Abstract
Narcolepsy is caused by the loss of hypocretin (Hcrt) neurons and is associated with multiple genetic and environmental factors. Although abnormalities in immunity are suggested to be involved in the etiology of narcolepsy, no decisive mechanism has been established. We previously reported chemokine (C-C motif) receptor 3 (CCR3) as a novel susceptibility gene for narcolepsy. To understand the role of CCR3 in the development of narcolepsy, we investigated sleep-wake patterns of Ccr3 knockout (KO) mice. Ccr3 KO mice exhibited fragmented sleep patterns in the light phase, whereas the overall sleep structure in the dark phase did not differ between Ccr3 KO mice and wild-type (WT) littermates. Intraperitoneal injection of lipopolysaccharide (LPS) promoted wakefulness and suppressed both REM and NREM sleep in the light phase in both Ccr3 KO and WT mice. Conversely, LPS suppressed wakefulness and promoted NREM sleep in the dark phase in both genotypes. After LPS administration, the proportion of time spent in wakefulness was higher, and the proportion of time spent in NREM sleep was lower in Ccr3 KO compared to WT mice only in the light phase. LPS-induced changes in sleep patterns were larger in Ccr3 KO compared to WT mice. Furthermore, we quantified the number of Hcrt neurons and found that Ccr3 KO mice had fewer Hcrt neurons in the lateral hypothalamus compared to WT mice. We found abnormalities in sleep patterns in the resting phase and in the number of Hcrt neurons in Ccr3 KO mice. These observations suggest a role for CCR3 in sleep-wake regulation in narcolepsy patients.
Highlights
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, fragmented nocturnal sleep, and abnormal rapid eye movement (REM) sleep symptoms
The percentages of time spent in wakefulness, REM sleep, and NREM sleep in the dark phase were not significantly different between the two genotypes, these sleep-wake patterns in Ccr3 KO mice in the light phase were significantly different compared to WT mice: the proportion of time spent in wakefulness was higher in Ccr3 KO mice (42.9 ± 6.8% in Ccr3 KO vs. 36.1 ± 3.1% in WT, P = 0.019), and the proportion of time spent in REM sleep (3.1 ± 1.2% in Ccr3 KO vs. 4.8 ± 1.3% in WT, P = 0.013) and NREM sleep (54.0 ± 6.4% in Ccr3 KO vs. 59.1 ± 2.3% in WT, P = 0.047) was lower in Ccr3 KO mice compared to WT mice (Fig 2)
These findings indicate that the increased number of NREM bouts and the shorter NREM sleep duration in Ccr3 KO mice are due to the increased number of wakefulness bouts, which suggests fragmented sleep
Summary
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, fragmented nocturnal sleep, and abnormal rapid eye movement (REM) sleep symptoms (cataplexy, hypnagogic hallucination, and sleep paralysis). Healthy individuals start nocturnal sleep with a non-REM (NREM) episode, narcolepsy patients show sleep-onset REM periods [1]. Narcolepsy is strongly associated with hypocretin (Hcrt) deficiency: cerebrospinal fluid hypocretin-1 levels are lower in patients relative to healthy individuals [2, 3], and hypocretin-. Animal studies have clearly shown that Hcrt deficient mice exhibit narcolepsy-like phenotypes including behavioral arrest that is equivalent to cataplexy in human narcolepsy, sleeponset REM periods, and fragmentation of sleep-wake episodes [6, 7]. These observations led to the simple hypothesis that narcolepsy is caused by the loss of Hcrt neurons
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