Dysfunction of retinal neurons and circuits early in diabetic retinopathy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Dopaminergic amacrine neurons are the only source of dopamine in the retina. Released locally at synapse- like varicosities to target neurons and also in a paracrine fashion to diffusely affect the retina, dopamine is critical in adjusting the retina from nighttime to daytime vision. Intriguing data from published studies indicate that dopaminergic processes and varicosities closely associate with the retinal capillaries, not just neurons, but whether dopamine is vasoactive in retina as in brain is unknown. In this application, we will test the novel hypothesis that dopamine regulates both neuronal and vascular function of the retina and that dysregulation of dopamine action at neurons and capillary endothelial cells in diabetes contributes significantly to the visual impairments of diabetic retinopathy. We propose that dopamine production is reduced in diabetic retina, exacerbating the neuronal and vascular dysfunctions that we have determined to occur in the Ins2Akita mouse model of diabetes. This is based on our preliminary data that dopamine release, tyrosine hydroxylase expression, and dopaminergic neuron number are all reduced in diabetic Akita retina. Further, we find deficits in retinal circuit function, visual behavior, and lood flow that are all remarkably consistent with reduced dopamine as a unifying mechanism. This is of fundamental importance for advancing our basic understanding of retinal function and, importantly, represents a translationally significant new hypothesis that could lead to new targets for improved clinical treatment of diabetic retinopathy. This postulated reduction in dopamine would interfere with retinal function because the normal uncoupling of gap junction networks by dopamine is necessary for matching retinal sensitivity to mean light intensity and for modulating receptive field function. We have demonstrated a marked impairment in diabetic Akita mice of optokinetic tracking (OKT) (Akimov and Renteria, 2012), a visual behavior that requires dopamine for optimal performance. The mechanisms of these neural deficits and how they recapitulate visual dysfunctions in human diabetic retinopathy will be explored in detail in Aim 1. This is translationally significant because our studies will show that treatments that maintain dopamine signaling will ameliorate visual behavior deficits and that dopaminergic dysfunction occurs early in the pathogenesis of diabetic retinopathy. We further hypothesize that dopamine action on retinal endothelial cells is a second critical pathogenic pathway of reduced dopamine in diabetic retinopathy. We propose that reduced dopamine exacerbates VEGF-associated permeability and contributes to the poor ocular blood flow we find in Akita mice. Aim 2 pursues these new ideas of dopamine action on endothelial cells in the retina and their outcomes for retinal neurons. This application is innovative because this pathway could be exploited using FDA-approved treatments as a novel adjunct to anti-VEGF therapy to further block the vascular permeabilizing activity of VEGF. The overall impact of the proposed work is that it provides novel insight for understanding how vision loss occurs in diabetic retinopathy and provides a new pathway to target for therapy.