CHARACTERIZATION OF GDNF ALPHA 1 (GFR ALPHA 1) RECEPTOR

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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 GFR alpha 1 is expressed in defined populations of cells. As expected, we found that GFR alpha 1 is expressed in DAergic cells of the substantia nigra compacta (SNC) and the ventral tegmental area. In addition, GFR alpha 1 is expressed in GABAergic cells located either in the lateral SNC or in the substantia nigra reticulata (SNR). These GABAergic cells are more abundant in the caudal levels of the SNR. Our results suggest that GDNF-induced improvements in the behavior of hemi-parkinsonian animal models might be also mediated by GDNF actions on GABAergic cells in the SNR. We will use a hemi-parkisonian rat and a mouse model to test this hypothesis. Within the hippocampal formation, GFR alpha 1 expressing cells are either glutaminergic (subicular, pyramidal and granule cells) or GABAergic (interneurons). The glutaminergic subicular neurons constitute a major excitatory input to the nucleus accumbens(NAcc), suggesting that actions of GDNF on subicular GFR alpha 1 expressing cells might result in regulation of cells located in the Nacc. We propose to investigate the nature of these cells. We found that hippocampal GABAergic cells expressing GFR alpha 1 contain the Ca2+-binding protein parvalbumin (PV). Furthermore, most of the hippocampal neurons that contain PV express GFR alpha 1. As PV interneurons are the main source of nerve growth factor (NGF) in the hippocampus (71% of NGF positive cells contain PV), we will investigate to what extent GDNF, via its GFR alpha 1 might regulate the expression of NGF in PV containing cells. Published results show that either GDNF- (GDNF-/-) or GFR alpha 1- (GFRa-1-/-) deficient mice lack kidneys and die one day after birth. In contrast, the brains of these mutant mice appear normal. Thus, it is believed that while GDNF and its receptor are important for the development and/or survival for the renal system, they are not essential for neurons of the CNS. Our data suggest that GFR alpha 1 is expressed in some cells that might mature after birth, therefore, we will investigate if the development and/or survival of these particular type of cells is compromised in newborn GDNF (-/-) and GFR alpha 1 (-/-) homozygous mice, and in the corresponding adult heterozygous. Using either a cerebral ischemia model (middle cerebral artery, ligation) or physical cortical injury, we found a robust up-regulation of GFR alpha 1 expression in granule cells ipsilateral to the area receiving the insult. In both models, GFR alpha 1 up-regulation peaks 6 hours following ischemia or physical injury. These results indicate that GFR alpha 1 might be part of an endogenous neuroprotective system, that is activated following a brain insult and may act as defense mechanism in the brain. We will investigate the possible brain circuitry involved in this defense mechanism and we will evaluate if a similar situation is observed during methamphetamine-induced brain injury.