Transplantation of fetal dopaminergic neurons to the striatum can ameliorate neurological deficits exhibited by experimental animals and human transplant recipients with Parkinson's disease. Recovery, however, is incomplete due to the suboptimal survival of transplanted cells and limited synaptic integration with the host brain. Recently, a number of neurotrophic factors have been shown to promote survival and differentiation of dopamine neurons in vitro. Of these neurotrophic factors, three (BDNF, GDNF and NT-4/5) have been shown to act directly upon dopaminergic neurons without intermediaries and exert potent neurotrophic effects on dopaminergic neurons. The primary objective of the proposed studies is to determine whether or not these three direct-acting neurotrophic factors can be used as adjuncts in neural transplantation studies to (1) increase the survival of transplanted fetal dopamine neurons and (2) enhance functional reinnervation of transplanted dopamine neurons with the denervated striatum. The first objective will examine the effect of individual neurotrophic factors on transplant development and function, using immunocytochemical techniques to characterize transplant development and to quantitatively determine the number of surviving transplanted neurons as well as estimate fiber outgrowth from transplants. In vivo electrochemistry and intracerebral dialysis will be used to determine whether these neurotrophic factors can improve and extend the functional influence of transplanted neurons within the host striatum. The second objective will be to determine whether neurotrophic factors infused into transplants alter the in situ expression of neurotrophic factors and neurotrophin receptors within the transplant or within the host tissue, thereby providing further trophic support for transplanted neurons. The third objective will test the hypothesis that combined regimens of neurotrophic factors affect transplant development and function better then individual neurotrophic factor treatment. The overall objectives are to determine if neurotrophic factors can be used in conjunction with transplants of dopamine neurons to improve the survival, fiber outgrowth and functional reinnervation of the striatum by fetal dopamine neurons.
