Toyoda Hiromi, Honda Yoshiko, Tanaka Susumu, Miyagawa Taku, Honda Makoto, Honda Kazuki, Tokunaga Katsushi, Kodama Tohru
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
PLoS One. 2017 Nov 29;12(11):e0187888. doi: 10.1371/journal.pone.0187888. eCollection 2017.
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.
发作性睡病由下丘脑泌素（Hcrt）神经元缺失引起，与多种遗传和环境因素相关。尽管有研究表明免疫异常参与了发作性睡病的病因，但尚未确立决定性机制。我们之前报道趋化因子（C-C基序）受体3（CCR3）是发作性睡病的一个新的易感基因。为了解CCR3在发作性睡病发病中的作用，我们研究了Ccr3基因敲除（KO）小鼠的睡眠-觉醒模式。Ccr3 KO小鼠在光照期表现出碎片化睡眠模式，而在黑暗期，Ccr3 KO小鼠与野生型（WT）同窝小鼠的整体睡眠结构并无差异。腹腔注射脂多糖（LPS）可促进Ccr3 KO小鼠和WT小鼠在光照期的觉醒，并抑制快速眼动（REM）睡眠和非快速眼动（NREM）睡眠。相反，在黑暗期，LPS可抑制两种基因型小鼠的觉醒并促进NREM睡眠。给予LPS后，仅在光照期，Ccr3 KO小鼠的觉醒时间比例较高，NREM睡眠的时间比例低于WT小鼠。与WT小鼠相比，LPS诱导的Ccr3 KO小鼠睡眠模式变化更大。此外，我们对Hcrt神经元数量进行了量化，发现与WT小鼠相比，Ccr3 KO小鼠下丘脑外侧的Hcrt神经元数量更少。我们发现Ccr3 KO小鼠在静息期的睡眠模式以及Hcrt神经元数量存在异常。这些观察结果表明CCR3在发作性睡病患者的睡眠-觉醒调节中发挥作用。
