Copyright © 2006 Elsevier Inc. All rights reserved.
A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra

H.A. Bogera, L.D. Middaugha, c, P. Huangb, V. Zamana, A.C. Smithd, B.J. Hoffere, A.C. Tomace and A.-Ch. Granholma, ,

aDepartment of Neurosciences, Center on Aging, MUSC, 26 Bee Street, Charleston, SC 29425, USA
bDepartment of Biometry and Epidemiology, Medical University of South Carolina, SC, USA
cDepartment of Psychiatry, Medical University of South Carolina, SC, USA
dDepartment of Comparative Medicine, Medical University of South Carolina, SC, USA
eIntramural Research Program, NIDA, Baltimore, MD, USA

Received 15 February 2006; revised 1 June 2006; accepted 19 June 2006. Available online 2 August 2006.




Abstract
Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for peripheral organs, spinal cord, and midbrain dopamine (DA) neurons. Levels of GDNF deteriorate in the substantia nigra in Parkinson's disease (PD). A heterozygous mouse model was created to assess whether chronic reductions in this neurotrophic factor impact motor function and the nigrostriatal dopamine system during the aging process. Due to the important role GDNF plays in kidney development, kidney function and histology were assessed and were found to be normal in both wild-type (WT) and GDNF+/− mice up to 22 months of age. Further, the animals of both genotypes had similar weights throughout the experiment. Locomotor activity was assessed for male WT and GDNF+/− mice at 4-month intervals from 4 to 20 months of age. Both GDNF+/− and WT mice exhibited an age-related decline in horizontal activity, although this was found 4 months earlier in GDNF+/− mice, at 12 months of age. Comparison of young (8 month old) and aged (20 month old) GDNF+/− and WT mice on an accelerating rotarod apparatus established a deficiency for aged but not young GDNF+/− mice, while aged WT mice performed as well as young WT mice on this task. Finally, both WT and GDNF+/− mice exhibited an age-related decrease in substantia nigra TH immunostaining, which was accelerated in the GDNF+/− mice. These behavioral and histological alterations suggest that GDNF may be an important factor for maintenance of motor coordination and spontaneous activity as well as DA neuronal function during aging, and further suggest that GDNF+/− mice may serve as a model for neuroprotective or rescue studies.

Keywords: Dopamine; Substantia nigra; Parkinson's disease; Animal models; Movement disorders; Neurodegeneration



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Experimental Neurology
Volume 202, Issue 2 , December 2006, Pages 336-347
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