For the next five years of this project, we shall focus on experiments designed to elucidate the role of dopamine in the inner retina. In particular, we shall carry out experiments designed to uncover to role of dopamine in mediating rod signal transmission through the inner plexiform layer of the zebrafish. We shall also develop more sophisticated electrophysiological tests, based on electroretinographic (ERG) recordings, to analyze zebrafish retinal mutations. With behavioral tests, we have identified both recessive and dominant mutations that affect retinal function in zebrafish. A number of the mutations resemble inherited retinal diseases in man including dominantly- inherited retinitis pigmentosa (our nba mutant) protanopia (our pob mutant) and congenital stationary night blindness (our noa mutant). Further, electrophysiological testing of these mutants will help identify where in the retina a specific defect resides and more about the nature of the defect. Specific sub-projects planned for the next five years include: 1) An analysis of ganglion cell responses in normal zebrafish and zebrafish deprived of dopamine by the intraocular injection of 6- hydroxydopamine. Ganglion cells will be patch-clamped and synaptic currents evoked in the cells by puffs of K+ applied in the inner plexiform layer. 2) The electroretinogram (ERG) of the zebrafish will be dissected pharmacologically by drugs that selectively block transmission from photoreceptor cells to all second-order cells, transmission from rod photoreceptor cells to ON-bipolar cells, and transmission from rod and cone photoreceptor cells to OFF-bipolar cells. As part of this sub- project, the effects of these pharmacological manipulations on the visual performance of zebrafish will be tested behaviorally. 3) The ERG responses of selected zebrafish mutants will be further studied using the pharmacological manipulations described in (2) above. In particular, the effects of the mutations on photoreceptor (ERG a-wave) function will be examined.
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