The overall objective of the proposed research program is to further our understanding of the functional and structural development of retinal ganglion cells, the neurons that convey all information from the eyes to the visual centers of the brain.
Five specific aims are proposed designed to fill major gaps in our current knowledge. As the first specific aim, patch-clamp recordings will be made from developing ganglion cells of the ferret in conjunction with their intracellular filling to allow for the morphological assessment of cells into major classes (alpha, beta and gamma) as well as On, Off and On-Off subtypes. Spontaneous activity patterns will be recorded at three well-defined stages of development and quantitative methods will be used to assess discharge patterns.
The aim of this study is to determine whether different classes of cells manifest class-specific spontaneous activity patterns during the developmental period when activity mediated refinements are known to occur at retinorecipient structures. The second specific aim is to determine whether two intrinsic membrane properties studied during the past grant period (speed of recovery from Na-channel inactivation and Ca-mediated potassium currents) relate to the spontaneous activity patterns manifested by developing ganglion cells. The third specific aim is to determine how the visual responses of developing ganglion cells to flashing spots of light correlate with the stratification of dendrites in these neurons. In particular, we want to learn whether immature ganglion cells with dendrites ramifying within both the On and Off sublaminae of the developing IPL respond to the onset as well as the offset of flashing spots of light. The third specific aim is to determine whether the functional circuitry underlying On and Off responses in the developing retina is equivalent to that found in the mature retina. For this purpose, we will assess the effects of APB application on the light-evoked responses of morphologically identified ganglion cells. This glutamate agonist selectively blocks On responses in the mature retina, but preliminary results indicate that both On and Of f pathways can be effectively blocked by this drug in multistratified ganglion cells of the developing retina. The fifth specific aim is to determine whether cholinergic amacrine cells play a role in the formation of segregated On- and Off-cone bipolar cell axonal projections and in the stratification of retinal ganglion cell dendrites. To address this issue we have devised a novel method for eliminating cholinergic amacrine cells from the developing retina. The successful completion of this research program will provide new insights into the development of the mammalian retina, and it will also have implications for elucidating the cellular mechanisms underlying the formation of neuronal connections at higher levels of the nervous system.
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