DESCRIPTION (investigator's abstract): The major objective of the proposed research program is to identify the subcellular origins of abnormalities that affect the structural and functional integrity of the photoreceptors in inherited night-blinding disorders. The defects associated with these types of disorder vary widely. In some stationary conditions, the abnormality appears to be confined to the cell's adaptive mechanism; in the progressive diseases, the structural architecture of the visual cell is affected, and a process of deterioration is set into motion that eventually involves the entire neural retina. The experiments to be conducted during this grant period are designed to test various hypotheses concerning the molecular bases of these abnormalities, as well as the basic features of the adaptive process that is perturbed by their expression. For example, neurotransmission from receptors to second-order neurons appears to be grossly attenuated in some forms of stationary night blindness. The role of the microtubular system in maintaining the functional competence of the cell's synaptic terminal will be determined in experiments in which the microtubules of the visual cells are disrupted, and the movement of proteins from sites of synthesis to the synaptic terminal is tracked autoradiographically. Other cytoskeletal elements (e.g., spectrin and several membrane-associated proteins) are thought to be involved in the ordered alignment of the disc membranes of the receptor outer segment. These proteins will be studied biochemically and immunocytochemically in Tibetan terriers affected with progressive retinal atrophy, a disease characterized in its early stages by disorientation and detachment of the bilamellar discs. In addition, basic features of the adaptive process will be examined in studies on the role of IRBP in shuttling retinoids between photoreceptors and the pigment epithelium, and in other experiments on the light-induced desensitization of vertebrate rods. Lastly, experiments to be performed on the radial glia (Muller cells) and horizontal cells reflect a growing awareness of the dependence of visual function on the organization and membrane properties of these cells, and their respective roles in the regulation of transmitter action in the retina. The latter has wide-ranging implications with regard to neurotoxicity, and in relation to neuron-glia interactions, the intercellular transfer of electrical signals, and the processing of visual information.