Glial cell-line derived neurotrophic factor (GDNF) replacement attenuates motor impairments and nigrostriatal dopamine deficits in 12-month-old mice with a partial deletion ofGDNF

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Abstract

Glial cell-line derived neurotrophic factor (GDNF) has been established as a growth factor for the survival and maintenance of dopamine (DA) neurons. In phase I clinical trials, GDNF treatment in Parkinson's disease patients led to improved motor function and GDNF has been found to be down regulated in Parkinson's disease patients. Studies using GDNF heterozygous (Gdnf+/−) mice have demonstrated that a partial reduction of GDNF leads to an age-related accelerated decline in nigrostriatal DA system- and motor-function and increased neuro-inflammation and oxidative stress in the substantia nigra (SN). Therefore, the purpose of the current studies was to determine if GDNF replacement restores motor function and functional markers within the nigrostriatal DA system in middle-aged Gdnf+/− mice. At 11 months of age, male Gdnf+/− and wildtype (WT) mice underwent bilateral intra-striatal injections of GDNF (10 μg) or vehicle. Locomotor activity was assessed weekly 1–4 weeks after treatment. Four weeks after treatment, their brains were processed for analysis of GDNF levels and various DAergic and oxidative stress markers. An intrastriatal injection of GDNF increased motor activity in Gdnf+/− mice to levels comparable to WT mice (1 week after injection) and this effect was maintained through the 4-week time point. This increase in locomotion was accompanied by a 40% increase in striatal GDNF protein levels and SN GDNF expression in Gdnf+/− mice. Additionally, GDNF treatment significantly increased the number of tyrosine hydroxylase (TH)-positive neurons in the SN of middle-aged Gdnf+/− mice, but not WT mice, which was coupled with reduced oxidative stress in the SN. These studies further support that long-term changes related to the dysfunction of the nigrostriatal pathway are influenced by GDNF expression and add that this dysfunction appears to be responsive to GDNF treatment. Additionally, these studies suggest that long-term GDNF depletion alters the biological and behavioral responses to GDNF treatment.

Highlights

▸ We examine the effects of GDNF replacement in mice with a GDNF depletion (Gdnf+/−). ▸ GDNF restores behavioral and biochemical deficits in Gdnf+/− mice. ▸ Gdnf+/− mice show altered responses to GDNF treatment compared to wild-type mice. ▸ Long-term changes in nigrostriatal function are influenced by GDNF expression. ▸ GDNF treatment reduces oxidative-stress markers in Gdnf+/− mice.

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