Functional architecture of the retina: Development and disease

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Abstract

Structure and function are highly correlated in the vertebrate retina, a sensory tissue that is organized into cell layers with microcircuits working in parallel and together to encode visual information. All vertebrate retinas share a fundamental plan, comprising five major neuronal cell classes with cell body distributions and connectivity arranged in stereotypic patterns. Conserved features in retinal design have enabled detailed analysis and comparisons of structure, connectivity and function across species. Each species, however, can adopt structural and/or functional retinal specializations, implementing variations to the basic design in order to satisfy unique requirements in visual function. Recent advances in molecular tools, imaging and electrophysiological approaches have greatly facilitated identification of the cellular and molecular mechanisms that establish the fundamental organization of the retina and the specializations of its microcircuits during development. Here, we review advances in our understanding of how these mechanisms act to shape structure and function at the single cell level, to coordinate the assembly of cell populations, and to define their specific circuitry. We also highlight how structure is rearranged and function is disrupted in disease, and discuss current approaches to re-establish the intricate functional architecture of the retina.

Introduction

The vertebrate retina is a layered structure with a large diversity of component cells that form morphologically and functionally distinct circuits that work in parallel, and in combination, to produce a complex visual output. Developmental mechanisms that establish the structure and function of retinal neurons are increasingly understood, largely due to advances in molecular biology, electrophysiological methods and imaging techniques. Here, we discuss our current knowledge of the cellular and molecular mechanisms that (i) shape the morphology of retinal neurons, (ii) organize their spatial distributions across the retina, and (iii) regulate the assembly of their circuitry. We will also compare the development of different cell types, and of similar circuits across species to highlight common and disparate strategies employed to attain optimal structure and function. In particular, we will discuss findings primarily in three well-studied species, each with its own advantages: (i) Mouse, for which there is an increasing availability of transgenic animals and is the current focus of ‘connectomics’, (ii) Monkey (primarily macaque retina), with structure and function closest to humans, and (iii) Zebrafish, that like mice are highly amenable to genetic manipulation, but have the added advantage of possessing a capacity for tissue-regeneration. We will end the review with a brief discussion of how retinal structure and function are disrupted in common retinal diseases, and postulate how studies of retinal development could contribute to future therapeutic interventions.

Section snippets

Organization of the vertebrate retina

The fundamental plan of the retina is conserved across vertebrates; five major neuronal cell classes (Fig. 1) with Müller glial cells providing metabolic and homeostatic support. Coding of visual information begins with conversion of light energy to membrane potential changes in photoreceptors that alters neurotransmitter release. Photoreceptors can be broadly categorized into rods and cones (Fig. 1). Rods have exquisite sensitivity to light and can detect even a single photon (Rieke, 2000,

Synapse structure and connectivity of retinal neurons

Much is now known about the overall structural and functional organization of mature retinal synapses and connectivity, but there are few circuits in the vertebrate retina for which we have complete connectivity maps and defined functions. Nevertheless, the recent availability of genetic tools and transgenic lines with labeled cell types (Ivanova et al., 2010, Kim et al., 2010, Siegert et al., 2012) together with technical advancements in imaging techniques is facilitating a rapid acquisition

Disease: alterations to structure and function

Pathologies of the neural retina represent some of the most common causes of visual impairment and blindness (Pascolini and Mariotti, 2012). The majority of retinal diseases can be categorized largely into those involving death of photoreceptors in the outer retina, and those directly affecting neurons of the inner retina, such as bipolar cells and ganglion cells. Table 1 lists some common retinal diseases, the associated animal models and the cell types that are the primary ‘targets’. In this

Future goals

Although there have been tremendous advances in restoring photosensitivity to retinal neurons, much remains to be done to recapture the intricate processing of visual information normally performed by the many parallel retinal circuits. As methods to replace retinal neurons become routine, the next major challenge is to ensure that the new neurons reconnect properly. This is not a simple task because the retinal environment can change drastically even when one cell type dies. Successful

Acknowledgments

Supported by NIH grants (EY10699, 17101, 14358) to R.O.L.W, Knights Templar Eye Foundation career starter grant to M.H. and a Human Frontier Science Program grant (RGP0035 to L. Lagnado, F. Schmitz and R.O.L.W.). We would like to thank the reviewers for their helpful comments and suggestions. We would also like to thank E. Strettoi, L. Galli-Resta, R. Sinha and F.D. D’Orazi for critical reading of the manuscript and useful comments. We are grateful to R. Sinha, F.A. Dunn, S.C. Suzuki and T.

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    Percentage of work contributed by each author in the production of the manuscript is as follows: M. Hoon: 60%; H. Okawa: 30%; L. Della Santina: 5%; R. Wong: 5%.

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