Document Detail

Disruption of Purkinje cell function prior to huntingtin accumulation and cell loss in an animal model of Huntington disease.
MedLine Citation:
PMID:  22579526     Owner:  NLM     Status:  MEDLINE    
Huntington Disease (HD) is a devastating neurological disorder characterized by progressive deterioration of psychiatric, motor, and cognitive function. Purkinje cells (PCs), the output neurons of the cerebellar cortex, have been found to be vulnerable in multiple CAG repeat disorders, but little is known about the involvement of PC dysfunction in HD. To investigate possible PC abnormalities, we performed quantitative real time PCR, Western blot analysis, and immunohistochemistry experiments to explore the changes in PC markers in the R6/2 mouse model of severe HD. There were reductions in the transcript and protein levels of the calcium-binding proteins parvalbumin and calbindin, as well as the enzyme glutamic acid decarboxylase 67. Immunohistochemistry supported these results, with the most substantial changes occurring in the PC layer. To determine whether the reductions in PC marker expression were due to cell loss, we performed stereology on both presymptomatic and end-stage R6/2 mice. Stereological counts indicated a significant reduction in PC number by end-stage but no change in presymptomatic animals (4 weeks of age). To assess cellular function prior to cell loss and symptom onset, we measured spontaneous firing in PCs from 4-week old animals and found a striking deficit in PC firing as indicated by a 57% decrease in spike rate. Interestingly, huntingtin inclusions were not widely observed in PCs until 12 weeks of age, indicating that soluble huntingtin and/or abnormalities in other cell types may contribute to PC dysfunction. Considering the roles for PCs in motor control, these data suggest that early PC dysfunction potentially contributes to motor impairment in this model of HD.
S E Dougherty; J L Reeves; E K Lucas; K L Gamble; M Lesort; R M Cowell
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-02
Journal Detail:
Title:  Experimental neurology     Volume:  236     ISSN:  1090-2430     ISO Abbreviation:  Exp. Neurol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-04     Completed Date:  2012-08-07     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0370712     Medline TA:  Exp Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  171-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Neuroscience Graduate Program, University of Alabama at Birmingham, USA.
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MeSH Terms
Age Factors
Disease Models, Animal
Huntington Disease / genetics,  metabolism*,  pathology*
Mice, Inbred Strains
Mice, Mutant Strains
Nerve Tissue Proteins / genetics*,  metabolism*
Nuclear Proteins / genetics*,  metabolism*
Purkinje Cells / pathology*
Grant Support
Reg. No./Substance:
0/Huntington protein, mouse; 0/Nerve Tissue Proteins; 0/Nuclear Proteins

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