The Fovea: Structure, Function, Development, and Tractional Disorders

The Fovea

Structure, Function, Development, and Tractional Disorders

First Edition

Andreas Bringmann

Head of the Research Laboratory of the Department of Ophthalmology and Eye Hospital, Medical Faculty, University of Leipzig, Leipzig, Germany

Peter Wiedemann

Head of the Department of Ophthalmology and Eye Hospital, Medical Faculty, University of Leipzig, Leipzig, Germany

Table of Contents

Cover image

Title page

Copyright

Acknowledgments

Introduction

Abstract

Chapter 1: Introduction: Optical properties of the retina

Abstract

1.1: Light guidance through Müller cells

1.2: Retinal areas of high cell densities

1.3: The fovea: A structural solution for high-acuity vision

Chapter 2: Basic structure of the retina

Abstract

2.1: Photoreceptors

2.2: Bipolar, horizontal, and amacrine cells

2.3: Retinal ganglion cells

2.4: Retinal vasculature

Chapter 3: Retinal glia

Abstract

3.1: RPE cells

3.2: Oligodendroglia

3.3: Microglia

3.4: Macroglia: Retinal astroglia

3.5: Macroglia: Müller glia

Chapter 4: Nonmammalian fovea

Abstract

4.1: Retinal localization of the nonmammalian fovea

4.2: Shape of the nonmammalian fovea

4.3: Histological structure of the nonmammalian fovea

4.4: Cellular arrangement in the nonmammalian fovea

4.5: Photoreceptors of the nonmammalian fovea

4.6: Optical function of the nonmammalian fovea

4.7: Motion detection and depth perception by the non-mammalian fovea

Chapter 5: Primate fovea

Abstract

5.1: Structure of the primate fovea

5.2: Glio-neuronal units of the primate fovea

5.3: Optical properties of the primate fovea

Chapter 6: Comparison of the nonmammalian and primate fovea

Abstract

Chapter 7: Development of the fovea

Abstract

7.1: Cytogenesis and retinal development

7.2: Development of the rod-free zone

7.3: Development of the area centralis

7.4: Development of the retinal vascularization

7.5: Development of the primate fovea interna

7.6: Development of the primate fovea externa

7.7: Variations in human foveal development

7.8: Improper foveal development

7.9: Development of the nonmammalian fovea

Chapter 8: Tractional disorders of the human fovea

Abstract

8.1: Posterior vitreous detachment

8.2: Vitreomacular traction

8.3: Epiretinal membranes

8.4: ILM detachment

8.5: Macular pucker

8.6: Macular pseudoholes

8.7: Myopic traction maculopathy

8.8: Macular telangiectasia type 2

8.9: Partial gap in the foveola

8.10: Foveal pseudocysts

8.11: Lamellar macular holes

8.12: Sealing and regeneration of outer foveal defects

8.13: Full-thickness macular holes

8.14: Cystoid macular edema

8.15: Glial scaffold of the foveal structure

List of abbreviations

List of figures

Index

Copyright

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Acknowledgments

We want to thank all colleagues and PhD and MD students who contributed to the research in our laboratories at the Department of Ophthalmology and Eye Hospital (Head, P. Wiedemann, MD) and the former Department of Neurophysiology of the Paul Flechsig Institute of Brain Research (Head, A. Reichenbach, MD), Medical Faculty of the University of Leipzig, Leipzig, Germany, in particular (in alphabetical order): Charlotte Ackmann, Silke Agte, Thomas Barth, Benjamin-Andreas Berk, Bernd Biedermann, Ricarda Brück, Erik Brückner, Eva Bühner, Rui Chen, Fabian Doktor, Franziska Drechsler, Sladjana Dukic-Stefanovic, Wolfram Eichler, Sarah Fischer, Tarcyane B. Garcia, Katja Görner, Antje Grosche, Frank Faude, Mike Francke, Kristian Franze, Iwona Goczalik, Wolfgang Härtig, Petra G. Hirrlinger, Margrit Hollborn, Ianors Iandiev, Karsten Jahn, Claudia Jochmann, Folke Kalisch, Anett Karl, Jana Kleiner, Christian Koch, Patricia Köferl, Stephanie Köhler, Nicole Körber, Katja Krügel, Heidrun Kuhrt, Franziska Kutzera, Wilhelm Lindenau, Regina Linnertz, Stephan Lipp, Silvana Löffler, Yun-Bi Lu, Luise Messerschmidt, Ivan Milenkovic, Florian Neumann, Thomas Pannicke, Carola Petto, Philipp Prager, Maik Raap, Matus Rehak, Martin B. Reichel, Katja Rillich, Ute E. K. Schnurrbusch, Marlen Seifert, Christina Stathopoulos, Anja Steffen, Steffen Syrbe, Solveig Tenckhoff, Susanne Trettner, Ortrud Uckermann, Susann Uhlmann, Elke Ulbricht, Jan Darius Unterlauft, Moritz Veltmann, Stefanie Vogler, Juliane Voigt, Vincent Wahl, Michael Weick, Malte Weuste, Renate Wiedemann, Anica Winges, Helge Winters, Antje Wolf, and Yousef Yafai.

