New Clues to Cause of Human Narcolepsy

The images show the amount of histamine cells in the hypothalamus of a healthy control (917) and a narcoleptic (1,604). Photo: Courtesy of Dr. Jerome Siegel

More than a decade ago, UCLA researchers demonstrated that a lack of hypocretin-containing neurons in the brain contributes to narcolepsy, a disorder characterized by uncontrollable periods of deep sleep. Now, the same team reveals that an excess of another brain-cell type — this one containing histamine — may be the cause of the loss of hypocretin cells in human narcoleptics.

Jerome Siegel, PhD, director of the Center for Sleep Research at the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, and colleagues found that people with the disorder have nearly 65 percent more brain cells containing the chemical histamine. Their research suggests that this excess of histamine cells causes the loss of hypocretin cells in human narcoleptics.

Narcolepsy is a chronic disorder of the central nervous system that is believed to affect one-in-3,000 Americans. It is characterized by the brain’s inability to control sleep-wake cycles, causing sudden bouts of sleep. It often is accompanied by cataplexy, an abrupt loss of voluntary muscle tone that can cause a person to collapse.

Histamine is a body chemical that works as part of the immune system to kill invading cells. When the immune system goes awry, histamine can act on a person’s eyes, nose, throat, lungs, skin or gastrointestinal tract, causing the symptoms of allergy that are familiar to many people. But histamine is also present in a type of brain cell.

For the study, researchers examined five narcoleptic brains and seven control brains from human cadavers. Prior to death, all the narcoleptics had been diagnosed by a sleep-disorder center as having narcolepsy with cataplexy. These brains were also compared with the brains of three narcoleptic mouse models and to the brains of narcoleptic dogs.

The researchers found that the humans with narcolepsy — but not the animals — had an average of 64 percent more histamine neurons. “Our current findings indicate that the increase of histamine cells that we see in human narcolepsy may cause the loss of hypocretin cells,” Dr. Siegel says.

The study results may also further understanding of brain plasticity, Dr. Siegel notes. While scientists have known of the existence neurogenesis — the process by which the brain is populated with new neurons — it was thought to function mainly to replace existing cells that had died. “This paper shows for the first time that neuronal numbers can increase greatly and not just serve as replacement cells,” he says. “In the current example, this process appears to be pathological with the destruction of hypocretin, but in other circumstances, it may underlie recovery and learning and open new routes to treatment of a number of neurological disorders.”

“Greatly Increased Numbers of Histamine Cells in Human Narcolepsy with Cataplexy,” Annals of Neurology, July 2013