The long-term objective of this project is to define the locus and mode of action of various compounds which are toxic to neurons. The experimental approach will involve examination of possible toxin-induced perturbations of metabolic events involved in the maintenance of neurons and their axons and synapses. Retinal ganglion cells in the rat visual system will be used as the experimental model and trimethyltin as the initi toxin. Radioactive precursors will be injected intraocularly into control and treated rats and, at various times later, animals sacrificed. Biochemical methods will be used to study the synthesis of macromolecules (proteins and phospholipids) and organelles, their post-translational processing (glycosylation of glycoproteins), and their axonal transport and deposition in axons and nerve endings. Data from trimethyltin-treated animals will be compared with that from control animals. Results of the biochemical studies will be correlated with parallel morphological and autoradiographic examinations of subcellular organelles and structures associated with the various metabolic events. Our general hypothesis is that different toxins will have different specificities with respect to the particular cell biological process (and its associated subcellular structures) affected. The overall significance of results for any individual toxin will be increased as more toxins are investigated and their effects compared. These studies are relevant to a better understanding of the manner in which various toxic compounds may alter normal nervous system function.