We also thank all collaborators outside of our laboratories, in particular, Jan Albrecht, Gernot I.W. Duncker, Tobias Duncker, Ulrich Gärtner, Christian Grimm, Gunnar Habermann, Franziska vom Hagen, Hans-Peter Hammes, Stefanie M. Hauck, Peter Illes, Hans Peter Iseli, Johannes Kacza, Leon Kohen, G. Astrid Limb, Felix N. Makarov, Neville N. Osborne, Leo Peichl, Charlotte E. Remé, Johannes Seeger, Serguei N. Skatchkov, Sebastian Wolf, and Herbert Zimmermann. We also thank Jens Grosche, Leipzig, Germany (effigos.com/de), for the preparation of excellent graphics for previous papers of our teams reproduced in this book.

The optical coherence tomography images shown in this book are derived from patients who were referred to the Department of Ophthalmology, University of Leipzig, Germany, between 2008 and 2020. The retrospective chart reviews followed the ethical standards of the 1964 Declaration of Helsinki and its later amendments. The protocol was approved by the Ethics Committee of the Medical Faculty of the University of Leipzig (#143/20-ek, 04/03/2020). The ethics committee is registered as Institutional Review Board at the Office for Human Research Protections (registration number, IORG0001320/IRB00001750). We thank all patients for the possibility to learn much about the normal and the pathologically altered fovea. We also thank for their faith in our medical art although we could not effectively help in several cases, as shown in various examples described in this book.

We dedicate this book the Father of the Müller Cell in Leipzig, Andreas Reichenbach, MD. We thank for long-lasting support, ideas, and enthusiasm in the research of the most exciting cell type we know, the Müller cell.

Introduction

Abstract

The fovea is the retinal site of the eye’s sharpest vision. It is a pitted invagination at the inner surface of thick retinal areas, which contain high photoreceptor and neuron numbers. There are two basic types of the vertebrate fovea, namely the fovea of nonmammalian species, which does not contain a foveola, and the primate (including human) fovea with a central foveola surrounded by sloping foveal walls. The different morphologies of both fovea types are associated with different optical properties and probably result from the absence and presence of retinal astrocytes. In both fovea types, Müller glial cells are the only macroglial cells. Müller cells play central roles in the development, structural stabilization, and optical function of the fovea. The structural stability of the primate fovea is provided by two different populations of Müller cells, namely cells that form the Müller cell cone in the foveola and the z-shaped Müller cells of the foveal walls and parafovea. Müller cells play crucial roles in the pathogenesis and healing of human macular disorders, which are associated with tractional alterations of the foveal structure, e.g., cystoid macular edema as well as lamellar and full-thickness macular holes.

Keywords

Fovea types, Histological structure, Foveal optics, Müller Glia, Astroglia, Function, Development, Macular pathology, Edema, Tractional disorders

Chapter 1: Introduction: Optical properties of the retina

Abstract

The inner layers of the inverted vertebrate retina contain structures (nerve fibers and synapses) which scatter light; light scattering and reflection decrease the visual acuity and sensitivity. In thin (peripheral) retinal areas, light scattering is avoided by light guidance through Müller cells. A high acuity of vision is achieved by a high density of photoreceptors and retinal ganglion cells. This results in thick retinal areas with many cells and structures which scatter light. In thick (central) retinal areas, light scattering is avoided by the formation of a fovea. There are two types of the vertebrate fovea: the fovea of nonmammalian species (without a foveola) and the primate fovea (with a foveola).

Keywords

Visual acuity; Light scattering; Light guidance; Müller glia; Nonmammalian fovea; Primate fovea

The vertebrate retina is inverted with respect to the light path (Kölliker, 1872a). The inverted structure allows an efficient metabolic and structural support of the photoreceptors by the retinal pigment epithelium (RPE) but has the disadvantage that the light has to pass the entire neural retina before it arrives at photoreceptors. The inner retina contains abundant cellular elements which have dimensions within or near the wavelength range of visible light (about 300–700 nm in birds and 380–770 nm in primates). Such elements are phase objects which reflect and scatter light (Zernike, 1955; Land, 1972; Tuchin, 2000, and references therein). Light reflection by the retinal tissue in the living eye is evidenced by the fact that optical coherence tomography delivers images of retinal layers; in these images, light-reflecting retinal layers appear bright (Fig. 1C). In spectral-domain optical coherence tomography (SD-OCT) images of the human retina, the highest light reflectivities are found in the nerve fiber layer (NFL), the inner plexiform layer (IPL), the outer plexiform layer (OPL), and in four lines of the outer retina: the external limiting membrane (ELM), the ellipsoid zone (EZ; the ellipsoid portion of the inner photoreceptor segments which contains the mitochondria; previously termed the inner/outer segment line), the interdigitation zone (IZ; the interdigitation between the outer photoreceptor segments and the apical microvilli of the RPE; previously termed the cone outer segment tip line), and the mitochondria-containing basal part of the RPE (Fig. 1C) (Srinivasan et al., 2008; Spaide and Curcio, 2011; Staurenghi et al., 2014; Cuenca et al., 2018). The back reflection of light within the NFL and both synaptic (plexiform) layers (Fig. 1A, B) shows that a substantial portion of the incident light is scattered at neuronal axons and synapses. These structures have dimensions close to 500 nm and thus are light-reflecting objects (Franze et al., 2007; Prasse et al., 2013). In addition, neuronal cell somata (perikarya), which contain organelles with dimensions within the wavelength range of visible light, reflect light (Fig. 1A, B). The three nuclear layers of the retina which contain the cell somata (ganglion cell layer [GCL], inner nuclear layer [INL], outer nuclear layer [ONL]) and the Henle fiber layer (HFL) have lower reflectivities compared to the plexiform layers (Fig. 1C). Among the nuclear layers, the GCL has the highest and the ONL the lowest reflectivity (Fig. 1C). The HFL has the same low reflectivity as the ONL; therefore, the HFL and ONL are normally not distinguishable in SD-OCT images (Fig. 1C). The low reflectivity of the HFL can be in part explained by the fact that the diameter of Henle fibers is about 2 μm (Fig. 2K) (Syrbe et al., 2018) which is above the wavelength range of visible light. However, the reflectivity of the HFL depends on the angle at which the light hits the retina (Lujan et al., 2011); tractional distortion of the fovel tissue may enhance the reflectivity of the HFL (Figs. 3B, E, J, 4C, 5Gf, and 6A). Light scattering in the inner retina reduces the visual sensitivity and acuity, and decreases the signal-to-noise ratio of the image transmitted through the neuroretina (Fig. 7E) (Agte et al., 2011; Reichenbach and Bringmann, 2013, 2015). Thus, avoidance of light scattering is a precondition for high visual sensitivity and acuity, in particular, under conditions of lower light intensities. In addition, the presence of retinal blood vessels, at which light is scattered and absorbed, in front of the photoreceptor layer decreases the quality and brightness of the visual image at the photoreceptor level and may produce angioscotomas (Fig. 1C) (Weale, 1966; Adams and Horton, 2003).

