GFR alpha-1 mRNA in dopaminergic and nondopaminergic neurons in the substantia nigra and ventral tegmental area

Glial cell line-derived neurotrophic factor (GDNF) is a survival factor for several types of neurons, including dopaminergic (DAergic) neurons. GDNF b inds with high affinity to the GDNF family receptor alpha -1 (GFR alpha -1) , which is highly expressed in the midbrain. Using anatomical and lesion te chniques, we demonstrated that GFR alpha -1 was expressed in DAergic and no n-DAergic neurons in the rat midbrain. Immunohistochemical characterization of GFR alpha -1-expressing neurons indicated that most of the neurons that were immunopositive for the DAergic marker tyrosine hydroxylase (TH) expre ssed GFR alpha -1 in the substantia nigra pars compacta (SNC). In contrast, fewer TH-containing neurons expressed GFR alpha -1 in the substantia nigra pars reticulata (SNR) and the ventral tegmental area (VTA). Depletion of G FR alpha -1/TH neurons was observed in the SNC following treatment with the neurotoxin 6-hydroxydopamine (6-OHDA); however, GFR alpha -1 expression re mained in some neurons located in the SNR. The gamma -aminobutyric acid (GA BA)ergic nature of GFR alpha -1-expressing neurons located in the SNR, whic h were resistant to (6-hydroxydopamine) 6-OHDA, was established by their ex pression of glutamic acid decarboxylase (GAD; the synthesizing enzyme for G ABA). Further analysis indicated that coexpression of GFR alpha -1 and GAD varied in a rostrocaudal gradient in the SNR, substantia nigra pars lateral is (SNL), and VTA. Midbrain DAergic and GABAergic neurons have been previou sly classified according to their Ca2+ binding protein (CaBP) content; thus , we also sought to investigate the proportion of midbrain GFR alpha -1-exp ressing neurons containing parvalbumin (PV), calbindin (CB), and calretinin (CR) in the midbrain. Although GFR alpha -1 expression was found mainly in CB- and CR-immunoreactive neurons, it was rarely observed in PV-immunolabe led neurons. Analysis of the proportion of GFR alpha -1-expressing neurons for each CaBP subpopulation indicated the coexistence of GFR alpha -1 with CR in the VTA and all subdivisions of the SN; double-labeled GFR alpha -1/C R neurons were distributed in the SNC, SNR, SNL, and VTA. GFR alpha -1/CB n eurons were also detected in the SNC, SNL, and VTA. Expression of GFR alpha -1 in DAergic and non-DAergic neurons in the rat SN and VTA suggests that GDNF, via GFR alpha -1, might modulate DAergic and GABAergic functions in t he nigrostriatal, mesolimbic, and nigrothalamic circuits of the adult rat. J. Comp. Neurol. 441:106-117, 2001. Published 2001 Wiley-Liss, Inc.dagger