Nigrostriatal neurons in rat express the glial cell line-derived neurotrophic factor receptor subunit c-RET

The substantia nigra neurons expressing c-RET, a glial cell line-derived neurotrophic factor (GDNF) receptor intracellular tyrosine kinase subunit, were investigated in rats by using a double labeling method which combined retrograde horseradish peroxidase (HRP) labeling after injection into the striatum with immunohistochemistry to c-RET. It was revealed that the distribution of c-RET-immunoreactive neurons and HRP-labeled nigrostriatal neurons overlapped. Numerous double-labeled HRP/c-RET neurons were found in the substantia nigra pars compacta with predominate distribution ipsilateral to the injected striatum. Semiquantitative cell count indicated that a large percentage (97%) of HRP-labeled neurons showed c-RET immunoreactivity. Furthermore, double-labeled HRP/c-RET ones constituted only 61% of total c-RET-immunoreactive neurons in the substantia nigra ipsolateral to the injected striatum. Taken together with previous observations on glial cell line-derived neurotrophic factor in the basal ganglia, this study provides evidence that the c-RET protein may mediate biological activity of GDNF family ligands in most of projecting neurons in the substantia nigra pars compacta where the dopaminergic neurons are numerously distributed. Specially, it suggests that c-RET-mediating signaling cascades may play important roles in neuron-glial interaction that support and sustain nigrostriatal neuronal circuits in the basal ganglia.