title: Progressive gene dose-dependent disruption of the methamphetamine-sensitive circadian oscillator-driven rhythms in a knock-in mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a progressive genetic neurodegenerative disorder characterised by motor and cognitive deficits, as well as sleep and circadian abnormalities. In the R6/2 mouse, a fragment model of HD, rest-activity rhythms controlled by the suprachiasmatic nucleus disintegrate completely by 4months of age. Rhythms driven by a second circadian oscillator, the methamphetamine-sensitive circadian oscillator (MASCO), are disrupted even earlier, and cannot be induced after 2months of age. Here, we studied the effect of the HD mutation on the expression of MASCO-driven rhythms in a more slowly developing, genetically relevant mouse model of HD, the Q175 'knock-in' mouse. We induced expression of MASCO output by administering low dose methamphetamine (0.005%) chronically via the drinking water. We measured locomotor activity in constant darkness in wild-type and Q175 mice at 2 (presymptomatic), 6 (early symptomatic), and 12 (symptomatic) months of age. At 2months, all mice expressed MASCO-driven rhythms, regardless of genotype. At older ages, however, there was a progressive gene dose-dependent deficit in MASCO output in Q175 mice. At 6months of age, these rhythms could be observed in only 45% of heterozygous and 15% of homozygous mice. By 1year of age, 90% of homozygous mice had an impaired MASCO output. There was also an age-dependent disruption of MASCO output seen in wild-type mice. The fact that the progressive deficit in MASCO-driven rhythms in Q175 mice is HD gene dose-dependent suggests that, whatever its role in humans, abnormalities in MASCO output may contribute to the HD circadian phenotype.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, Downing Street, CB2 3DY, United Kingdom. Electronic address: ko303@cam.ac.uk.
authors.forename: Koliane
authors.initials: K
authors.lastname: Ouk
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, Downing Street, CB2 3DY, United Kingdom. Electronic address: ja448@cam.ac.uk.
authors.forename: Juliet
authors.initials: J
authors.lastname: Aungier
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, Downing Street, CB2 3DY, United Kingdom. Electronic address: ajm41@cam.ac.uk.
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Morton
mesh_terms: D000367:Age Factors; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D021081:Chronobiology Disorders / Q000209:etiology*; D002940:Circadian Rhythm / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics*; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000235:genetics
chemical_list: D000697:Central Nervous System Stimulants; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008694:Methamphetamine
keywords: Dopamine; Preconditioning; Sleep; Transgenic mice