Anyone affected by the sleep disorder narcolepsy can experience sudden paralysis that causes them to collapse in the middle of their day, a symptom called cataplexy. Drug treatments for cataplexy are available but must be taken in two doses, one at bedtime and the other in the middle of the night, disrupting sleep. Researchers at the University of Toronto have shown promising results in mice for treating cataplexy with therapeutic cells.
Dr Sara Pintwala of the Peever laboratory in Cell & Systems Biology focused her studies of cataplexy on the neurotransmitter orexin. The daytime sleepiness and cataplexy of narcolepsy occur when orexin neurons in the lateral hypothalamus of the brain either degenerate or fail to produce orexin.
Pintwala collaborated with the Belsham laboratory in the Department of Physiology to grow orexin-expressing neurons in the lab. She engineered these cells so that they were activated to express orexin by a specific chemical, a technique known as chemogenetics. This allowed her to tune the levels of orexin produced by the cell prior to transplantation, reducing the number of mice needed for the experiment.
Cataplexy occurs more often when the affected individuals experience positive stimuli. Pintwala was able to increase observed cataplexy episodes by keeping mice in a social environment with exercise wheels and by including chocolate with their food. She could then test the ability of her treatments to relieve cataplexy in this environment.
Stable patterns of behaviour like sleep and wakefulness are coordinated in the lateral hypothalamus of the brain. Pintwala was demoralized to find that transplanting her engineered orexin-expressing cells into this region failed to restore normal patterns of behaviour in mice lacking orexin. However, she knew that the neural circuits that promote wakefulness and motor behaviours form connections to a separate brain region called the dorsal raphe.
Pintwala felt guarded optimism when she observed that transplanting orexin-expressing cells directly into the dorsal raphe reduced both the number of cataplexy episodes and the severity of cataplexy. Further experiments confirmed relief from the symptoms of cataplexy. Pintwala was certain of her success when she observed that the treated brains showed hundreds of orexin-expressing neurons enervating the dorsal raphe.
Pintwala and Peever’s research, published in Current Biology as “Immortal orexin cell transplants restore motor-arousal synchrony during cataplexy” provides evidence towards the use of cell replacement therapy as a therapeutic strategy for narcolepsy.
The next step in this process will be alleviating the sleepiness experienced by those affected by narcolepsy. This means future experiments will focus on the sleep circuits that impact a region called the locus coereleus as a target for treatment.