Progressive sleep and electroencephalogram changes in mice carrying the Huntington’s disease mutation

Abstract

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 electroencephalo-gram/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.

Sleep deficits but no metabolic deficits in premanifest Huntington's disease

“…This suggests that even in the presence of sufficient sleep duration, the restorative effects may be compromised during the premanifest stage. These results of fragmented sleep are in line with a recent paper showing major sleep disturbances in manifest HD patients that were also characterized by increased arousals and awakenings55 and data from transgenic animal models of HD showing that sleep quality as well as oscillatory brain activity (EEG) and circadian rhythmicity becomes gradually more disrupted as the disease progresses 11, 12, 14. Furthermore, it has recently been shown that resting EEG alterations in pre‐HD individuals may be related to the course of the pathological process and to HD endophenotype 43.…”

“…Our study therefore is the first qEEG study performed during sleep in premanifest and manifest patients with HD and indicates alterations in the NREM‐ and particularly the REM‐dependent oscillatory activity of the brain associated with disease burden in gene carriers. Some of our findings such as the decrease in the 3 to 8Hz range and the increase in the high‐frequency (32–36Hz) range in the early HD group are somewhat similar to findings in transgenic animal studies reporting a progressive decrease in low‐frequency (delta) and increase in high‐frequency (beta–gamma) activity in sleep 11, 12, 58. The REM‐dependent increase in the 1 to 2Hz range is unexpected and could be related to increased REM intensity (density of REM), a hypothesis that remains to be tested.…”

“…These results are intriguing, because EEG activity reflects characteristics of cortical and subcortical neural activity and has the potential to become a biomarker for HD onset and progression in the future 56. Whereas there are a number of quantitative EEG (qEEG) studies of waking brain activity in HD (for a review see Nguyen et al56), there are only a couple of studies looking at spectral features of EEG during sleep, and only in transgenic animal models of HD,11, 12, 14, 57, 58 with no studies in humans. Our study therefore is the first qEEG study performed during sleep in premanifest and manifest patients with HD and indicates alterations in the NREM‐ and particularly the REM‐dependent oscillatory activity of the brain associated with disease burden in gene carriers.…”

“…Although pathogenic pathways are beginning to be unraveled offering targets for treatment,8 the precise pathophysiological mechanisms of HD are poorly understood 9. Previously we have shown that sleep disturbances are present in early manifest disease,10 and several studies on transgenic animal models of HD have shown that sleep progressively worsens as the disease develops11, 12, 13, 14 dependently on age and gene dosage 15. However, we do not know whether sleep problems are present during the premanifest stage in individuals carrying the HD gene mutation.…”

Application of neurophysiological biomarkers for Huntington's disease: Evaluating a phosphodiesterase 9A inhibitor

“…Since abnormal changes in gamma band power have been recently reported in R6/2 mouse model of Huntington's disease (Fisher et al, 2013;Kantor et al, 2013) field potential oscillations were recorded for determining power of gamma-band (30 to 90 Hz) activity in these brain regions. Most importantly, one of the critical goals of our studies was to establish if auditory gating deficit in these transgenic animals could serve as a translational biomarker in drug development of Huntington's disease.…”