The research proposed in this application is intended to examine the effects of age on plasticity and repair in the damaged dopamine (DA) system. The primary model to be used in this research is the MPTP-treated mouse. A comparative analysis of the effects of GM1 ganglioside and putative DAergic neurotrophic factors in young mice with and without significant substantia nigra (SN) DA cell loss and in aged mice with significant SN cell loss will be performed. These studies will provide information concerning the ability of trophic factors to stimulate recovery in the DA system under different lesion conditions and to assess the effect of age on the trophic response.
The specific aims of the proposed research are to: 1)compare the effects of GM1 ganglioside, bFGF, IFG-I, BDNF and EGF and the effects of GM1 alone and in combination with the above-mentioned trophic factors in young mice with different degrees of MPTP-induced damage and in aged mice. These studies will assess in vivo regenerative capacity and response of the DA system to trophic influences under the conditions mentioned above; 2) examine possible mechanisms responsible for increases in striatal DA in young MPTP-lesioned mice and in medial forebrain bundle transected rats, and; 3) examine possible mechanisms contributing to age-related decline in GMl effectiveness. Mechanistic issues will be addressed with in vivo studies and more directly by studying GM1 and trophic factor effects on cultured DA neurons exposed to the toxin MPP+. These studies will specifically examine the extent to which GM1-induced recovery in the DA system is due to a biochemical up-regulation of remaining DA neurons and/or a sprouting response. DA turnover, DA uptake, tyrosine hydroxylase (TH) and GAP-43 immunohistochemistry and TH, GAP-43, and tubulin in situ hybridization will be studied in vivo and in vitro. These studies, should provide basic information concerning the effects of GM1 and other trophic agents on the damaged DA system in young and aged animals and provide further insight into basic mechanisms of these responses. This work might have potential clinical significance for the future treatment of degenerative CNS disorders and particularly disorders such as Parkinson's disease which are associated with aging.
