Department of Chronobiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan.
PLoS One. 2009 Nov 9;4(11):e7737. doi: 10.1371/journal.pone.0007737.
THE SLEEP SEQUENCE: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, but the underlying mechanisms are unknown. It has been shown that this sequence is disrupted by sudden REM sleep onset during active wakefulness (i.e., narcolepsy) in orexin-deficient mutant animals. Phospholipase C (PLC) mediates the signaling of numerous metabotropic receptors, including orexin receptors. Among the several PLC subtypes, the beta4 subtype is uniquely localized in the geniculate nucleus of thalamus which is hypothesized to have a critical role in the transition and maintenance of sleep stages. In fact, we have reported irregular theta wave frequency during REM sleep in PLC-beta4-deficient mutant (PLC-beta4-/-) mice. Daily behavioral phenotypes and metabotropic receptors involved have not been analyzed in detail in PLC-beta4-/- mice, however.
METHODOLOGY/PRINCIPAL FINDINGS: Therefore, we analyzed 24-h sleep electroencephalogram in PLC-beta4-/- mice. PLC-beta4-/- mice exhibited normal non-REM sleep both during the day and nighttime. PLC-beta4-/- mice, however, exhibited increased REM sleep during the night, their active period. Also, their sleep was fragmented with unusual wake-to-REM sleep transitions, both during the day and nighttime. In addition, PLC-beta4-/- mice reduced ultradian body temperature rhythms and elevated body temperatures during the daytime, but had normal homeothermal response to acute shifts in ambient temperatures (22 degrees C-4 degrees C). Within the most likely brain areas to produce these behavioral phenotypes, we found that, not orexin, but group-1 metabotropic glutamate receptor (mGluR)-mediated Ca(2+) mobilization was significantly reduced in the dorsal lateral geniculate nucleus (LGNd) of PLC-beta4-/- mice. Voltage clamp recordings revealed that group-1 mGluR-mediated currents in LGNd relay neurons (inward in wild-type mice) were outward in PLC-beta4-/- mice.
CONCLUSIONS/SIGNIFICANCE: These lines of evidence indicate that impaired LGNd relay, possibly mediated via group-1 mGluR, may underlie irregular sleep sequences and ultradian body temperature rhythms in PLC-beta4-/- mice.
睡眠序列：i）非快速眼动睡眠，ii）快速眼动睡眠，和 iii）觉醒，在哺乳动物中是稳定且广泛存在的，但潜在机制尚不清楚。已经表明，这种序列在 orexin 缺乏突变动物的活跃觉醒期间（即发作性睡病）突然出现快速眼动睡眠时会被打乱。磷酸脂酶 C（PLC）介导包括 orexin 受体在内的许多代谢型受体的信号转导。在几种 PLC 亚型中，beta4 亚型特异性定位于丘脑膝状体核，据推测其在睡眠阶段的转换和维持中具有关键作用。事实上，我们已经报道了 PLC-beta4 缺陷型突变（PLC-beta4-/-）小鼠的快速眼动睡眠期间不规则的 theta 波频率。然而，尚未详细分析 PLC-beta4-/- 小鼠的日常行为表型和涉及的代谢型受体。
方法/主要发现：因此，我们在 PLC-beta4-/- 小鼠中分析了 24 小时睡眠脑电图。PLC-beta4-/- 小鼠在白天和夜间均表现出正常的非快速眼动睡眠。然而，PLC-beta4-/- 小鼠在夜间，即其活跃期，表现出 REM 睡眠增加。此外，它们的睡眠也被打断，白天和夜间的异常觉醒到快速眼动睡眠的转换。此外，PLC-beta4-/- 小鼠减少了超昼夜体温节律并在白天升高体温，但对环境温度的急性变化（22°C-4°C）有正常的体温调节反应。在最有可能产生这些行为表型的大脑区域内，我们发现，不是 orexin，而是第 1 组代谢型谷氨酸受体（mGluR）介导的 Ca（2+）动员在 PLC-beta4-/- 小鼠的背外侧膝状体核（LGNd）中显著减少。电压钳记录显示，第 1 组 mGluR 介导的 LGNd 中继神经元（在野生型小鼠中为内向电流）在 PLC-beta4-/- 小鼠中为外向电流。
结论/意义：这些证据表明，LGNd 中继的损伤，可能通过第 1 组 mGluR 介导，可能是 PLC-beta4-/- 小鼠不规则睡眠序列和超昼夜体温节律的基础。