Fig. 1 Optical properties of the mammalian retina. (A) Light reflection occurs in the retinal neuropil but not in Müller cells. The images were taken in the reflection mode from a freshly isolated wholemount of the retina of a guinea pig ( Cavia porcellus ) which is oriented with the vitreal side up. Light reflection from various retinal layers is indicated by the bright structures. At the dark structures, the light is not reflected. Three different retinal levels are shown, (a) nerve fiber layer (NFL), (b) inner plexiform layer (IPL), and (c) outer plexiform layer (OPL). At the top of (a–c), orthogonal z-axis reconstructions (side views) of the confocal image stacks are shown; the green lines indicate the levels at which the images shown in (a–c) were taken. A regular pattern of non-reflecting ( dark ) tubes is apparent which traverses the entire neuroretina. (a) Large parts of the innermost retinal layers (NFL, ganglion cell layer [GCL]) are non-reflecting ( dark ) Müller cell endfeet. Retinal ganglion cell somata and axon bundles in the NFL strongly reflect light and appear bright . (b, c) Both plexiform layers display a uniform ( bright ) background reflection while the many circular cross-sections through Müller cell processes are non-reflecting ( dark ). Bar, 25 μm. (B) Supervision on the NFL/GCL ( left ), IPL ( middle ), and inner nuclear layer (INL; right ) of a freshly isolated peripheral human retina. The images were recorded in the reflection mode, i.e., cellular structures which backscatter (reflect) the light appear bright . In the GCL, blood vessels ( blue arrowhead ), nerve fiber bundles ( red arrows ), and neuronal somata ( yellow arrowhead ) reflect light. The IPL contains light-reflecting synapses and dark dots which represent cross-sections through nonreflecting inner stem processes of Müller cells. The INL contains light-reflecting neuronal somata which are enclosed by nonreflecting sheaths of Müller cells. The absence of light reflection in the Müller cell processes indicates that these processes guide the light through the tissue. Bars, 25 μm. (C) Linear horizontal SD-OCT scans through the macula of two human subjects without apparent eye disease. Light-reflecting structures appear bright . In the foveola, neuron-containing and light-scattering inner retinal layers are absent; light reflection of medium intensity occurs only in the thin inner Müller cell layer. In the foveal walls and parafovea, strong light reflections are present in the NFL, IPL, and OPL. There is very small light reflection in the Henle fiber layer (HFL) and outer nuclear layer (ONL). The blue arrowhead indicates a shadow in the retinal tissue due to a large blood vessel at the inner retinal surface. The red arrowhead indicates the fovea externa in the foveola which is formed by the elongated photoreceptor outer segments and that is visible at the inclined courses of the external limiting membrane (ELM) and ellipsoid zone (EZ) lines. The yellow arrowhead indicates the point-shaped light reflex in the inner layer of the foveola at or (in dependence on the angle of laser light application) beside the deepest point of the foveal pit that lies in front of the tip of the fovea externa. Scale bars, 200 μm. (D) SD-OCT images of horizontal ( above ) and vertical sections ( below ) through the fovea of a normal human subject. Note the hyperreflective dot in the inner layer of the central foveola which is the central light reflex at the deepest point of the foveal pit. (E) Presumed optics of the primate fovea. The central foveola allows a short pathway of the image from the inner retinal surface to the central photoreceptors, without light-scattering at inner retinal layers. The central foveal walls may have an image-magnifying function. The peripheral retina does not provide image magnification. CHO, choriocapillaris; IZ, interdigitation zone; RPE, retinal pigment epithelium. (Images are modified after Reichenbach, A., Bringmann, A., 2013. New functions of Müller cells. Glia 61, 651–678; Reichenbach, A., Bringmann, A., 2020. Glia of the human retina. Glia 68, 768–796 and Bringmann, A., Syrbe, S., Görner, K., Kacza, J., Francke, M., Wiedemann, P., Reichenbach, A., 2018. The primate fovea: structure, function and development. Prog. Retin. Eye Res. 66, 49–84, and show unpublished data (A. Bringmann and P. Wiedemann, Leipzig).)

