Differential effects of the dopamine neurotoxin MPTP in animals with a partial deletion of the GDNF receptor, GFR alpha1, gene.

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor beta (TGFbeta) superfamily, is a potent neurotrophic protein promoting the survival and maintenance of dopaminergic (DA) neurons in the substantia nigra during development and adulthood. DA neurons that project to the striatum in the nigrostriatal pathway express GDNF receptors, GFR alpha1. The purpose of this study was to determine whether these neurons are especially sensitive to neurotoxic insults. Therefore, we examined effects of the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on locomotion and DA neurons in 26-month-old male GFR alpha1 heterozygous (GFR alpha1(+/-)) mice compared to aged-matched wild-type (WT) littermates. MPTP gave rise to increased locomotion, regardless of genotype, while GFR alpha1(+/-) mice treated with saline exhibited lower spontaneous locomotion, compared to WT mice. Moreover, GFR alpha1(+/-) saline mice had fewer TH-positive neurons, greater expression of inflammatory markers (CD45 immunostaining and phosphorylated p38 MAPK) in the nigra, and reduced striatal TH staining. MPTP exacerbated these effects, with the lowest density of striatal TH and highest density of nigral CD45 and phospho-p38 MAPK immunoreactivity observed in GFR alpha1(+/-) mice. The findings point to increased sensitivity of the DAergic system with age and neurotoxic exposure as a result of a genetic reduction of GFR alpha1.