The Underlying Mechanisms of Visual Impairment and Myopia in Prematurity

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PROJECT SUMMARY The long-term goal of this project is to determine the neuronal and vascular mechanisms of visual impairment and myopia resulting from prematurity in order to develop preventive and therapeutic strategies. Prenatal and early postnatal vertebrate retinas generate correlated spontaneous neuronal activity, termed “retinal waves,” that are essential for normal neuronal development and vision. Premature retinal wave termination may contribute to preterm birth-associated vision problems and refractive errors. Preterm birth, in combination with postnatal oxy- gen therapy, can also cause retinal vascular complications known as retinopathy of prematurity (ROP). ROP is closely associated with incurable visual impairment and myopia in premature infants. The cellular and molecular mechanisms underlying the pathogeneses of eye disorders related to ROP and the early retinal wave activity termination are not yet well defined. Our objectives in this project are to define how spontaneous retinal waves mediate ocular growth before visual experience and how oxygen-induced retinopathy (OIR) causes vision impairment and myopia. Our preliminary data demonstrated that cholinergic retinal waves generated by starburst amacrine cells (SACs) can excite dopaminergic amacrine cells (DACs), the sole source of ocular dopamine—an ocular development regulator. We hypothesize that cholinergic waves drive normal eye development via dopamine signaling and that suppression of this pathway will disrupt normal ocular growth. In Aim 1, we will test this hypothesis by identifying the cholinergic wave–dopamine signaling pathway and assessing how this pathway impacts ocular growth. In addition, we have found that, in an OIR animal model, AII amacrine cells (AII-ACs) and DACs—two classes of inner retinal neurons that contribute to scotopic and photopic vision, respectively—were substantially lost. We hypothesize that the loss of AII-ACs and DACs in OIR causes myopia. In Aim 2, we will test this hypothesis by determining the relative contributions of AII-ACs and DACs to OIR-induced myopia and assessing the impact of OIR-induced visual impairments on myopia development. Expected outcomes include determining how retinal waves influence dopamine signaling to mediate ocular growth and how oxygen treatment perturbs the rod and cone signaling systems through the loss of retinal interneurons to cause vision loss and the development of myopia. The broader impact of this work on understanding the causes and mechanisms of preterm vision impairment and myopia in children will enable the rational discovery of new therapeutic interventions.