Synaptic changes in the outer retina of a diabetic zebrafish model
Diabetic retinopathy is the leading cause of vision impairment and blindness among working-age adults, and impacts blood vessels in the light-sensitive tissue called the retina in the back of the eye. Typically, in the non-proliferative stage, diabetic retinopathy presents as alterations to retinal structure and function with deficits in the neural retina before and independent of classical microvascular diabetic retinopathy. However, previous studies have failed to demonstrate which neurons and circuits are affected at the earliest stages of diabetes. Our long-term goal is to understand how the neural retina and visual processing is impacted by diabetes and hyperglycemia, with the primary aim focused on develop therapeutic approaches to treat and prevent destruction of retinal neurons. Large gaps remain in our knowledge about the cause of neuronal deficits in diabetes, therefore is difficult to treat or prevent any damage from occurring in patients with diabetes. This proposal aims to take advantage of a proven model of non-proliferative diabetic retinopathy in adult zebrafish, in which adult zebrafish are subjected to oscillating hyperglycemia and assessed at 30, 60, 90, and 120 days. In aim 1, we test whether hyperglycemia alters presynaptic properties and synaptic architecture in neurotransmission at the first synapse in visual processing. In aim 2, Test whether hyperglycemia alters post-synaptic responses and receptors involved in neurotransmission at the first synapse in visual processing. This proposal will provide the framework for preliminary data and manuscripts that will result in a broader more expanded study that will be submitted to the NIH as an RO1 application. This project is aligned with the National Eye Institute’s (NEI) framework for vision research, and targets three of the five major areas of the strategic plan put forth by the NEI. First, this project aims to gather comprehensive knowledge of the molecular basis of ocular health and disease, and use that knowledge to improve diagnosis, treatment, and prevention of eye disease. This study fulfills this aim by characterizing the changes in molecular processes that affected the neural retina in diabetes, and will provide a better understanding of the neural changes in non-proliferative stage of diabetic retinopathy. Secondly, understand the systems biology underlying visual function. Our approach utilizes a simple model of hyperglycemia to understand the integration of retinal structural and neural processes that constitute the unique physiology of the ocular system in a diabetic state and compare that to normal retinal structure and function. Finally, this study will accelerate the translation of basic research into clinical studies, by developing appropriate animal models. Zebrafish provide incredible power to study the diabetic state and uncover disease mechanisms and evaluate potential investigational therapies. Using zebrafish as a model for the non-proliferative stage of diabetic retinopathy will provide a springboard for a potential drug assay or high-throughput screen with the goal of developing new targeted therapies for the treatment of diabetic retinopathy.

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