Fig. 2 Müller cells of the primate foveal walls and parafovea. (A) Schematic cross-section through the human fovea. The main processes of the z-shaped Müller cells of the parafovea are shown in red . (B) Histological cross-section through the fovea of a siamang ( Symphalangus syndactylus ). Müller cells were immunolabeled for vimentin ( brown ); cell nuclei are blue -stained. The arrowheads indicate the centralmost blood vessels. Bar, 100 μm. (C) Linear horizontal SD-OCT scans through the macula of four human subjects without apparent eye disease. The Henle fiber layer (HFL) is shown in yellow . The temporal macula is shown at the left side , the nasal macula at the right side . (D) Cross-section through a human parafovea showing the spatial arrangement of Müller cell processes. The outer processes draw obliquely through the HFL. The inner processes are centrifugally displaced between the horizontal cell layer (HCL) and ganglion cell layer (GCL) near the central foveal wall ( left ); the processes are bended at the interface between the bipolar (BCL) and amacrine cell layers (ACL). More peripherally ( right ), the inner processes draw straight through the tissue. Note the side processes of Müller cells in the inner (IPL) and outer plexiform layers (OPL). (E–H) Golgi-stained Müller cells in sections through the parafovea of a cynomolgus macaque ( Macaca fascicularis ). (E) Note the horizontal layering of the inner fibrous part of the OPL ( arrow ). (F) Section through the inner retinal layers of the parafovea. In addition to Müller cells, an amacrine cell and neuronal somata in the GCL are stained. The soma of the amacrine cell ( green arrow ) lies in the inner nuclear layer (INL); the amacrine cell processes form a tree in the IPL. The red arrows indicate Müller cell somata which contain the cell nuclei. Note that the nucleus of the left marked cell is located out of the cell axis. The red arrowhead indicates side processes of Müller cells which draw horizontally through the inner part of the OPL. Further side processes of Müller cells draw horizontally through the IPL. (G) Note the horizontal Müller cell side processes in the inner part of the OPL ( red arrowheads ) and the thickening of Müller cell processes in the outer part of the OPL ( blue arrowhead ). Red arrows , Müller cell somata. Blue arrow , soma of a bipolar cell. Green arrows , somata of amacrine cells. (H) Sections through the outer retina of the parafovea. In the outer nuclear layer (ONL), glial processes surround the somata of photoreceptor cells. The arrowheads indicate microvilli of Müller cells (length, 4–6 μm) which extend from the external limiting membrane (ELM) into the subretinal space. In the right image , the microvilli of a Müller cell surround the inner segment of a cone cell. (I) Section through a human parafovea. The arrowhead indicates a vessel of the outer vascular plexus which lies at the INL-OPL interface. (J) Cross-sections through the parafovea (a), the foveal wall (b), and the foveola (c) of a rhesus macaque ( Macaca mulatta ). Note the oblique arrangement of the Henle fibers in the HFL. Note also that the OPL is composed of two parts: an inner fibrous layer and an outer layer which contains photoreceptor synapses. Bar, 50 μm. (K) Ultrastructure of the HFL in the foveal wall of a cynomolgus macaque. The photoreceptor cell axons are separated by Müller cell processes. (L) SD-OCT scans of the foveas and parafoveas of various human subjects. The curved hyperreflective structures in the HFL and ONL, which are associated with small sites of lost photoreceptor integrity, display the spatial arrangements of Henle fibers in the HFL and photoreceptor somata rows in the ONL. The hyperreflectivities are caused by light reflection at gliotic outer processes of the Müller cells of the foveal walls and parafovea and/or at extracellular accumulations of serum or other proteins. (M, N) Examples of the development of such curved hyperreflectivities in the central outer retina after transient serous detachments of the fovea from the retinal pigment epithelium (RPE). The months after the first visit (0) are indicated left of the images. Scale bars, 200 μm. CHO, choriocapillaris; ELM, external limiting membrane; EZ, ellipsoid zone; ILM, internal limiting membrane; IZ, interdigitation zone; NFL, nerve fiber layer; PRS, photoreceptor segments. (Images are modified after Piersol, G.A., 1897. The microscopical anatomy of the eyeball. In: Norris, W.F., Oliver, C.A. (Eds.), System of Diseases of the Eye. Vol. I. Embryology, Anatomy, and Physiology of the Eye. JB Lippincott, Philadelphia, PA, pp. 217–382; Polyak, S.L., 1941. The Retina. University of Chicago Press, Chicago, IL; Syrbe, S., Kuhrt, H., Gärtner, U., Habermann, G., Wiedemann, P., Bringmann, A., Reichenbach, A., 2018. Müller glial cells of the primate foveola: an electron microscopical study. Exp. Eye Res. 167, 110–117; Bringmann, A., Syrbe, S., Görner, K., Kacza, J., Francke, M., Wiedemann, P., Reichenbach, A., 2018. The primate fovea: structure, function and development. Prog. Retin. Eye Res. 66, 49–84; Bringmann, A., Unterlauft, J.D., Wiedemann, R., Barth, T., Rehak, M., Wiedemann, P., 2020d. Two different populations of Müller cells stabilize the structure of the fovea: an optical coherence tomography study. Int. Ophthalmol. 40, 2931–2948, and show unpublished data (A. Bringmann and P. Wiedemann, Leipzig).)

