BALTIMORE—Early changes in quantitative EEG measures, such as increased gamma and theta activity in all sleep–wake states, may be a reliable biomarker of Huntington’s disease in mice, according to research presented at the 27th Annual Meeting of the Associated Professional Sleep Societies.
“Identifying the source of the abnormal gamma oscillations in this model could tell us a lot about the pathophysiology of the disease,” said Simon P. Fisher, PhD. Increased theta activity and a slowing of theta peak frequency suggest the involvement of the hippocampus, and previous investigations of the R6/2 mouse model of Huntington’s disease have found inclusion bodies and polyglutamine aggregates in the hippocampus.
Sleep–wake disruption and abnormalities in the EEG are evident in R6/2 mice and in humans with Huntington’s disease, but neurologists cannot yet make direct translational inferences from these data, said Dr. Fisher, Research Scientist at SRI International in Menlo Park, California. Further studies of EEG changes in other preclinical models will be necessary to validate these findings, particularly because no single model recapitulates all features of the human disease. Nevertheless, the present study supports the EEG as a potential biomarker in preclinical drug development for Huntington’s disease, he added.
A Longitudinal Analysis of Sleep Phenotype
Dr. Fisher and colleagues conducted a longitudinal analysis of the sleep phenotype in R6/2 mice. The investigators implanted 7-week-old male and female R6/2 mice for EEG and performed 48-hour baseline recordings at 9, 13, and 17 weeks of age. During the 10-week study, the mice underwent three sleep-deprivation periods at each of these ages, each of which was followed by a recovery period. Throughout the study, the researchers recorded the mice’s activity and body temperature continuously using inductive telemetry.
During the study, activity patterns for R6/2 mice disintegrated, and the mice displayed a consistent low level of activity throughout each 24-hour day by 17 weeks. In addition, the diurnal rhythm of body temperature flattened in R6/2 mice by 13 weeks and was disrupted dramatically by 17 weeks. Pronounced hypothermia during the dark period at this time suggested severe metabolic disturbances in the mouse model, said Dr. Fisher.
Gamma Activity Increased in R6/2 Mice
Gamma activity was between six and eight times greater in the non-REM sleep of R6/2 mice, compared with wild type mice, by 17 weeks. Theta power also increased in REM and non-REM sleep for the R6/2 mice, compared with wild type mice.
In addition, baseline non-REM delta power decreased in R6/2 mice, compared with wild type mice. The investigators also examined non-REM delta power after sleep deprivation. No differences were evident between R6/2 and wild type mice at 9 weeks, but the researchers observed crested impairments in R6/2 mice at 13 weeks that progressed to 17 weeks, suggesting that the sleep rebound is compromised in these mice. Theta peak frequency also decreased progressively for R6/2 mice.
“One of the main aims of future research is to understand how these sleep abnormalities in this phenotype interact with the other symptoms in this model—particularly cognitive dysfunction and altered metabolism,” said Dr. Fisher. In previous studies, cognitive function improved in R6/2 mice that received hypnotics and stimulants to normalize their sleep–wake cycles. This work suggests that treating sleep disorders “might be a novel therapeutic angle in Huntington’s disease,” concluded Dr. Fisher.
—Erik Greb
Senior Associate Editor