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Progressive gene dose-dependent disruption of the methamphetamine-sensitive circadian oscillator-driven rhythms in a knock-in mouse model of Huntington's disease.

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Ouk, Koliane 
Morton, A Jennifer 


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.



Dopamine, Preconditioning, Sleep, Transgenic mice, Age Factors, Animals, Central Nervous System Stimulants, Chronobiology Disorders, Circadian Rhythm, Disease Models, Animal, Disease Progression, Dose-Response Relationship, Drug, Humans, Huntingtin Protein, Huntington Disease, Methamphetamine, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Mutation

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Exp Neurol

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Elsevier BV
This work was supported by a grant from CHDI Foundation, Inc. (USA).