Fig. 3 Morphology of partial-thickness defects of the human fovea. In (F), (I), and (J), the months after the first visit (0) are indicated left of the SD-OCT images. (A) Three foveas with a disruption of the connection between the horizontal layer of the Müller cell cone and the left foveal wall produced by anterior hyaloidal traction. (B) Different foveas with a gap in the foveola. (C) Four eyes with outer lamellar holes (OLH). (D) Left side: Four eyes with a degenerative lamellar hole (DLH). The arrowheads indicate lamellar hole-associated epiretinal proliferation (LHEP). Degenerative cavitations of the foveal pit in the lower foveal walls were present below the elevated inner layers of the foveal walls. The arrows indicate tissue masses of medium reflectivity which covered a part of the vitreal side of the foveola and that were connected to the LHEP at the vitreal surface of the foveal walls. These tissue masses were likely formed by hypertrophied and proliferating cells of the disrupted Müller cell cone and caused a pressure onto the underlying outer retina, as indicated by the outward deflections of the external limiting membrane (ELM) and ellipsoid zone (EZ) lines. Right side: A DLH in an eye with high myopia ( above ). Note the schistic tissue splitting between the OPL and HFL in the perifovea ( above ) and in the HFL in the more peripheral retina ( below ). (E) Various eyes with a tractional lamellar hole (TLH). Anterior hyaloidal traction caused a disruption of the connection between the inner layer of the Müller cell cone and the foveal walls and an elevation of the inner layers of the walls; the latter produced a schistic splitting of the foveal walls between the outer plexiform layer (OPL) and Henle fiber layer (HFL), and cystic cavities in the inner nuclear layer (INL). The outer retina was not affected. The presence of an operculum, which adhered to the posterior hyaloid in front of the hole ( arrows ), may suggest that hyaloidal traction removed the inner Müller cell layer from the foveola and caused the elevation of the inner layers of the foveal walls. Left uppermost image: Because tractional forces onto the macula may distort the foveal tissue which alters the position of the tissue layers to the direction of the incoming light, the HFL can be distinguished from the ONL by the increased reflectivity. In the two lower images at the right side , TLH in eyes with macular pucker were produced by contraction and detachment ( above ) of epiretinal membranes (ERM). (F) Development of a TLH after disruption of the Müller cell cone produced by anterior hyaloidal traction. (G) Progression of a TLH to a retinoschisis. (H) Macular pseudoholes (MPH). Contraction of ERM produced inner retinal folds and a thickening and straightening of the foveal walls. The central outer retina is not or little affected. (I, J) Two eyes with a MPH with foveoschisis, i.e., a schistic splitting of the foveal walls between the OPL and HFL. (J) After vitrectomy with internal limiting membrane and ERM peeling performed 2.5 months after the first visit, the size of the schistic tissue splitting decreased. (K) Development of a MPH with foveoschisis from a foveal pseudocyst in an eye with macular pucker. (L) Comparison of the morphologies of the degenerative cavitations in DLH ( left ) and schistic cavities in TLH ( right ). The arrows indicate the levels of the widest lateral extensions of the cavitations. Degenerative cavitations of DLH have two levels of the widest lateral extension into the foveal walls: the interface between the inner plexiform layer (IPL) and the INL, and the OPL-HFL interface. Schistic cavities in TLH have one level of the widest lateral extension, at the OPL-HFL interface. The arrowhead indicates a band of glial tissue which covers the vitreal side of the right foveal wall and that is connected to the LHEP. Scale bars, 200 μm. GCL, ganglion cell layer; IZ, interdigitation zone; NFL, nerve fiber layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium. (Images are modified after Bringmann, A., Unterlauft, J.D., Wiedemann, R., Rehak, M., Wiedemann, P., 2020c. Morphology of partial-thickness macular defects: presumed roles of Müller cells and tissue layer interfaces of low mechanical stability. Int. J. Retina Vitreous. 6, 28 and show unpublished data (A. Bringmann and P. Wiedemann, Leipzig).)

