GFRα‐1 mRNA in dopaminergic and nondopaminergic neurons in the substantia nigra and ventral tegmental area

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Abstract
Glial cell line-derived neurotrophic factor (GDNF) is a survival factor for several types of neurons, including dopaminergic (DAergic) neurons. GDNF binds with high affinity to the GDNF family receptor α-1 (GFRα-1), which is highly expressed in the midbrain. Using anatomical and lesion techniques, we demonstrated that GFRα-1 was expressed in DAergic and non-DAergic neurons in the rat midbrain. Immunohistochemical characterization of GFRα-1-expressing neurons indicated that most of the neurons that were immunopositive for the DAergic marker tyrosine hydroxylase (TH) expressed GFRα-1 in the substantia nigra pars compacta (SNC). In contrast, fewer TH-containing neurons expressed GFRα-1 in the substantia nigra pars reticulata (SNR) and the ventral tegmental area (VTA). Depletion of GFRα-1/TH neurons was observed in the SNC following treatment with the neurotoxin 6-hydroxydopamine (6-OHDA); however, GFRα-1 expression remained in some neurons located in the SNR. The γ-aminobutyric acid (GABA)ergic nature of GFRα-1-expressing neurons located in the SNR, which were resistant to (6-hydroxydopamine) 6-OHDA, was established by their expression of glutamic acid decarboxylase (GAD; the synthesizing enzyme for GABA). Further analysis indicated that coexpression of GFRα-1 and GAD varied in a rostrocaudal gradient in the SNR, substantia nigra pars lateralis (SNL), and VTA. Midbrain DAergic and GABAergic neurons have been previously classified according to their Ca2+ binding protein (CaBP) content; thus, we also sought to investigate the proportion of midbrain GFRα-1-expressing neurons containing parvalbumin (PV), calbindin (CB), and calretinin (CR) in the midbrain. Although GFRα-1 expression was found mainly in CB- and CR-immunoreactive neurons, it was rarely observed in PV-immunolabeled neurons. Analysis of the proportion of GFRα-1-expressing neurons for each CaBP subpopulation indicated the coexistence of GFRα-1 with CR in the VTA and all subdivisions of the SN; double-labeled GFRα-1/CR neurons were distributed in the SNC, SNR, SNL, and VTA. GFRα-1/CB neurons were also detected in the SNC, SNL, and VTA. Expression of GFRα-1 in DAergic and non-DAergic neurons in the rat SN and VTA suggests that GDNF, via GFRα-1, might modulate DAergic and GABAergic functions in the nigrostriatal, mesolimbic, and nigrothalamic circuits of the adult rat. J. Comp. Neurol. 441:106–117, 2001. Published 2001 Wiley-Liss, Inc.