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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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Related in: MedlinePlus

PC firing rate remains constant in WT but progressively decreases with age in ATXN2Q127 mice. To the left of each panel are examples of extracellular recordings from PCs at the indicated ages in WT and transgenic ATXN2Q127 mice. These one second traces show that firing decreases progressively with age in the transgenic (ATXN2Q127) but not WT mice. To the right of each panel are histograms of inter spike intervals for the 2 min recording periods from the same neuron. Indicated on each histogram are the mean firing rate and the local coefficient of variation (CV). All recordings were made at 34.5 ± 1°C and the experimenter was blinded to the genotype.
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DDS427F5: PC firing rate remains constant in WT but progressively decreases with age in ATXN2Q127 mice. To the left of each panel are examples of extracellular recordings from PCs at the indicated ages in WT and transgenic ATXN2Q127 mice. These one second traces show that firing decreases progressively with age in the transgenic (ATXN2Q127) but not WT mice. To the right of each panel are histograms of inter spike intervals for the 2 min recording periods from the same neuron. Indicated on each histogram are the mean firing rate and the local coefficient of variation (CV). All recordings were made at 34.5 ± 1°C and the experimenter was blinded to the genotype.

Mentions: Representative traces of both WT and ATXN2Q127 mice from each age group investigated are presented in Figure 5. Each panel shows recording data from one second in time and includes as an inset a histogram of all interspike intervals (ISI) in a 2 min recording period from that PC. The mean firing frequency and the coefficient of variation of the ISI are indicated in each inset. These data from individual PCs highlight a marked slowing in the firing rate with age in the ATXN2Q127mice.Figure 5.


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)

PC firing rate remains constant in WT but progressively decreases with age in ATXN2Q127 mice. To the left of each panel are examples of extracellular recordings from PCs at the indicated ages in WT and transgenic ATXN2Q127 mice. These one second traces show that firing decreases progressively with age in the transgenic (ATXN2Q127) but not WT mice. To the right of each panel are histograms of inter spike intervals for the 2 min recording periods from the same neuron. Indicated on each histogram are the mean firing rate and the local coefficient of variation (CV). All recordings were made at 34.5 ± 1°C and the experimenter was blinded to the genotype.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDS427F5: PC firing rate remains constant in WT but progressively decreases with age in ATXN2Q127 mice. To the left of each panel are examples of extracellular recordings from PCs at the indicated ages in WT and transgenic ATXN2Q127 mice. These one second traces show that firing decreases progressively with age in the transgenic (ATXN2Q127) but not WT mice. To the right of each panel are histograms of inter spike intervals for the 2 min recording periods from the same neuron. Indicated on each histogram are the mean firing rate and the local coefficient of variation (CV). All recordings were made at 34.5 ± 1°C and the experimenter was blinded to the genotype.
Mentions: Representative traces of both WT and ATXN2Q127 mice from each age group investigated are presented in Figure 5. Each panel shows recording data from one second in time and includes as an inset a histogram of all interspike intervals (ISI) in a 2 min recording period from that PC. The mean firing frequency and the coefficient of variation of the ISI are indicated in each inset. These data from individual PCs highlight a marked slowing in the firing rate with age in the ATXN2Q127mice.Figure 5.

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