Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease.

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. Central nervous system (CNS) contributions to disease were revealed using f-ATXN1146Q/2Q;Nestin-Cre mice, which showed improved rotarod, open field, and Barnes maze performance by 6-12 weeks of age. In contrast, striatal contributions to motor deficits using f-ATXN1146Q/2Q;Rgs9-Cre mice revealed that mice lacking ATXN1146Q/2Q in striatal medium-spiny neurons showed a trending improvement in rotarod performance at 30 weeks of age. Surprisingly, a prominent role for muscle contributions to disease was revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice based on their recovery from kyphosis and absence of muscle pathology. Collectively, data from the targeted conditional deletion of the expanded allele demonstrated CNS and peripheral contributions to disease and highlighted the need to consider muscle in addition to the brain for optimal SCA1 therapeutics.

Rates of cerebral protein synthesis in primary visual cortex during sleep-dependent memory consolidation, a study in human subjects.

If protein synthesis during sleep is required for sleep-dependent memory consolidation, we might expect rates of cerebral protein synthesis (rCPS) to increase during sleep in the local brain circuits that support performance on a particular task following training on that task. To measure circuit-specific brain protein synthesis during a daytime nap opportunity, we used the L-[1-(11)C]leucine positron emission tomography (PET) method with simultaneous polysomnography. We trained subjects on the visual texture discrimination task (TDT). This was followed by a nap opportunity during the PET scan, and we retested them later in the day after the scan. The TDT is considered retinotopically specific, so we hypothesized that higher rCPS in primary visual cortex would be observed in the trained hemisphere compared to the untrained hemisphere in subjects who were randomized to a sleep condition. Our results indicate that the changes in rCPS in primary visual cortex depended on whether subjects were in the wakefulness or sleep condition but were independent of the side of the visual field trained. That is, only in the subjects randomized to sleep, rCPS in the right primary visual cortex was higher than the left regardless of side trained. Other brain regions examined were not so affected. In the subjects who slept, performance on the TDT improved similarly regardless of the side trained. Results indicate a regionally selective and sleep-dependent effect that occurs with improved performance on the TDT.

Deficient Sleep in Mouse Models of Fragile X Syndrome.

In patients with fragile X syndrome (FXS), sleep problems are commonly observed but are not well characterized. In animal models of FXS (dfmr1 and Fmr1 knockout (KO)/Fxr2 heterozygote) circadian rhythmicity is affected, but sleep per se has not been examined. We used a home-cage monitoring system to assess total sleep time in both light and dark phases in Fmr1 KO mice at different developmental stages. Fmr1 KOs at P21 do not differ from controls, but genotype × phase interactions in both adult (P70 and P180) groups are statistically significant indicating that sleep in Fmr1 KOs is reduced selectively in the light phase compared to controls. Our results show the emergence of abnormal sleep in Fmr1 KOs during the later stages of brain maturation. Treatment of adult Fmr1 KO mice with a GABAB agonist, R-baclofen, did not restore sleep duration in the light phase. In adult (P70) Fmr1 KO/Fxr2 heterozygote animals, total sleep time was further reduced, once again in the light phase. Our data highlight the importance of the fragile X genes (Fmr1 and Fxr2) in sleep physiology and confirm the utility of these mouse models in enhancing our understanding of sleep disorders in FXS.