GDNF improves cerebellar Purkinje neuron function in aged F344 rats.
Aging is associated with a decline in the function of beta-adrenergic receptor responses in the cerebellum. This decline in noradrenergic receptor sensitivity may underlie some of the accompanying age-related declines in motoric learning behaviors. Glial cell line-derived neurotrophic factor (GDNF) has been reported to prevent the degeneration of noradrenergic neurons following neurotoxic lesions. Thus, it was of interest to examine if GDNF would have a beneficial effect on age-related declines in noradrenergic function. Eighteen-month-old F344 rats were injected with 500 microg GDNF in 20 microl into the cisterna magna. Three weeks following GDNF or vehicle treatment, rats were tested on a motor coordination task and then examined electrophysiologically under urethane anesthesia. GDNF did not produce an improvement in performance on an inclined balance beam or an accelerating rotorod. In young (3-month-old) F344 rats isoproterenol (ISO) will increase GABAergic inhibitions in the majority of cells examined; however, in aged rats only about 30% of neurons demonstrate this phenotype. In the aged rats treated with GDNF, ISO was able to increase GABAergic inhibitions in greater than 75% of the neurons tested, thus returning the neurons to a young phenotype. We examined the brains for expression of bcl-2, which has been shown to be increased in the aged cerebellum. GDNF was able to down-regulate this neuronal signal. Thus, intra-cisterna magna delivery of GDNF to aged rats improved beta-adrenergic receptor function and reduced stress related signaling of bcl-2 in the aged F344 rats to a level similar to that observed in young rats.
Bickford
P C
PC
Veterans Administration Medical Center, Tampa, Florida 33612, USA. pbickfor@hsc.usf.edu
Bowenkamp
K
K
Taglialatela
G
G
Hoertig
G
G
Granholm
A C
AC
D000375:Aging / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2