S105 Changes in sleep-related abnormal EEG oscillations may predict the therapeutic efficacy of drugs in mouse models of Huntington’s disease

Abstract

Objectives Sleep and EEG abnormalities typically appear in Huntington’s disease (HD) before the onset of overt motor symptoms. Since drugs used for the symptomatic treatment of HD also affect sleep, we tested whether they might correct the sleep and EEG abnormalities seen in HD. Methods We treated wild-type (WT) mice and a transgenic mouse model of HD (R6/2) acutely with zolpidem, amitriptyline, or paroxetine (0, 5, 10 and 20 mg/kg for each drug). A subgroup of R6/2 mice was also treated chronically with paroxetine (0 or 20 mg/kg/daily) from a pre-symptomatic age. EEG/EMG was recorded after acute treatments, at the end of chronic treatment period, and two weeks after chronic treatment stopped. Results All drugs supressed REM sleep in both genotypes. R6/2 mice treated acutely with zolpidem and amitriptyline, but not paroxetine, showed suppression of abnormal low-gamma (25–45 Hz) EEG oscillations. However, chronic treatment with paroxetine prevented the development of abnormal gamma oscillations in R6/2 mice, an effect that persisted for at least two weeks after treatment stopped. Discussion/Conclusions We demonstrate that the pathophysiological changes seen in sleep and EEG are not ‘hard-wired’ in HD brain and can be prevented or reversed by drugs. Furthermore, sleep and EEG measures proved to be valuable tools for assessing the therapeutic potential of treatment options for HD. Significance Since the abnormal sleep-EEG changes are likely to be correlates of altered brain function in HD, correcting these abnormalities might also be reflected in improvements in HD symptoms other than sleep and sleep-dependent brain oscillations.