Limits...
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

Purkinje cell degeneration is observed long after the onset of motor phenotype at 2 years in SCA684Q/84Q mice. A, Representative images of calbindin-stained Purkinje cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse cerebellar slices. The height of the molecular layer is indicated. Scale bar, 20 μm. B, Density of Purkinje cells in 7-month-old cerebellum is not significantly different in SCA684Q/84Q mice compared with WT mice (Genotype: F(1,109) = 0.002, p = 0.96). However, reduced Purkinje cell density is observed at 2 years in SCA684Q/84Q mice (Genotype: F(1,97) = 18.76, p = <0.0001; right). C, Representative images of 2-year-old WT (left) and SCA684Q/84Q (right) Purkinje cells. Scale bar, 20 μm. D, No significant difference in the Purkinje cell molecular layer is observed at 7 months in SCA684Q/84Q and WT mice (F(1,203) = 0.79, p = 0.37; left), while molecular layer thickness is reduced at 2 years in SCA684Q/84Q mice compared with WT mice (F(1,189) = 33.12, p < 0.0001; right). N = 3-4 animals for each genotype at each age; at least 10 mm of the Purkinje cell layer was measured for each comparison; one-way ANOVA with post hoc Tukey’s test. ***p < 0.0001, **p < 0.01, *p < 0.05; p > 0.05, where not indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4697081&req=5

Figure 7: Purkinje cell degeneration is observed long after the onset of motor phenotype at 2 years in SCA684Q/84Q mice. A, Representative images of calbindin-stained Purkinje cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse cerebellar slices. The height of the molecular layer is indicated. Scale bar, 20 μm. B, Density of Purkinje cells in 7-month-old cerebellum is not significantly different in SCA684Q/84Q mice compared with WT mice (Genotype: F(1,109) = 0.002, p = 0.96). However, reduced Purkinje cell density is observed at 2 years in SCA684Q/84Q mice (Genotype: F(1,97) = 18.76, p = <0.0001; right). C, Representative images of 2-year-old WT (left) and SCA684Q/84Q (right) Purkinje cells. Scale bar, 20 μm. D, No significant difference in the Purkinje cell molecular layer is observed at 7 months in SCA684Q/84Q and WT mice (F(1,203) = 0.79, p = 0.37; left), while molecular layer thickness is reduced at 2 years in SCA684Q/84Q mice compared with WT mice (F(1,189) = 33.12, p < 0.0001; right). N = 3-4 animals for each genotype at each age; at least 10 mm of the Purkinje cell layer was measured for each comparison; one-way ANOVA with post hoc Tukey’s test. ***p < 0.0001, **p < 0.01, *p < 0.05; p > 0.05, where not indicated.

Mentions: The transgenic SCA684Q/84Q mice that we used in this study have previously been reported to exhibit no Purkinje cells degeneration at 20 months old (Watase et al., 2008), which is in contrast to the degeneration observed early in 118Q hyperexpanded mice (Unno et al., 2012) and postmortem in human SCA6 patient data (Yang et al., 2000). We first examined Purkinje cell density in 7-month-old mice and found 5.2 ± 0.17 cells/100 μm Purkinje cell layer in WT mice, with no significant differences in SCA684Q/84Q mice (WT mice, 496 cells measured in 9.7 mm of the Purkinje cell layer from N = 3 animals; SCA684Q/84Q mice, 490 cells in 9.7 mm of the Purkinje cell layer from N = 3 animals; Fig. 7A,B), which is consistent with previous reports (Watase et al., 2008). We wondered whether subtle changes in Purkinje cell numbers or morphology might be restricted to only part of the cerebellum, since Purkinje cell degeneration has been reported to be more prevalent in anterior lobules of cerebellar vermis in some human patients (Gierga et al., 2009; Nanri et al., 2010). To address whether changes might be localized to subregions of the cerebellar vermis, we measured Purkinje cell density in anterior and posterior lobules, but observed no significant differences in both WT and SCA684Q/84Q mice (data not shown). To look in more detail at Purkinje cell morphology at disease onset, we measured the height of the molecular layer (Fig. 7A) as an estimate of the height of Purkinje cell dendritic trees and found no significant differences between WT and SCA684Q/84Q mice at 7 months (WT mice, 291.8 ± 6.8 μm; SCA684Q/84Q mice, 301.2 ± 8.1 μm; Fig. 7A,D). Thus, the onset of disease symptoms in SCA684Q mice is not associated with alterations in Purkinje cell number or gross dendritic morphology.


