COMPUTATIONAL AND PHYSIOLOGICAL STUDY OF RETINAL NEURONS

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This research proposal is designed to improve our understanding of the physiological mechanisms which regulate the excitability of ganglion and amacrine cells in the vertebrate retina. The methods we will use in this study represent a unique combination of modeling and computer simulation analysis together with physiological and morphological experiments. One of the major objectives of this combined study will be to expand and refine a detailed, multichannel model of impulse generation in ganglion cells with special emphasis on the role which dendrites play in contributing to the impulse encoding properties of these cells. For this project we will use patch-electrode techniques directed to studies of the dendrites of single, identified, dissociated ganglion cells to identify and characterize the types of voltage-gated ion channels in dendrites. Data from these studies will be used to refine our ganglion cell model to more accurately reflect the contribution which dendrites make to impulse generation. Similar modeling studies will be carried out in amacrine cells which generate impulse activity. A second phase of this research is to examine the mechanisms of transmitter release from bipolar cell terminals with special emphasis on the ribbon synapses which appear to serve as an amplification device for exocytotic release of glutamate. This approach will also include models of AMPA and NMDA receptors connected to different cellular regions using compartmental models of realistic cell morphologies. Models of the time course of synaptic currents generated by AMPA and NMDA glutamate receptors will be based on kinetic studies we will carry out using rapid perfusion techniques. We will also generate a multiple ion channel model to simulate impulse encoding in mammalian ganglion cells, based on realistic morphologies and impulse train records from whole-cell recordings of cat ganglion cells. The purpose of this research is to formulate models which will work in synergy to guide and enhance our experimental efforts to decipher to mechanisms that are critical for function among third-order retinal neurons.