite for normal brain function,” Valdez said. “We theorized that when CLOCK is decreased, there are either too many excitatory or too few inhibitory synapses. Either one leads to too much neuronal activity and thus seizures.”

The researchers modeled mouse lines with targeted deletions of the CLOCK gene in neurons and found fewer inhibitory synapses.

“These findings open another avenue for treating epileptic seizures that arise from genetic and non-genetic causes,” Valdez said. “Our challenge now is to figure out where targeting CLOCK or one of its many effectors is most beneficial for preventing the loss of inhibitory synapses, and thus seizures.”

Valdez will continue to work with Liu and collaborators from Children’s National Medical Center, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, the school of medicine at the University of Colorado, the University of Virginia Health System, Georgetown University, the University of Maryland School of Medicine, and Brown University. They’re currently exploring approaches to restore levels — and function — of CLOCK, with the goal of preventing seizures.