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Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration.

Jayabal S, Ljungberg L, Erwes T, Cormier A, Quilez S, El Jaouhari S, Watt AJ - eNeuro (2015)

Bottom Line: Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells.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 SCA6(84Q) mice.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 SCA6(84Q) mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.

ABSTRACT
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 at 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 midlife-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 SCA6(84Q) 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 SCA6(84Q) 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 SCA6(84Q) mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.

No MeSH data available.


Related in: MedlinePlus

Increased footslips on narrow elevated beam at 7 months in SCA684Q/84Q mice. A–D, The number of mice that display footslips (0 footslips = lightest color, >2 footslips = darkest color, and 1 and 2 footslips graded in between) when crossing beams for the following three genotypes: WT (grayscale) SCA684Q/+ (orange scale), and SCA684Q/84Q mice (red scale); see legend on the right. No differences were seen across genotypes and age for the following: A, 22-mm-diameter beam (F(2,37) = 0.17; p = 0.85); B,18-mm-diameter beam (F(2,37) = 1.91; p = 0.16); C, 15-mm-diameter beam (F(2,37) = 0.65; p = 0.53); D, a significant increase in the number of footslips was observed for the 12-mm-diameter beam at 7 months for SCA684Q/84Q mice (F(2,37) = 4.19; p = 0.02). *p < 0.05; p > 0.05 where not indicated, one-way ANOVA followed by post hoc Tukey’s test; N = 8 − 10 SCA684Q/84Q mice depending on age, 5 − 9 SCA684Q/+ mice, and 6 − 9 WT mice (consult Table 1 for sample size at each age).
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Figure 3: Increased footslips on narrow elevated beam at 7 months in SCA684Q/84Q mice. A–D, The number of mice that display footslips (0 footslips = lightest color, >2 footslips = darkest color, and 1 and 2 footslips graded in between) when crossing beams for the following three genotypes: WT (grayscale) SCA684Q/+ (orange scale), and SCA684Q/84Q mice (red scale); see legend on the right. No differences were seen across genotypes and age for the following: A, 22-mm-diameter beam (F(2,37) = 0.17; p = 0.85); B,18-mm-diameter beam (F(2,37) = 1.91; p = 0.16); C, 15-mm-diameter beam (F(2,37) = 0.65; p = 0.53); D, a significant increase in the number of footslips was observed for the 12-mm-diameter beam at 7 months for SCA684Q/84Q mice (F(2,37) = 4.19; p = 0.02). *p < 0.05; p > 0.05 where not indicated, one-way ANOVA followed by post hoc Tukey’s test; N = 8 − 10 SCA684Q/84Q mice depending on age, 5 − 9 SCA684Q/+ mice, and 6 − 9 WT mice (consult Table 1 for sample size at each age).

Mentions: Animals were trained to swim across a custom-built Plexiglas swimming tank (100 cm long by 6 cm wide) toward a dry, boxed-in escape platform (Carter et al., 1999; Fig. 3A; Movie 5-7). Bright light at the starting location was used as an aversive stimulus to encourage swimming across the tank. The mice were initially trained to swim across the swim tank toward the escape platform for two trials per day. D1 and D2 were considered training days, while testing days correspond to D3−D5. Mice were videotaped, and latency to traverse a 60 cm distance was recorded. The number of hindlimb kicks to cross the tank was counted during post hoc video analysis. See Movie 6,7; after the assay, mice were towel dried and monitored in their home cage for 20 min after the assay.


Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration.

Jayabal S, Ljungberg L, Erwes T, Cormier A, Quilez S, El Jaouhari S, Watt AJ - eNeuro (2015)

Increased footslips on narrow elevated beam at 7 months in SCA684Q/84Q mice. A–D, The number of mice that display footslips (0 footslips = lightest color, >2 footslips = darkest color, and 1 and 2 footslips graded in between) when crossing beams for the following three genotypes: WT (grayscale) SCA684Q/+ (orange scale), and SCA684Q/84Q mice (red scale); see legend on the right. No differences were seen across genotypes and age for the following: A, 22-mm-diameter beam (F(2,37) = 0.17; p = 0.85); B,18-mm-diameter beam (F(2,37) = 1.91; p = 0.16); C, 15-mm-diameter beam (F(2,37) = 0.65; p = 0.53); D, a significant increase in the number of footslips was observed for the 12-mm-diameter beam at 7 months for SCA684Q/84Q mice (F(2,37) = 4.19; p = 0.02). *p < 0.05; p > 0.05 where not indicated, one-way ANOVA followed by post hoc Tukey’s test; N = 8 − 10 SCA684Q/84Q mice depending on age, 5 − 9 SCA684Q/+ mice, and 6 − 9 WT mice (consult Table 1 for sample size at each age).
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Related In: Results  -  Collection

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Show All Figures
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Figure 3: Increased footslips on narrow elevated beam at 7 months in SCA684Q/84Q mice. A–D, The number of mice that display footslips (0 footslips = lightest color, >2 footslips = darkest color, and 1 and 2 footslips graded in between) when crossing beams for the following three genotypes: WT (grayscale) SCA684Q/+ (orange scale), and SCA684Q/84Q mice (red scale); see legend on the right. No differences were seen across genotypes and age for the following: A, 22-mm-diameter beam (F(2,37) = 0.17; p = 0.85); B,18-mm-diameter beam (F(2,37) = 1.91; p = 0.16); C, 15-mm-diameter beam (F(2,37) = 0.65; p = 0.53); D, a significant increase in the number of footslips was observed for the 12-mm-diameter beam at 7 months for SCA684Q/84Q mice (F(2,37) = 4.19; p = 0.02). *p < 0.05; p > 0.05 where not indicated, one-way ANOVA followed by post hoc Tukey’s test; N = 8 − 10 SCA684Q/84Q mice depending on age, 5 − 9 SCA684Q/+ mice, and 6 − 9 WT mice (consult Table 1 for sample size at each age).
Mentions: Animals were trained to swim across a custom-built Plexiglas swimming tank (100 cm long by 6 cm wide) toward a dry, boxed-in escape platform (Carter et al., 1999; Fig. 3A; Movie 5-7). Bright light at the starting location was used as an aversive stimulus to encourage swimming across the tank. The mice were initially trained to swim across the swim tank toward the escape platform for two trials per day. D1 and D2 were considered training days, while testing days correspond to D3−D5. Mice were videotaped, and latency to traverse a 60 cm distance was recorded. The number of hindlimb kicks to cross the tank was counted during post hoc video analysis. See Movie 6,7; after the assay, mice were towel dried and monitored in their home cage for 20 min after the assay.

Bottom Line: Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells.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 SCA6(84Q) mice.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 SCA6(84Q) mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.

ABSTRACT
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 at 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 midlife-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 SCA6(84Q) 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 SCA6(84Q) 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 SCA6(84Q) mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.

No MeSH data available.


Related in: MedlinePlus