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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 latency on elevated beam at 7 months in SCA684Q/84Q mice. A, Schematic of experimental design for elevated beam assay. Two days of training were followed by 2 d of testing (D1 and D2 in B−E). B−E, Latency to cross the beam was measured for each genotype at each age (3, 4, 5, 6, and 7 months) over D1 and D2. SCA684Q/84Q mice were significantly slower at traversing the beam at 7 months on D2 for the following diameters: B, 22 mm (F(2,17) = 7.36; p = 0.005); C, 18 mm (F(2,17) = 7.46; p = 0.005); D, 15 mm (F(2,17) = 4.34; p = 0.03); and E, 12 mm (F(2,17) = 5.27; p = 0.017). SCA684Q/+ mice were indistinguishable from WT mice. *p < 0.05, **p < 0.01, ***p < 0.005; 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 2: Increased latency on elevated beam at 7 months in SCA684Q/84Q mice. A, Schematic of experimental design for elevated beam assay. Two days of training were followed by 2 d of testing (D1 and D2 in B−E). B−E, Latency to cross the beam was measured for each genotype at each age (3, 4, 5, 6, and 7 months) over D1 and D2. SCA684Q/84Q mice were significantly slower at traversing the beam at 7 months on D2 for the following diameters: B, 22 mm (F(2,17) = 7.36; p = 0.005); C, 18 mm (F(2,17) = 7.46; p = 0.005); D, 15 mm (F(2,17) = 4.34; p = 0.03); and E, 12 mm (F(2,17) = 5.27; p = 0.017). SCA684Q/+ mice were indistinguishable from WT mice. *p < 0.05, **p < 0.01, ***p < 0.005; 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 walked along a custom-built apparatus consisting of raised round wooden beams (100 cm long), toward a dark escape box, as previously described (Carter et al., 2001; Fig. 2A; Movie 3). Bright light shining on the starting point was used as an aversive stimulus to encourage mice to traverse the beam. D1 and D2 were training days, during which mice were trained to cross a beam 22 mm in diameter. On D3 and D4, corresponding to testing D1 and D2, each mouse performed a trial on beams with diameters of 22, 18, 15, and 12 mm, totaling four trials per day. The time taken to traverse 80 cm was recorded, and the number of times the foot of the mouse slipped while crossing the beams was counted during post hoc video analysis (for an example of a mouse whose foot slips three times during the assay, see Movie 4).


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 latency on elevated beam at 7 months in SCA684Q/84Q mice. A, Schematic of experimental design for elevated beam assay. Two days of training were followed by 2 d of testing (D1 and D2 in B−E). B−E, Latency to cross the beam was measured for each genotype at each age (3, 4, 5, 6, and 7 months) over D1 and D2. SCA684Q/84Q mice were significantly slower at traversing the beam at 7 months on D2 for the following diameters: B, 22 mm (F(2,17) = 7.36; p = 0.005); C, 18 mm (F(2,17) = 7.46; p = 0.005); D, 15 mm (F(2,17) = 4.34; p = 0.03); and E, 12 mm (F(2,17) = 5.27; p = 0.017). SCA684Q/+ mice were indistinguishable from WT mice. *p < 0.05, **p < 0.01, ***p < 0.005; 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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Figure 2: Increased latency on elevated beam at 7 months in SCA684Q/84Q mice. A, Schematic of experimental design for elevated beam assay. Two days of training were followed by 2 d of testing (D1 and D2 in B−E). B−E, Latency to cross the beam was measured for each genotype at each age (3, 4, 5, 6, and 7 months) over D1 and D2. SCA684Q/84Q mice were significantly slower at traversing the beam at 7 months on D2 for the following diameters: B, 22 mm (F(2,17) = 7.36; p = 0.005); C, 18 mm (F(2,17) = 7.46; p = 0.005); D, 15 mm (F(2,17) = 4.34; p = 0.03); and E, 12 mm (F(2,17) = 5.27; p = 0.017). SCA684Q/+ mice were indistinguishable from WT mice. *p < 0.05, **p < 0.01, ***p < 0.005; 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 walked along a custom-built apparatus consisting of raised round wooden beams (100 cm long), toward a dark escape box, as previously described (Carter et al., 2001; Fig. 2A; Movie 3). Bright light shining on the starting point was used as an aversive stimulus to encourage mice to traverse the beam. D1 and D2 were training days, during which mice were trained to cross a beam 22 mm in diameter. On D3 and D4, corresponding to testing D1 and D2, each mouse performed a trial on beams with diameters of 22, 18, 15, and 12 mm, totaling four trials per day. The time taken to traverse 80 cm was recorded, and the number of times the foot of the mouse slipped while crossing the beams was counted during post hoc video analysis (for an example of a mouse whose foot slips three times during the assay, see Movie 4).

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