Nigral GFRα1 Infusion in Aged Rats Increases Locomotor Activity, Nigral Tyrosine Hydroxylase, and Dopamine Content in Synchronicity

Delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) increases locomotor activity in rodent models of aging and Parkinson's disease in conjunction with increased dopamine (DA) tissue content in substantia nigra (SN). Striatal GDNF infusion also increases expression of GDNF's cognate receptor, GFR alpha 1, and tyrosine hydroxylase (TH) ser31 phosphorylation in the SN of aged rats long after elevated GDNF is no longer detectable. In aging, expression of soluble GFR alpha 1 in the SN decreases in association with decreased TH expression, TH ser31 phosphorylation, DA tissue content, and locomotor activity. Thus, we hypothesized that, in aged rats, replenishing soluble GFR alpha 1 in SN could reverse these deficits and increase locomotor activity. We determined that the quantity of soluble GFR alpha 1 in young adult rat SN is similar to 3.6 ng. To replenish age-related loss, which is similar to 30 %, we infused 1 ng soluble GFR alpha 1 bilaterally into SN of aged male rats and observed increased locomotor activity compared to vehicle-infused rats up to 4 days following infusion, with maximal effects on day 3. Five days after infusion, however, neither locomotor activity nor nigrostriatal neurochemical measures were significantly different between groups. In a separate cohort of male rats, nigral, but not striatal, DA, TH, and TH ser31 phosphorylation were increased 3 days following unilateral infusion of 1 ng soluble GFR alpha 1into SN. Therefore, in aged male rats, the transient increase in locomotor activity induced by replenishing age-related loss of soluble GFR alpha 1is temporally matched with increased nigral dopaminergic function. Thus, expression of soluble GFR alpha 1 in SN may be a key component in locomotor activity regulation through its influence over TH regulation and DA biosynthesis.