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Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2.

Hansen ST, Meera P, Otis TS, Pulst SM - Hum. Mol. Genet. (2012)

Bottom Line: Although motor performance began to deteriorate at 8 weeks of age, reductions in PC number were not seen until after 12 weeks.Transcription changes in several PC-specific genes such as Calb1 and Pcp2 mirrored the time course of changes in PC physiology with calbindin-28 K changes showing the first small, but significant decreases at 4 weeks.These results emphasize that in this model of SCA2, physiological and behavioral phenotypes precede morphological changes by several weeks and provide a rationale for future studies examining the effects of restoration of firing frequency on motor function and prevention of future loss of PCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Utah, UT, USA.

ABSTRACT
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited disorder, which is caused by a pathological expansion of a polyglutamine (polyQ) tract in the coding region of the ATXN2 gene. Like other ataxias, SCA2 most overtly affects Purkinje cells (PCs) in the cerebellum. Using a transgenic mouse model expressing a full-length ATXN2(Q127)-complementary DNA under control of the Pcp2 promoter (a PC-specific promoter), we examined the time course of behavioral, morphologic, biochemical and physiological changes with particular attention to PC firing in the cerebellar slice. Although motor performance began to deteriorate at 8 weeks of age, reductions in PC number were not seen until after 12 weeks. Decreases in the PC firing frequency first showed at 6 weeks and paralleled deterioration of motor performance with progression of disease. Transcription changes in several PC-specific genes such as Calb1 and Pcp2 mirrored the time course of changes in PC physiology with calbindin-28 K changes showing the first small, but significant decreases at 4 weeks. These results emphasize that in this model of SCA2, physiological and behavioral phenotypes precede morphological changes by several weeks and provide a rationale for future studies examining the effects of restoration of firing frequency on motor function and prevention of future loss of PCs.

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Progressive deterioration of motor performance on the accelerating rotarod beginning after 4 weeks of age. Latency to fall off the accelerating rotarod (left Y-axis) and RPMs (right Y-axis) data for ATXN2Q127 (gray circle) and WT animals (white circle). Data represent the mean ± SEM of three trials on the test day. Number of animals tested for WT and ATXN2Q127 animals are listed above and below, respectively. Two-way ANOVA comparing the age × genotype; Bonferroni post-hoc tests. *P < 0.5, **P < 0.01, ***P < 0.001. Error bars represent ±SEM.
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DDS427F1: Progressive deterioration of motor performance on the accelerating rotarod beginning after 4 weeks of age. Latency to fall off the accelerating rotarod (left Y-axis) and RPMs (right Y-axis) data for ATXN2Q127 (gray circle) and WT animals (white circle). Data represent the mean ± SEM of three trials on the test day. Number of animals tested for WT and ATXN2Q127 animals are listed above and below, respectively. Two-way ANOVA comparing the age × genotype; Bonferroni post-hoc tests. *P < 0.5, **P < 0.01, ***P < 0.001. Error bars represent ±SEM.

Mentions: SCAs commonly show disease onset in early adulthood with progressive worsening of symptoms with age. In modeling the human SCA2 phenotype, we therefore sought to recapitulate normal motor function in young animals followed by a progressive deficit with age. Indeed, ATXN2Q127 mice at 4 weeks performed similar to wild-type (WT) littermates on the accelerating rotarod (Fig. 1). With age, however, ATXN2Q127-mutant mice demonstrated a progressive decline in motor performance. Two-way analysis of variance (ANOVA) determined that ATXN2Q127 mice exhibited a significant age-related decrease of motor performance. Significant main effects were detected for genotype (F = 54.51,107), age (F = 15.24,107) and an interaction of genotype × age (F = 4.14,107). Bonferroni post-hoc tests revealed no significant difference between genotypes at 4 weeks of age. However, statistically significant differences emerged as early as 8 weeks (P < 0.05), and increased at ages 12 (P < 0.001), 24 (P < 0.0001) and 36 (P < 0.001) weeks. Thus, motor behavior was normal from birth to 4 weeks, showed minor, but significant impairment by 8 weeks, which then progressively worsened over the ensuing 28 weeks.Figure 1.


Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2.