Fig. 4 Tractionally induced pseudocysts in the fovea. In (D) and (G–L), the months after the first visit (0) are indicated left of the SD-OCT images. (A) Hematoxylin/eosin-stained histological sections through the foveola of a rhesus macaque ( Macaca mulatta ). The preparation of the sections caused tissue disruptions at two sites in the foveola ( arrows ): a horizontal disruption between the inner Müller cell layer and the Henle fiber layer (HFL)/outer nuclear layer (ONL) and a vertical disruption between the inner layer and the ELM in the center of the foveola. The presence of the tissue disruptions suggest that these regions have a low resistance against mechanical stress. The image above shows the traction vectors which are present in the foveola. (B) Two modes of full-thickness macular hole formation in the human fovea caused by vitreofoveal traction, as shown by Chung and Byeon (2017). Anterior traction exerted by the partially detached posterior hyaloid produces a tissue disruption and pseudocyst formation within the foveola (left side) or a detachment of the foveolar neuroretina from the retinal pigment epithelium (RPE; right side). In eyes with pseudocyst formation (left), there are often horizontal cleavages at the boundary between the inner Müller cell layer and the HFL/ONL of the peripheral foveola, and a vertical cleavage in the center of the foveola (red circle). (C, D) Pseudocysts in the human fovea which were produced by tangential traction of epiretinal membranes (ERM). (C) The tractional elevation of the inner Müller cell layer of the foveola is associated with a drawbridge elevation of the inner layers of the foveal walls (nerve fiber layer [NFL] to outer plexiform layer [OPL]). The latter causes a schistic tissue splitting between the OPL and Henle fiber layer (HFL); the schistic cavities are traversed by bundles of Henle fibers. The central outer retina is not or little affected. (D) Time-dependent enlargement of a foveal pseudocyst in an eye with macular pucker. The schisis between the OPL and HFL developed along with the thickening of the inner layers of the parafovea and the elevation of the inner layers of the foveal walls. (E) Pseudocysts in the human fovea which were produced by anterior traction exerted by the partially detached posterior hyaloid. The traction produced a detachment of the inner Müller cell layer from the HFL/ONL in the foveola. This was associated with a drawbridge elevation of the inner layers of the foveal walls (NFL to OPL) and the formation of a schisis between the OPL and HFL. With the exception of the eye shown in the lowest image, the central outer retina was not or little affected. (F) Two eyes with a retinoschisis in the HFL. In the image above, the splitting was likely produced by traction of the partially detached posterior hyaloid which adhered at the large superficial blood vessel of the left perifovea (arrowhead). (G) Pseudocyst formation by anterior hyaloidal traction. Note the tractionally induced hyperreflectivity of the inner Müller cell layer of the foveola at the first visit. (H) Two different modes of the development of a tractional foveal pseudocyst in one eye. The pseudocyst in the foveola observed at the first visit was caused by anterior hyaloidal traction. After resolution of the cyst resulting from a detachment of the posterior hyaloid from the fovea, macular pucker developed. Tangential contraction of the ERM produced an elevation of the inner layer of the foveola and the inner layers of the foveal walls (NFL to OPL); the latter caused a schistic splitting of the walls between the OPL and HFL. (I) Increase of a foveal pseudocyst produced by anterior hyaloidal traction, resulting in a schistic splitting of the foveal walls between the OPL and HFL. (J) Regeneration of the foveal shape after relief of the vitreofoveal traction. (K, L) Reduction in the size of foveal pseudocysts due to a decrease in the strength of the anterior traction (K) and after detachment of the posterior hyaloid from the fovea (L). (M) Schematic sections through foveas with pseudocysts which were induced by traction of ERM (above) and the partially detached posterior hyaloid which adheres at the foveola (below). The red arrows indicate the anterior traction transmitted by the Müller cells of the foveal walls. Scale bars, 200 μm. ELM, external limiting membrane; EZ, ellipsoid zone; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IZ, interdigitation zone; PRS, photoreceptor segments. (Images are modified after Bringmann, A., Syrbe, S., Görner, K., Kacza, J., Francke, M., Wiedemann, P., Reichenbach, A., 2018. The primate fovea: structure, function and development. Prog. Retin. Eye Res. 66, 49–84; Bringmann, A., Unterlauft, J.D., Wiedemann, R., Rehak, M., Wiedemann, P., 2020c. Morphology of partial-thickness macular defects: presumed roles of Müller cells and tissue layer interfaces of low mechanical stability. Int. J. Retina Vitreous 6, 28 and show unpublished data (A. Bringmann and P. Wiedemann, Leipzig).)

