The Q175 Mouse Model of Huntington’s Disease Shows Gene Dosage- and Age-Related Decline in Circadian Rhythms of Activity and Sleep

Abstract

Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington’s disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.

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

“…These findings were unexpected since the C57BL/6 background mice show normal physiological gating (Amann et al, 2010;Stevens et al, 1996), and a clear gene-dose effect was predicted on auditory gating in these mice. Although Q175 mice have been successfully used in various preclinical studies since they display a number of cardinal symptoms and pathophysiology of Huntington's disease (Loh et al, 2013), it seems they are less suitable for recapturing auditory gating abnormalities present in Huntington's disease. Furthermore, PF-04447943 did not improve either cortical or hippocampal auditory gating deficit at an efficacious dose in either WT or TG Q175 mice, although each group showed poor baseline gating.…”

Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT

“…Methods used were similar to those described previously (Loh et al, 2013). Male Mecp2 −/y mutant mice and WT littermates (7-8 weeks old) were housed in 12:12 LD conditions.…”

“…Methods used were similar to those described previously (Kudo et al, 2011;Loh et al, 2013). Male Mecp2 −/y mutant mice and WT littermates were housed in cages containing running wheels (Mini Mitter Co., Bend, OR) from 6 to 7 weeks of age and their wheelrunning activity recorded as revolutions (rev) per 3 min intervals.…”

“…IHC was performed as previously reported (Loh et al, 2013) with minor modifications. Briefly, brain sections (30 μm) were incubated in blocking serum overnight at 4°C (3% bovine serum albumin, 0.1% triton X-100 and 0.025% sodium azide in PB), and then incubated with primary antibodies against VIP (rabbit polyclonal 1:2000; ImmunoStar; Hudson, WI, USA) for 24 h at 4°C with gentle shaking.…”

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

“…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.…”