The goals of this research are focused on understanding signaling mechanisms that regulate the development of visual function and spatial organization of retinal ganglion cells and how they are altered in retinal disease. Normal vision begins in the retina and is initiated by photoreceptor detection of light. Parallel pathways of information flow are initiated at the first synapse between photoreceptors and depolarizing and hyperpolarizing bipolar cells, which detect luminance increases and decreases and/or vision under dark- and light-adapted conditions. As a result, the pathways extend the dynamic range of information processing in the intensity domain, and increase specialization of information processing for salient environmental features, e.g., motion, direction and size. Signaling within these circuits is refined by inhibitory inputs in the outer and inner retina and these interactions culminate in and define the receptive field organization of the retinal ganglion cells. The receptive field is a basic property, shared across all sensory neurons in all species. It defines the types and range of environmental stimuli that each cell encodes. Thus, understanding how receptive field properties develop is key to understanding visual function in the retina and the ganglion cells are a vital part because they represent both the culmination of all retinal processing and the scaffold for the rest of visual processing. Because basic RF spatial organization is already present at the onset of visual responses in ganglion cells, the processes underlying their development have been relatively intractable to investigation. That normal vision requires signaling through the depolarizing and hyperpolarizing pathways is amply indicated by the visual defects that occur in patients with and mouse models of congenital stationary night blindness (CSNB), where depolarizing bipolar cell processing is eliminated. We have three unique mouse models of CSNB1 that we will continue to use to probe the synaptic circuitry underlying CSNB, in which normal photoreceptor function is retained. The nature of the changes in spontaneous and visually-evoked responses across GCs in the three mutants provides a unique opening to study the development of receptive field organization and ganglion cell signaling. The phylogenetic conservation of receptive field organization suggests that our findings in the mouse will be relevant to primate peripheral retinal processing. We suggest that the characterization of these mouse models represents a significant opportunity, not afforded by other mouse or vertebrate models and represents a critical step in our understanding both the disease mechanisms in CSNB1 and normal retinal development and function.
This proposal seeks to understand the mechanisms that govern the development of vision in the retina and to investigate the changes in the downstream synaptic mechanisms when signaling is eliminated from one of the parallel pathways of information processing in the retina. One focus is to understand the exact changes that occur in complete congenital stationary night blindness, a retinal disease that does not involve photoreceptor dysfunction or morphological defects. A second focus is to understand the fundamental processes that regulate the development of normal retinal function, particularly in the ganglion cells. We believe that our results will guide diagnosis and therapeutic approaches to restore or rescue CSNB and also will be relevant to other blinding diseases in people of all ages.
Showing the most recent 10 out of 23 publications
