EFFECTS OF GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR ON DEVELOPING AND MATURE VENTRAL MESENCEPHALIC GRAFTS IN OCULO

The search for trophic factors that can support injured dopaminergic n eurons and can enhance dopaminergic graft survival and outgrowth for t herapeutic uses in Parkinson's disease has lately focused on members o f the transforming growth factor (TGF) beta superfamily. In this paper we have studied the effects of a member of the TGB beta family, glial cell line-derived neurotrophic factor (GDNF), on immature and mature ventral mesencephalic tissue grafted to the anterior chamber of the ey e. The results confirm that GDNF increases survival of TH-positive neu rons and enhances TH-immunoreactive nerve fiber formation when the gra fts are treated during their development. The distribution of nerve te rminals is densest within the area of TH-immunoreactive neurons and at the surface of the grafts. However, there is no change in the number of calcium-binding protein (CaBP)-positive neurons, suggesting that th e subpopulation of TH-positive neurons that is increased are the CaBP- negative neurons of the ventral tier of pars compacta. Terminals from those neurons form the striatal patches during normal development. Whe n the grafts are treated with GDNF after maturation, no change in TH-p ositive cell survival is seen but an increase of nerve terminals is st ill found within the cell dense area of the graft. Potassium-evoked do pamine release, measured using irt vivo chronoamperometry, revealed si gnificantly increased extracellular overflow in transplants treated wi th GDNF during development. The dopamine uptake blocker nomifensine si gnificantly increased the time for clearance of the released dopamine. These data suggest that GDNF treatment of immature grafts enhances su rvival of TH-positive neurons, which would have innervated the striata l patches, and also increases TH-immunoreactive nerve fiber formation and dopamine release. Furthermore, GDNF treatment of mature grafts als o increases dopamine fiber formation within the TH-positive neuronal a rea, indicating that adult dopaminergic neurons are also responsive to this agent. (C) 1995 Academic Press, Inc.