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The nigrostriatal dopamine system of aging GFRα‐1 heterozygous mice: neurochemistry, morphology and behavior

Given the established importance of glial cell line‐derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high‐affinity receptor, GDNF receptor (GFR)α‐1 (GFRα‐1+/−), were compared with wild‐type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRα‐1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRα‐1+/− mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRα‐1+/− mice. DA in the striatum was reduced in the GFRα‐1+/− mice at both ages, and tyrosine hydroxylase‐positive cell numbers in the SN were reduced most substantially in the older GFRα‐1+/− mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRα‐1+/− mice that are indicative of an exacerbated aging‐related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRα‐1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging‐related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRα‐1 can contribute to the degenerative changes observed in this system during the aging process.