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)

Purkinje cell degeneration is observed long after the onset of motor phenotype at 2 years in SCA684Q/84Q mice. A, Representative images of calbindin-stained Purkinje cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse cerebellar slices. The height of the molecular layer is indicated. Scale bar, 20 μm. B, Density of Purkinje cells in 7-month-old cerebellum is not significantly different in SCA684Q/84Q mice compared with WT mice (Genotype: F(1,109) = 0.002, p = 0.96). However, reduced Purkinje cell density is observed at 2 years in SCA684Q/84Q mice (Genotype: F(1,97) = 18.76, p = <0.0001; right). C, Representative images of 2-year-old WT (left) and SCA684Q/84Q (right) Purkinje cells. Scale bar, 20 μm. D, No significant difference in the Purkinje cell molecular layer is observed at 7 months in SCA684Q/84Q and WT mice (F(1,203) = 0.79, p = 0.37; left), while molecular layer thickness is reduced at 2 years in SCA684Q/84Q mice compared with WT mice (F(1,189) = 33.12, p < 0.0001; right). N = 3-4 animals for each genotype at each age; at least 10 mm of the Purkinje cell layer was measured for each comparison; one-way ANOVA with post hoc Tukey’s test. ***p < 0.0001, **p < 0.01, *p < 0.05; p > 0.05, where not indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Purkinje cell degeneration is observed long after the onset of motor phenotype at 2 years in SCA684Q/84Q mice. A, Representative images of calbindin-stained Purkinje cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse cerebellar slices. The height of the molecular layer is indicated. Scale bar, 20 μm. B, Density of Purkinje cells in 7-month-old cerebellum is not significantly different in SCA684Q/84Q mice compared with WT mice (Genotype: F(1,109) = 0.002, p = 0.96). However, reduced Purkinje cell density is observed at 2 years in SCA684Q/84Q mice (Genotype: F(1,97) = 18.76, p = <0.0001; right). C, Representative images of 2-year-old WT (left) and SCA684Q/84Q (right) Purkinje cells. Scale bar, 20 μm. D, No significant difference in the Purkinje cell molecular layer is observed at 7 months in SCA684Q/84Q and WT mice (F(1,203) = 0.79, p = 0.37; left), while molecular layer thickness is reduced at 2 years in SCA684Q/84Q mice compared with WT mice (F(1,189) = 33.12, p < 0.0001; right). N = 3-4 animals for each genotype at each age; at least 10 mm of the Purkinje cell layer was measured for each comparison; one-way ANOVA with post hoc Tukey’s test. ***p < 0.0001, **p < 0.01, *p < 0.05; p > 0.05, where not indicated.
Mentions: The transgenic SCA684Q/84Q mice that we used in this study have previously been reported to exhibit no Purkinje cells degeneration at 20 months old (Watase et al., 2008), which is in contrast to the degeneration observed early in 118Q hyperexpanded mice (Unno et al., 2012) and postmortem in human SCA6 patient data (Yang et al., 2000). We first examined Purkinje cell density in 7-month-old mice and found 5.2 ± 0.17 cells/100 μm Purkinje cell layer in WT mice, with no significant differences in SCA684Q/84Q mice (WT mice, 496 cells measured in 9.7 mm of the Purkinje cell layer from N = 3 animals; SCA684Q/84Q mice, 490 cells in 9.7 mm of the Purkinje cell layer from N = 3 animals; Fig. 7A,B), which is consistent with previous reports (Watase et al., 2008). We wondered whether subtle changes in Purkinje cell numbers or morphology might be restricted to only part of the cerebellum, since Purkinje cell degeneration has been reported to be more prevalent in anterior lobules of cerebellar vermis in some human patients (Gierga et al., 2009; Nanri et al., 2010). To address whether changes might be localized to subregions of the cerebellar vermis, we measured Purkinje cell density in anterior and posterior lobules, but observed no significant differences in both WT and SCA684Q/84Q mice (data not shown). To look in more detail at Purkinje cell morphology at disease onset, we measured the height of the molecular layer (Fig. 7A) as an estimate of the height of Purkinje cell dendritic trees and found no significant differences between WT and SCA684Q/84Q mice at 7 months (WT mice, 291.8 ± 6.8 μm; SCA684Q/84Q mice, 301.2 ± 8.1 μm; Fig. 7A,D). Thus, the onset of disease symptoms in SCA684Q mice is not associated with alterations in Purkinje cell number or gross dendritic morphology.

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