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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

Rotarod deficits at 7 months in SCA684Q/84Q mice. A, Schematic of experimental paradigm: accelerating rotarod experiments were conducted in four trials per day for 5 days of testing at each age. B, No significant differences on D4 and D5 were observed among SCA684Q/84Q, SCA684Q/+, and WT genotypes at 3, 4, 5, or 6 months old; however, SCA684Q/84Q mice display poorer performance on rotarod on D4 and D5 at 7 months compared with WT mice (Genotype: F(2,37) = 12.19; p = 0.0004, one-way ANOVA with post hoc Tukey’s test; ***p < 0.0005; p > 0.05 where not indicated; 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 1: Rotarod deficits at 7 months in SCA684Q/84Q mice. A, Schematic of experimental paradigm: accelerating rotarod experiments were conducted in four trials per day for 5 days of testing at each age. B, No significant differences on D4 and D5 were observed among SCA684Q/84Q, SCA684Q/+, and WT genotypes at 3, 4, 5, or 6 months old; however, SCA684Q/84Q mice display poorer performance on rotarod on D4 and D5 at 7 months compared with WT mice (Genotype: F(2,37) = 12.19; p = 0.0004, one-way ANOVA with post hoc Tukey’s test; ***p < 0.0005; p > 0.05 where not indicated; 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 placed on a rotarod (Stoelting Europe) using a standard 10-min-long accelerating assay where the rod accelerates from 4 to 40 rpm in the first 5 min and then continues to rotate at 40 rpm for the last 5 min (Carter et al., 2001; Watase et al., 2007; Fig. 1A; Movie 1, 2). The latency to fall was recorded for each mouse as a measure of cerebellum-related motor coordination (Watase et al., 2007). Mice performed four trials (T1–T4) per day, and had at least a 15 min resting period between trials, over 5 consecutive days of testing (D1–D5).


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)

Rotarod deficits at 7 months in SCA684Q/84Q mice. A, Schematic of experimental paradigm: accelerating rotarod experiments were conducted in four trials per day for 5 days of testing at each age. B, No significant differences on D4 and D5 were observed among SCA684Q/84Q, SCA684Q/+, and WT genotypes at 3, 4, 5, or 6 months old; however, SCA684Q/84Q mice display poorer performance on rotarod on D4 and D5 at 7 months compared with WT mice (Genotype: F(2,37) = 12.19; p = 0.0004, one-way ANOVA with post hoc Tukey’s test; ***p < 0.0005; p > 0.05 where not indicated; 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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697081&req=5

Figure 1: Rotarod deficits at 7 months in SCA684Q/84Q mice. A, Schematic of experimental paradigm: accelerating rotarod experiments were conducted in four trials per day for 5 days of testing at each age. B, No significant differences on D4 and D5 were observed among SCA684Q/84Q, SCA684Q/+, and WT genotypes at 3, 4, 5, or 6 months old; however, SCA684Q/84Q mice display poorer performance on rotarod on D4 and D5 at 7 months compared with WT mice (Genotype: F(2,37) = 12.19; p = 0.0004, one-way ANOVA with post hoc Tukey’s test; ***p < 0.0005; p > 0.05 where not indicated; 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 placed on a rotarod (Stoelting Europe) using a standard 10-min-long accelerating assay where the rod accelerates from 4 to 40 rpm in the first 5 min and then continues to rotate at 40 rpm for the last 5 min (Carter et al., 2001; Watase et al., 2007; Fig. 1A; Movie 1, 2). The latency to fall was recorded for each mouse as a measure of cerebellum-related motor coordination (Watase et al., 2007). Mice performed four trials (T1–T4) per day, and had at least a 15 min resting period between trials, over 5 consecutive days of testing (D1–D5).

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