Fig. 5 A hyperreflective glial tissue band near and at the external limiting membrane (ELM) ( arrowheads ) seals and contributes to the regeneration of outer layer defects of the human fovea. The months after the first visit (0) are indicated left of the SD-OCT images. (A) Four eyes with a tractional disruption of the Müller cell cone in the foveola. (B) Foveal regeneration after a tractional detachment and disruption of the Müller cell cone in the foveola. (C) Foveal pseudocysts. (a) Two eyes with foveal pseudocysts produced by anterior hyaloidal traction. Above: Note the stretched stalk of the Müller cell cone between the horizontal layer of the Müller cell cone and the hyperreflective Müller cell band which seals the hole in the central outer retina at the ELM. (b) Two eyes with foveal pseudocysts which were produced by traction of contractile epiretinal membranes (ERM). (c) A foveal pseudocyst produced by anterior hyaloidal traction. The foveal walls kept together by the inner Müller cell layer of the foveola and the ELM. The gap in the central outer nuclear layer (ONL) closed within 4.5 months, likely by a centripetal displacement of the photoreceptor cell somata, despite the sustained presence of the anterior traction which is visible at the irregular foveal contour. In the further course, the thickness of the central ONL increased. (d) Another eye with a foveal pseudocyst which was caused by anterior hyaloidal traction. The foveal walls kept together by the inner Müller cell layer of the foveola and the ELM. The gap in the central ONL closed within 3 months, likely by a centripetal displacement of the photoreceptor cell somata. In the further course, the thickness of the central ONL increased despite a tractional disruption of the inner layer of the foveola. (D) Macular pseudohole (MPH) with foveoschisis produced by traction of epiretinal membranes (ERM) in an eye with macular pucker. The central outer retina kept together only by the ELM. Within 4.5 months after the first visit, the central ONL- and photoreceptor-free area closed, likely by a centripetal displacement of the photoreceptor cell somata mediated by Müller cells. (E) Tractional lamellar holes (TLH). (a) Development of a tractional lamellar hole (TLH) by anterior hyaloidal traction. The traction caused a detachment of the whole foveola from the RPE. After disruption of the junction between the inner layer of the foveola and the right foveal wall, the central outer retina reattached at the RPE. This and the sustained elevation of the inner layers of the foveal walls caused a schistic splitting of the walls between the outer plexiform layer (OPL) and Henle fiber layer (HFL). (b) An OLH which evolved into a TLH within 2.5 months after the first examination. The elevation of the inner layers of the left foveal wall caused a schistic tissue splitting between the OPL and HFL. The hyperreflective glial tissue bridge at the ELM was present 2.5 months after the first visit. The foveal structure regenerated in part after vitrectomy with internal limiting membrane (ILM) peeling performed 2.6 months after the first visit; the regeneration proceeded by a centripetal displacement of the ONL which closed the hole in the central outer retina. (F) Degenerative lamellar holes (DLH). The arrows indicate lamellar macular hole-associated epiretinal proliferation. (a) Various eyes with a DLH. (b) Cystoid macular edema (CME) precedes the development of a DLH. The CME was induced by traction of the partially detached posterior hyaloid which adhered at the foveola. After resolution of the large central cyst (21.5 months), the inner layer of the foveola still underwent traction and was hyperreflective. Thereafter, an ERM developed at the vitreal surfaces of the foveal walls and parafovea. Contraction of the ERM produced a MPH with retinal folds at the vitreal surfaces of the para- and perifovea and a thickening of the foveal walls associated with a centrifugal displacement of the central ONL; the foveal center was composed only by the hyperreflective ELM (71.5 months). Along with the contraction of the ELM, small LHEP developed at the vitreal surfaces of the foveal walls. Thereafter, a large degenerative cavitation developed in one foveal wall due to a degeneration of the INL, OPL, and HFL. The outer layer of the elevated foveal wall, which protruded centripetally above the degenerative cavitation, was the inner plexiform layer (IPL). (c) A DLH with a transient development of a CME. The resolution of the edematous cysts allowed a drop of the elevated inner layers of the foveal walls and resulted in a regeneration of the foveal configuration to a morphology similar to that observed at the first visit. (G) Outer lamellar holes (OLH). (a) The diameter of the hole in the central outer retina decreased between 6 and 12 months after the first examination. This was associated with the formation of a hyperreflective glial tissue band which sealed the hole at the ELM. (b) Tractional generation and partial regeneration of an OLH. Vitrectomy with ILM peeling performed 8.1 months after the first visit removed the vitreofoveal adhesions and caused a drop of the elevated foveal walls associated with a decrease in the diameter of the hole in the outer retina and a reattachment of the central photoreceptors at the retinal pigment epithelium (RPE). The stalk of the Müller cell cone connected the horizontal inner layer of the foveola with the ELM which bridged the hole in the central outer retina. (c) In this OLH, the elevated inner layers of the foveal walls dropped within 3 months after the first visit. This was associated with a disappearance of the schistic cavities in the foveal walls and a decrease in the diameter of the hole in the central outer retina. The hole was sealed by a hyperreflective tissue band at the ELM. (d) After vitrectomy with ILM peeling performed 0.5 month after the first visit, the hole in the central outer retina was sealed by a hyperreflective ELM and a tissue of medium reflectivity, likely composed of Müller cells. Between 4.5 and 9.5 months, the gap in the central ONL closed by a centripetal displacement of photoreceptor cell somata; this was associated with a decrease in the size of the central photoreceptor-free area and a disappearance of the hyperreflectivity of the ELM. (e) Partial restoration of the shape of the central fovea after regeneration of the central ELM in an OLH. The central fovea remained free of photoreceptors and was composed of cystic spaces and a glial tissue of medium reflectivity. (f) Serous macular detachment produced a large OLH. After the nearly complete resolution of the edematous cysts (7.5 months), the foveola did not contain an ONL and photoreceptors. Thereafter, the gap in the central ONL was closed by a centripeal displacement of the photoreceptor cell somata in the ONL, and by the formation of a hyperreflective tissue band which bridged the gap at the ELM. The centripeal displacement of the photoreceptor cell somata was associated with a decrease in the distance between the central ELM and the RPE. There remained a small photoreceptor-free area combined with a hyperreflective ELM and a curved hyperreflectivity in the ONL. The latter may indicate that the outer processes of the Müller cells of the foveal walls were gliotic in this area. The lowest image , which shows the left foveal wall at higher magnification, illustrates that the schisis is localized at the OPL-HFL interface. (H) Spontaneous (a, c) and surgical closure (b, d) of full-thickness macular holes (FTMH) in four eyes. The holes closed by the formation of a hyperreflective tissue band at the ELM. In (a), the hole sealed after spontaneous detachment of the posterior hyaloid from the fovea. In (b) and (d), a subsequent centripetal displacement of the ONL regenerated the foveal structure. Vitrectomy with internal limiting membrane peeling was performed 1.5 (b) and 0.5 months (d) after the first visit, respectively. (I) CME. (a) Two eyes with CME. The large central cysts produced a dehiscence of the ONL in the foveola; the gap in the ONL was bridged by the ELM. Note the elongated photoreceptor outer segments in the detached central foveas. The arrows indicate the adhesions of the partially detached posterior hyaloid. (b) Diabetic CME. The central outer retina kept together by the ELM. Between 6 and 12 months, the thickness of the central ONL increased, likely by a Müller cell-mediated centripetal displacement of the photoreceptor cell somata. Note the structures with medium reflectivity in the fluid of the central cyst which are light reflections at exudates. (c) Diabetic CME caused by anterior hyaloidal traction. The posterior hyaloid adhered at the left foveal wall. (d) Resolution of a CME. (e) Twofold development and resolution of an edematous cyst in the foveola. Scale bars, 200 μm. EZ, ellipsoid zone; GCL, ganglion cell layer; INL, inner nuclear layer; IZ, interdigitation zone; NFL, nerve fiber layer. (Images are modified after Bringmann, A., Unterlauft, J.D., Wiedemann, R., Barth, T., Rehak, M., Wiedemann, P., 2020d. Two different populations of Müller cells stabilize the structure of the fovea: an optical coherence tomography study. Int. Ophthalmol. 40, 2931–2948; Bringmann, A., Unterlauft, J.D., Wiedemann, R., Barth, T., Rehak, M., Wiedemann, P., 2020f. Degenerative lamellar macular holes: tractional development and morphological alterations. Int. Ophthalmol., in press and show unpublished data (A. Bringmann and P. Wiedemann, Leipzig).)

