Date of Defense

Summer 7-1-2004

Department

Biological Sciences

First Advisor

John Spitsbergen, Biological Sciences

Second Advisor

Sungho Maeng, National Institutes of Health

Third Advisor

Gordon Gurley, Biological Sciences

Abstract

Glial cell line-derived neurotrophic factor (Gdnf) is known for its neuroprotective role in dopaminergic neurons. In addition to its neurotrophic effects, Gdnf also plays a significant role in the development and maintenance of the kidneys, GI tract, heart, and brain. It has been found that Gdnf -/- newborn mice, which are unable to produce Gdnf, die at birth from renal agenesis and enteric neuron deficiency. Similarly Gdnf +/- mice, that are heterozygous with only one copy of the allele, show an accelerated decline in neuronal function leading to an earlier onset of age related brain disorders comparable to senile dementia, Alzheimer's disease, and Parkinson's disease when their memory was tested. Senile dementia is a life incapacitating disease that affects more than 4 million men and women between ages 60 and 90. Individuals with senile dementia live distraught lives for up to 8 to 9 years after diagnosis, though the disease can be present for more than 20 years. Using a Pavlovian fear-conditioning test, it was found that the memory of Gdnf +/- mice showed a deficiency in cognitive function at an age as early as one year. In comparing the mitochondria from the hippocampus of the brain, the number of mitochondria did not change. However, the size of the mitochondria increased, thus increasing the total area in both Gdnf +/- and wildtypes. Alternatively, the mitochondria functional change with age was also tested. The mitochondria membrane potential was not significantly different between the Gdnf +/- and wildtypes, while the complex IV activity showed a marked decline in Gdnf +/- mice with age and was significantly different between the two genotypes after eighteen months. These results suggest that the memory deficiency is related to the mitochondrial functional change with age.

Access Setting

Honors Thesis-Campus Only

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