Development and Dynamics of Transmission at Mammalian Rod Bipolar Cell Synapses

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DESCRIPTION (provided by applicant): My career goal is to study information processing in the retina as an independent investigator at a research university. The project proposed here will provide me with the training necessary to accomplish this goal. Specifically, the proposed work will address two specific aims using the rod bipolar pathway of the mouse retina as an experimental model. One: how does transmission at the rod bipolar-All amacrine cell synapse of the mammalian retina develop? Two: when deprived of visual input, resulting either from dark- rearing or from rod degeneration in a mouse model of retinitis pigmentosa, does the rod bipolar-All synapse behave as an immature synapse, as a mature synapse, or as something different? The answer to this second question has significant implications for treatment of retinal pathologies arising from photoreceptor degeneration such as that occurring in retinitis pigmentosa. It is important to establish the functional properties of inner retinal synapses and to determine whether these synapses are capable of transferring visual signals before attempting to restore vision by replacement or regeneration of photoreceptors. Experiments designed to achieve these specific aims will be performed in an in vitro slice preparation of murine retina. Rod bipolar and All amacrine cells will be visualized and paired voltage-clamp recordings will be made from synaptically coupled neurons. Depolarization of the presynaptic rod bipolar will elicit Ca^* into its axon terminal, and this Ca^* influx will be recorded as a Ca current. Ca^* influx will evoke exocytosis of glutamatergic vesicles from the terminal; excitatory postsynaptic currents recorded in the All amacrine will allow me to assay this exocytosis. Relevance to public health: Many retinal pathologies cause photoreceptor (rod and cone) death, which deprives retinal neurons of their normal inputs and results in changes in the synaptic connections between them. Because tremendous efforts are being made to regenerate photoreceptors to treat or cure retinal pathologies, it is critical to understand the extent to which the neural circuitry of the diseased retina is capable of processing visual information. The work proposed here will examine a well-characterized retinal synapse to determine the normal course of the development of synaptic transmission and to understand how synaptic transmission following photoreceptor degeneration compares to that in the developing retina.