Hansen ST, Meera P, Otis TS, Pulst SM - Hum. Mol. Genet. (2012)

Progressive deterioration of motor performance on the accelerating rotarod beginning after 4 weeks of age. Latency to fall off the accelerating rotarod (left Y-axis) and RPMs (right Y-axis) data for ATXN2Q127 (gray circle) and WT animals (white circle). Data represent the mean ± SEM of three trials on the test day. Number of animals tested for WT and ATXN2Q127 animals are listed above and below, respectively. Two-way ANOVA comparing the age × genotype; Bonferroni post-hoc tests. *P < 0.5, **P < 0.01, ***P < 0.001. Error bars represent ±SEM.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3526159&req=5

DDS427F1: Progressive deterioration of motor performance on the accelerating rotarod beginning after 4 weeks of age. Latency to fall off the accelerating rotarod (left Y-axis) and RPMs (right Y-axis) data for ATXN2Q127 (gray circle) and WT animals (white circle). Data represent the mean ± SEM of three trials on the test day. Number of animals tested for WT and ATXN2Q127 animals are listed above and below, respectively. Two-way ANOVA comparing the age × genotype; Bonferroni post-hoc tests. *P < 0.5, **P < 0.01, ***P < 0.001. Error bars represent ±SEM.
Mentions: SCAs commonly show disease onset in early adulthood with progressive worsening of symptoms with age. In modeling the human SCA2 phenotype, we therefore sought to recapitulate normal motor function in young animals followed by a progressive deficit with age. Indeed, ATXN2Q127 mice at 4 weeks performed similar to wild-type (WT) littermates on the accelerating rotarod (Fig. 1). With age, however, ATXN2Q127-mutant mice demonstrated a progressive decline in motor performance. Two-way analysis of variance (ANOVA) determined that ATXN2Q127 mice exhibited a significant age-related decrease of motor performance. Significant main effects were detected for genotype (F = 54.51,107), age (F = 15.24,107) and an interaction of genotype × age (F = 4.14,107). Bonferroni post-hoc tests revealed no significant difference between genotypes at 4 weeks of age. However, statistically significant differences emerged as early as 8 weeks (P < 0.05), and increased at ages 12 (P < 0.001), 24 (P < 0.0001) and 36 (P < 0.001) weeks. Thus, motor behavior was normal from birth to 4 weeks, showed minor, but significant impairment by 8 weeks, which then progressively worsened over the ensuing 28 weeks.Figure 1.

Bottom Line: Although motor performance began to deteriorate at 8 weeks of age, reductions in PC number were not seen until after 12 weeks.Transcription changes in several PC-specific genes such as Calb1 and Pcp2 mirrored the time course of changes in PC physiology with calbindin-28 K changes showing the first small, but significant decreases at 4 weeks.These results emphasize that in this model of SCA2, physiological and behavioral phenotypes precede morphological changes by several weeks and provide a rationale for future studies examining the effects of restoration of firing frequency on motor function and prevention of future loss of PCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Utah, UT, USA.

ABSTRACT
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited disorder, which is caused by a pathological expansion of a polyglutamine (polyQ) tract in the coding region of the ATXN2 gene. Like other ataxias, SCA2 most overtly affects Purkinje cells (PCs) in the cerebellum. Using a transgenic mouse model expressing a full-length ATXN2(Q127)-complementary DNA under control of the Pcp2 promoter (a PC-specific promoter), we examined the time course of behavioral, morphologic, biochemical and physiological changes with particular attention to PC firing in the cerebellar slice. Although motor performance began to deteriorate at 8 weeks of age, reductions in PC number were not seen until after 12 weeks. Decreases in the PC firing frequency first showed at 6 weeks and paralleled deterioration of motor performance with progression of disease. Transcription changes in several PC-specific genes such as Calb1 and Pcp2 mirrored the time course of changes in PC physiology with calbindin-28 K changes showing the first small, but significant decreases at 4 weeks. These results emphasize that in this model of SCA2, physiological and behavioral phenotypes precede morphological changes by several weeks and provide a rationale for future studies examining the effects of restoration of firing frequency on motor function and prevention of future loss of PCs.

Show MeSH
Related in: MedlinePlus