The glial cell line-derived neurotrophic factor (GDNF) rescues motoneurons and nigral dopaminergic (DA) cells from induced cell death in different species of animals. In addition, GDNF results in a remarkable improvement of behavioral functions in Parkinsonian monkeys. A high affinity receptor for GDNF has been cloned (GFR alpha-1), whose pattern of expression indicates that it is not restricted to those brain areas containing motoneurons and DAergic cells, suggesting that GDNF might activate several sub-types of cells. To identify the phenotype of GFR alpha-1 expressing cells, we used a combination of anatomical techniques and found that GFRa-1 is expressed in defined populations of cells. We found that GFR alpha-1 is expressed in DAergic cells of the substantia nigra pars compacta (SNC), ventral tegmental area (VTA) and hypothalamus. We were able to establish that within the midbrain, GFR alpha-1 expression is not confined to dopaminergic neurons but is also expressed in GABAergic cells located either in the substantia nigra pars lateralis (SNL) or reticulata (SNR), being more abundant in the caudal levels of the SNR. These results suggest that GDNF-induced improvements in the behavior of semi-parkinsonian animal models might be also mediated by GDNF actions on GABAergic cells in the SNL and SNR. To test this hypothesis, we are processing brains from semi-parkisonian rats to analyze the levels of expression of GFR alpha- 1 and its relationship with the dopaminergic and GABAergic systems. Aside from the midbrain, we identified GFR alpha-1 expression in GABAergis cells located in the reticular thalamic nucleus, septum, cortex and hippocampus. While these results suggest the participation of the GDNF system in the regulation of dopaminergic and GABAergic functions, GDNF might also influence the cholinergic and serotonergic systems since expression of GFR alpha-1 was found in several septal cholinergic neurons and all serotonergic cells of the raphe nucleus. - GDNF, Substantia Nigra, Hippocampus, Neuroprotection
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| Sarabi, A; Chang, C F; Wang, Y et al. (2001) Time course study of GFRalpha-1 expression in an animal model of stroke. Exp Neurol 170:283-9 |
