Differential effects of the dopamine neurotoxin MPTP in animals with a partial deletion of the GDNF receptor, GFRα1, gene

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming factor beta (TGF) superfamily, is a potent neurotrophic protein promoting the maintenance of dopaminergic (DA) neurons in the substantia nigra during adulthood. DA neurons that project to the striatum in the nigrostriatal pathway GDNF receptors, GFR alpha 1. The purpose of this study was to determine whether these are especially sensitive to neurotoxic insults. Therefore, we examined effects dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on and DA neurons in 26-month-old male GFR alpha 1 heterozygous (GFR alpha 1(+/-)) mice aged-matched wild-type (WT) littermates. MPTP gave rise to increased locomotion, of genotype, while GFR alpha 1(+/-) mice treated with saline exhibited lower spontaneous compared to WT mice. Moreover, GFR alpha 1(+/-) saline mice had fewer TH-positive greater expression of inflammatory markers (CD45 immunostaining and phosphorylated p38 MAPK) in the nigra, and reduced striatal TH staining. MPTP exacerbated these with the lowest density of striatal TH and highest density of nigral CD45 and MAPK immunoreactivity observed in GFR alpha 1(+/-) mice. The findings point to sensitivity of the DAergic system with age and neurotoxic exposure as a result of a reduction of GFR alpha 1. Published by Elsevier B.V.