To restore vision, we must understand how information is processed in the mature retina and how structural and functional organization are affected during degeneration. The divergence of signals at the first synapse in the visual system, where a single cone provides input to 10-12 types of cone bipolar cells, provides a unique opportunity to study the origin of parallel pathways. This synapse also exhibits convergence, where each type of cone bipolar cell receives inputs from a stereotyped number of cones. Our recent work demonstrates that three types of cone bipolar cells establish their unique patterns of structural contact with presynaptic cone photoreceptors according to different strategies and segregated timelines. However, we know little about how these differences translate into functional properties in the mature circuit. Moreover, how cone bipolar cell types respond to progressive loss of photoreceptors during disease is unclear. The long-term goal of the proposed work is to understand how visual information is parsed and processed in the retina at the cone-to-cone bipolar synapse, and to determine how this information is perturbed in disease. The objectives of the proposed work are to determine the functional properties of three morphologically characterized bipolar cells types, for which we already know structural connectivity patterns, and to determine these bipolars'structural and functional changes in a degenerating retina.
In Aim 1, we will determine how cone convergence and divergence shapes the functional properties of three types of cone bipolar cells. We will make functional measures of the bipolar cells'spatial, temporal, and gain properties.
In Aim 2, we will identify the effect of cone degeneration on bipolar cell structure, connectivity, and function. Many retinal diseases leading to blindness originate with death of photoreceptors. How disease progresses to affect postsynaptic neurons remains largely unknown. We will use laser ablation and transgenic approaches to control the extent and timing of cone death. Imaging and electrophysiology will allow us to determine the structural connectivity patterns, glutamate receptor distributions, and responses to light stimuli of bipolar cells following controlled cone death. The approach is innovative because we are separately determining the function and response of specific bipolar cell types to photoreceptor degeneration. The proposed work is significant because it will reveal how a bipolar cell's functional properties are determined by its anatomical connections with cones and will provide an understanding of how bipolar cells respond to photoreceptor degeneration as a model of potential circuit rearrangements in retinal disease.

Public Health Relevance

This project is relevant to public health because treating retinal disease requires an understanding of how visual information is processed in the healthy retina and how organization is affected during the degeneration of photoreceptors, a common cause of blindness. The results from the proposed research are expected to have a two-fold positive impact: (1) further understanding of circuit processing in the mature retina will facilitae the development of prosthetic devices that perform more similarly to the retina, and (2) knowledge of the restructuring of the retinal circuit during degeneration will provide insight into treating retinal disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Career Transition Award (K99)
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Special Emphasis Panel (ZEY1-VSN (07))
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Agarwal, Neeraj
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University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
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Dunn, Felice A; Della Santina, Luca; Parker, Edward D et al. (2013) Sensory experience shapes the development of the visual system's first synapse. Neuron 80:1159-66