The overall objective of the proposed research program is to enhance our knowledge of the cellular development of retinal ganglion cells, with the ultimate goal of relating this information to molecular interactions guiding the structural/functional development of these neurons. In order to understand the mechanisms underlying the functional development of mammalian retinal ganglion cells, it is essential to document the dominant conductances responsible for the excitable membrane properties of these neurons. During the last grant period, we showed that isolated fetal ganglion cells exhibit dramatic changes in their spiking properties injected currents. Concomitant with these ontogenetic changes in spiking properties, we demonstrated developmental alteration in sodium and potassium currents. To gain a full account of the membrane conductances underlying spike generations, it is now necessary to study the expression and development of calcium an calcium- mediated potassium currents. The knowledge gained from these experiments will allow the formulation of a quantitative model relating combinations of specific conductances to the spiking properties exhibited by developing and mature retinal ganglion cells. This is the first specific aim. Work completed curing the last grant period also revealed an unexpected diversity of response patterns among retinal ganglion c ells to maintained depolarizing currents. Some neurons responded in a sustained fashion over a broad range of current intensities, while others manifested only rapidly adapting discharges, suggesting that different retinal ganglion cells are characterized by fundamental differences in their intrinsic membrane properties. These findings were unexpected because it is commonly believed that the diverse visual response patterns that characterize distinct c lasses of retinal ganglion cells are due to differences in retinal circuitry. As the second specific aim, we will establish the degree to which differences in intrinsic membrane properties relate to morphologically defined retinal ganglion cell classes in developing and mature retinas. We will also determine how the establishment of specific intrinsic membrane properties relates to the morphological differentiation of retinal ganglion cell classes. As the third specific aim, we will investigate the ontogeny of ligand-gated responses in fetal ganglion cells. Once this information is established, we will test the hypothesis that the early expression of ligand-gated response reflects the regulation of ganglion cell morphological differentiation by common neurotransmitters. At maturity, ON and OFF ganglion cells of a given class are distributed in regular arrays across the retinal surface. Such mosaic patterns are thought to be essential for the efficient processing of visual information, but as yet we know nothing about how such orderly distributions of cells are established. The fourth specific aim is to assess the hypothesis that ganglion cell death plays a key role in establishing ON and OFF ganglion cell mosaics, and that sodium voltage- gated activity regulates this developmental process. The results of this research program will significantly enhance our understanding of the events and mechanisms shaping the normal development of mammalian retinal ganglion cells.
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