TY - JOUR T1 - Rapid onset of motor deficits in a mouse model of spinocerebellar ataxia type 6 precedes late cerebellar degeneration JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0094-15.2015 SP - ENEURO.0094-15.2015 AU - Sriram Jayabal AU - Lovisa Ljungberg AU - Thomas Erwes AU - Alexander Cormier AU - Sabrina Quilez AU - Sara El Jaouhari AU - Alanna J. Watt Y1 - 2015/12/04 UR - http://www.eneuro.org/content/early/2015/12/03/ENEURO.0094-15.2015.abstract N2 - Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells. Disease onset is typically midlife, although it can vary widely from late teens to old age in SCA6 patients. Our study focused on an SCA6 knock-in mouse model with a hyper-expanded (84X) CAG repeat expansion that displays midlife-onset motor deficits at ∼7 months old, reminiscent of mid-life onset symptoms in SCA6 patients, although a detailed phenotypic analysis of these mice has not yet been reported. Here, we characterize the onset of motor deficits in SCA684Q mice using a battery of behavioral assays to test for impairments in motor coordination, balance, and gait. We found that these mice performed normally on these assays up to and including at 6 months, but motor impairment was detected at 7 months with all motor coordination assays used, suggesting that motor deficits emerge rapidly during a narrow age window in SCA684Q mice. In contrast to what is seen in SCA6 patients, the decrease in motor coordination was observed without alterations in gait. No loss of cerebellar Purkinje cells or striatal neurons were observed at 7 months, the age at which motor deficits were first detected, but significant Purkinje cell loss was observed in 2-year-old SCA684Q mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.Significance Statement: We confirm that disease onset in an 84Q-hyperexpanded polyglutamine mouse model of spinocerebellar ataxia type 6 (SCA6) occurs at 7 months of age, in agreement with a previous study by Watase and colleagues (2008). We characterize disease onset more precisely using a barrage of behavioral tests at multiple ages, and identify that motor coordination abnormalities emerge in a narrow time window between 6 and 7 months, in contrast to the variable age of onset observed in human patients. We find that Purkinje cell degeneration occurs in this SCA6 mouse model at 2 years, nearly 1.5 years after the onset of motor deficits, demonstrating that Purkinje cell loss is not necessary for early SCA6 disease symptoms. ER -