Abstract
Narcolepsy is a sleep disorder caused by selective death of the orexin neurons that often begins in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, episodes of paralysis during wakefulness. Cataplexy is often worse when narcolepsy develops in children compared to adults, but the reason for this difference remains unknown. We used orexin-tTA; TetO DTA mice to model narcolepsy at different ages. When doxycycline is removed from the diet, the orexin neurons of these mice express diphtheria toxin A and die within 2–3 weeks. We removed doxycycline at 4 weeks (young-onset) or 14 weeks (adult-onset) of age in male and female mice. We implanted electroencephalography (EEG) and electromyography (EMG) electrodes for sleep recordings two weeks later and then recorded EEG/EMG/video for 24 h at 3 and 13 weeks after removal of doxycycline. Age-matched controls had access to doxycycline diet for the entire experiment. Three weeks after doxycycline removal, both young-onset and adult-onset mice developed severe cataplexy and the sleep-wake fragmentation characteristic of narcolepsy. Cataplexy and maintenance of wake were no worse in young-onset compared to adult-onset mice, but female mice had more bouts of cataplexy than males. Orexin neuron loss was similarly rapid in both young- and adult-onset mice. As age of orexin neuron loss does not impact the severity of narcolepsy symptoms in mice, the worse symptoms in children with narcolepsy may be due to more rapid orexin neuron loss than in adults.
Highlights
Orexins are wake-promoting neuropeptides necessary for the maintenance of long periods of wakefulness and the regulation of REM sleep (Saper et al, 2001; Lu et al, 2006; Branch et al, 2016; Chowdhury et al, 2019)
Most patients develop narcolepsy before the age of 25, Abbreviations: DOX, doxycycline; DOX−, mice removed from doxycycline; DOX+, mice maintained on doxycycline
The group × sex, group × time since DOX removal, and group × sex × time since DOX removal interactions were all non-significant for the percentage of time spent in cataplexy and for the number of cataplexy bouts
Summary
Orexins are wake-promoting neuropeptides necessary for the maintenance of long periods of wakefulness and the regulation of REM sleep (Saper et al, 2001; Lu et al, 2006; Branch et al, 2016; Chowdhury et al, 2019). Cataplexy is usually triggered by strong, positive emotions, but children can have spontaneous cataplexy (Serra et al, 2008; Overeem et al, 2011; Plazzi et al, 2011). Though longitudinal studies are sparse, it appears that this severe sleepiness and cataplexy with childhood-onset narcolepsy lessens over a few years, developing into the pattern typical of adults (Plazzi et al, 2011; Pizza et al, 2013). Narcolepsy onset in younger children is disruptive because it is associated with more severe symptoms and with precocious puberty and obesity, indicating multisystem disruption (Kotagal et al, 1990, 2004; Plazzi et al, 2006; Vendrame et al, 2008; Poli et al, 2013; Ponziani et al, 2016)
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