Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Neurotherapeutics. 2017 Oct;14(4):1120-1133. doi: 10.1007/s13311-017-0546-7.
Disturbance of rapid eye movement (REM) sleep appears early in both patients with Huntington's disease (HD) and mouse models of HD. Selective serotonin reuptake inhibitors are widely prescribed for patients with HD, and are also known to suppress REM sleep in healthy subjects. To test whether selective serotonin reuptake inhibitors can correct abnormal REM sleep and sleep-dependent brain oscillations in HD mice, we treated wild-type and symptomatic R6/2 mice acutely with vehicle and paroxetine (5, 10, and 20 mg/kg). In addition, we treated a group of R6/2 mice chronically with vehicle or paroxetine (20 mg/kg/day) for 8 weeks, with treatment starting before the onset of overt motor symptoms. During and after treatment, we recorded electroencephalogram/electromyogram from the mice. We found that both acute and chronic paroxetine treatment normalized REM sleep in R6/2 mice. However, only chronic paroxetine treatment prevented the emergence of abnormal low-gamma (25-45 Hz) electroencephalogram oscillations in R6/2 mice, an effect that persisted for at least 2 weeks after treatment stopped. Chronic paroxetine treatment also normalized REM sleep theta rhythm in R6/2 mice, but, interestingly, this effect was restricted to the treatment period. By contrast, acute paroxetine treatment slowed REM sleep theta rhythm in WT mice but had no effect on abnormal theta or low-gamma oscillations in R6/2 mice. Our data show that paroxetine treatment, when initiated before the onset of symptoms, corrects both REM sleep disturbances and abnormal brain oscillations, suggesting a possible mechanistic link between early disruption of REM sleep and the subsequent abnormal brain activity in HD mice.
快速眼动 (REM) 睡眠障碍在亨廷顿病 (HD) 患者和 HD 小鼠模型中均较早出现。选择性 5-羟色胺再摄取抑制剂被广泛用于治疗 HD 患者，也已知可抑制健康受试者的 REM 睡眠。为了测试选择性 5-羟色胺再摄取抑制剂是否可以纠正 HD 小鼠异常的 REM 睡眠和睡眠依赖性脑振荡，我们用载体和帕罗西汀（5、10 和 20mg/kg）急性处理野生型和有症状的 R6/2 小鼠。此外，我们用载体或帕罗西汀（20mg/kg/天）对一组 R6/2 小鼠进行慢性治疗 8 周，治疗在明显运动症状出现之前开始。在治疗期间和之后，我们从小鼠记录脑电图/肌电图。我们发现，帕罗西汀的急性和慢性治疗均可使 R6/2 小鼠的 REM 睡眠正常化。然而，只有慢性帕罗西汀治疗可防止 R6/2 小鼠出现异常的低伽马（25-45Hz）脑电图振荡，这种作用在治疗停止后至少持续 2 周。慢性帕罗西汀治疗还可使 R6/2 小鼠的 REM 睡眠θ节律正常化，但有趣的是，这种作用仅限于治疗期。相比之下，急性帕罗西汀治疗会使 WT 小鼠的 REM 睡眠θ节律减慢，但对 R6/2 小鼠的异常θ或低伽马振荡没有影响。我们的数据表明，在症状出现之前开始帕罗西汀治疗可纠正 REM 睡眠障碍和异常脑振荡，这表明 REM 睡眠早期中断与 HD 小鼠随后的异常大脑活动之间可能存在机制联系。
