CHARACTERIZATION OF GDNF ALPHA 1 (GFR ALPHA 1) RECEPTOR

胶质细胞源性神经营养因子（GDNF）在不同动物中拯救运动神经元和黑质多巴胺能（DA）细胞免于诱导细胞死亡。此外，GDNF导致帕金森病猴的行为功能显著改善。GDNF的高亲和力受体已被克隆（GFR α-1），其表达模式表明它不限于含有运动神经元和DA能细胞的脑区，这表明GDNF可能激活几种亚型的细胞。为了鉴定表达GFR α-1的细胞的表型，我们使用了解剖学技术的组合，发现GFR α-1在确定的细胞群中表达。我们发现GFR α-1在黑质腹侧被盖区（VTA）和下丘脑的DA能细胞中表达。我们能够确定，在中脑内，GFR α-1表达不仅限于多巴胺能神经元，还表达于位于黑质外侧部（SNL）或网状部（SNR）的GABA能细胞中，在SNR的尾部水平更丰富。这些结果表明，GDNF诱导的半帕金森病动物模型的行为改善也可能通过GDNF对SNL和SNR中GABA能细胞的作用介导。为了验证这一假设，我们正在处理半帕金森病大鼠的大脑，以分析GFR α-1的表达水平及其与多巴胺能和GABA能系统的关系。除中脑外，我们还在位于丘脑网状核、隔、皮质和海马的GABA能细胞中鉴定了GFR α-1表达。虽然这些结果表明GDNF系统参与了多巴胺能和GABA能功能的调节，但GDNF也可能影响胆碱能和多巴胺能系统，因为在几个隔胆碱能神经元和中缝核的所有多巴胺能细胞中发现了GFR α-1的表达。- GDNF，黑质，海马，神经保护

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