News — DALLAS () – Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although the underlying mechanisms have historically remained shrouded in mystery, new findings from the lab of SMU biology professor are beginning to provide valuable clues.
Around 3 million people in the U.S. have epilepsy, making it the country’s fourth most common neurological disease; SUDEP claims more lives in the United States every year than the more widely publicized sudden infant death syndrome (SIDS).
In new research published in the journal , Kelsey Paulhus, a post-doctoral researcher in the Glasscock lab and lead author of the study, reveals that excitatory neurons within the brain’s corticolimbic circuits have a prominent role to play in epilepsy and SUDEP. Their findings are the first to show that circuits lacking a specific protein, Kv1.1, in this subset of neurons promote seizures that can lead to lethal cardiorespiratory failure.
“Identifying specific proteins and brain circuits involved in SUDEP moves us closer to developing interventions that may prevent this tragic epilepsy-related outcome,” said Vicky Whittemore, program director at the NIH’s National Institute of Neurological Disorders and Stroke, which funded the study.
“For a long time, SUDEP has been suspected to involve a fatal breakdown in communication between the brain, heart, and lungs.” Paulhus said. “In this study, we actually observed this breakdown in real time using simultaneous recordings of brain, heart, and lung activity in mice without Kv1.1 in select brain circuits.”
“Given the unpredictable nature of SUDEP, observing the physiological mechanisms associated with lethal seizures is challenging and has only been accomplished experimentally a handful of times worldwide,” Glasscock said. “Therefore, this work provides a rare glimpse into the potential sequence of events that lead to sudden death in epilepsy.”
The Kv1.1 protein investigated in the study is encoded by the Kcna1 gene and belongs to a family of voltage-gated potassium channels known for their role in controlling signals in and between brain and heart cells. Mutations in Kcna1 are a common genetic cause of epilepsy in people. More severe mutations can lead to epileptic encephalopathy, an especially severe form of epilepsy associated with an increased risk of SUDEP.
Finding new clues in the brain
Although the brainstem is often thought of as the place where the body regulates heart and lung function, the corticolimbic circuit, which is part of the forebrain, also holds significant regulatory power over these organs and their function. In addition to being a frequent seizure onset zone, this circuit, which includes the cortex, hippocampus, and amygdala, is also important for learning and memory function.
In people with epilepsy, seizures or direct simulation of the amygdala and/or hippocampus can pause breathing and impair heart function –suddenly and without warning –potentially increasing the chances of sudden death when seizures invade these brain structures.
Resetting electrical signals in the heart
In another recent paper from the Glasscock lab in the post-doctoral fellow Man Si and colleagues investigated the role of Kv1.1 in cardiac pacemaker cells located in the heart’s sinoatrial node, a patch of cells located along the upper wall of the right atrium. These cells generate electrical impulses that start every heartbeat.
Using mice, Si discovered that when Kv1.1 is missing or blocked, pacemaker cells have difficulty in maintaining normal electrical activity resulting in abnormal heart rhythms.
“Given the importance of Kv1.1 in maintaining proper brain and heart function, mutations affecting this protein could represent a significant genetic risk factor for SUDEP,” Glasscock said.
Ultimately, this study and the one published in Brain Communications, suggests Kv1.1 is a significant research target to uncover the complex multi-organ causes of SUDEP.
These studies are part of Glasscock’s ongoing research funded by the National Institutes of Health (NIH). Glasscock is the Prothro Distinguished Chair of Biological Sciences in SMU’s Dedman College of Humanities and Sciences. Paulhus’ work was also supported by a predoctoral fellowship from the American Epilepsy Society. She was also a part of the Journal of General Physiology study, as were SMU’s Man Si and Praveen Kumar; Northwestern State’s Ahmad Darvish and Louisiana State University Health Sciences Center’s Kathryn Hamilton.
Research reported in this press release was supported by the NIH’s National Institute Of Neurological Disorders And Stroke (R01NS129643, R01NS100954, and R01NS099188). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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