Fig. 6 Tractional development of degenerative lamellar holes (DLH) in human eyes. The months after the first visit (0) are indicated left of the SD-OCT images. The arrowheads indicate lamellar hole-associated epiretinal proliferation (LHEP). The arrows indicate morphological connections between Müller cells in the foveola and LHEP. (A) Unilateral development of a DLH. Traction exerted by an epiretinal membrane (ERM) which lay at the vitreal surface of the right foveal wall caused an alteration of the foveal contour; this likely resulted from a disruption of the connection between the inner Müller cell layer of the foveola to this wall which produced an indentation of the foveal pit between the outer plexiform layer (OPL) and Henle fiber layer (HFL) (first visit and 2.5 months). Until 4.5 months, this indentation developed to a schisis which was associated with a thinning of the HFL/ONL in this part of the foveola and a loss of the integrity of the central photoreceptors, as indicated by the hyporeflectivities of the ellipsoid zone (EZ) and interdigitation zone (IZ) lines. Thereafter, the schisis developed to a degenerative cavitation which was traversed by thin bundles of Henle fibers. Along with the development of the degenerative cavitation, LHEP appeared at the foveal wall and parafovea. Between 23 and 30.5 months, there was an enlargement of a tissue with medium reflectivity at the inner side of the foveola, likely representing proliferating cells of the Müller cell cone. (B) Development of a DLH after a detachment of the foveola from the retinal pigment epithelium (RPE) due to tangential traction of ERM. The detachment of the foveola was associated with a gap in the central ONL which was filled by a tissue composed of Müller cells. Between 1 and 5.5 months after the first visit, LHEP developed at the vitreal surface of one foveal wall. The reattachment of the foveola to the RPE between 5.5 and 35 months was associated with the formation of a DLH characterized by the development of a degenerative cavitation, an increase of the LHEP, and a nearly full absence of photoreceptors in the foveal center which was filled by a tissue composed of Müller cells; this tissue also covered the central surface of one foveal wall. In the further course, the degenerative cavitations below the elevated inner layers of the foveal walls increased; this was associated with a disruption of the connection between the foveolar Müller cells and the edge of the foveal wall. (C) Development of a DLH due to tangential traction of ERM in the parafovea. Contraction of the ERM caused an anterior stretching and thickening of the foveola. A large degenerative cavitation developed via a cystic disruption of the foveola; this was associated with a loss of the integrity of the centralmost photoreceptors (as indicated by the defects of the external limiting membrane [ELM], EZ, and IZ lines) and the formation of LHEP at the inner surface of one foveal wall. A tissue composed of Müller cells covered the vitreal side of the foveola. (D) Development of a DLH due to anteroposterior traction which caused a disruption of the inner Müller cell layer of the foveola and an elevation of the inner layers of the foveal walls. The latter was associated with a schistic splitting of the foveal walls between the OPL and HFL, and cystic cavities in the inner plexiform layer (IPL). The foveola contained a small photoreceptor- and outer nuclear layer (ONL)-free area; this area was filled by a tissue formed by Müller cells. Until the end of the examination period, the tissue composed of Müller cells in the foveola and the LHEP increased, and the connection between both tissues thickened. This was associated with a disappearance of the cyst between the OPL and HFL in this wall. (E) Development of a DLH after surgical treatment of a tractional lamellar hole (TLH). Vitrectomy with internal limiting membrane and ERM peeling was performed 2.5 months after the first visit. Until the end of the examination period, a large cavitation developed in the left foveal wall. An ONL-free part of the foveola was filled by a tissue composed of Müller cells; this tissue had contact to the LHEP at the right foveal wall. (F) Traction of ERM caused the development of a foveal pseudocyst (1.5 months) and a cystoid macular edema (CME; 2.5 and 6 months) before the development of a DLH (7.5 months). A morphological connection developed between the Müller cells in the foveola and the edge of the nonelevated foveal wall which did not contain a degenerative cavitation. (G) Traction of ERM caused a CME (first visit). The resolution of the cysts allowed a drop of the inner layers of the foveal walls and an almost normal restoration of the foveal morphology (2 months). Between 2 and 9.5 months, a DLH developed due to a degeneration of the inner nuclear layer (INL) and OPL in the right foveal wall. Thereafter, a CME episode occurred again which was associated with the formation of LHEP at the vitreal surface of the foveal walls; the ERM continued to the inner hyperreflective layer of LHEP. After 29 months, the DLH was reestablished. The foveal center and the central surface of the left foveal wall were covered by a tissue composed of Müller cells. Between 37 and 42.5 months, a small full-thickness macular hole (FTMH) developed due to the formation of edematous cysts in the INL and between the OPL and HFL which caused a high elevation of the inner layers of the foveal walls that produced an oblique anterior displacement and a detachment of the central outer retina from the RPE. Thereafter, the FTMH closed spontaneously due to the resolution of the edematous cysts which allowed a drop of the elevated inner layers of the foveal walls. At the end of the examination period, the fovea showed again a DLH configuration. (H) Schematic summary of different modes of the development of DLH induced by traction onto the fovea. The blue arrows indicate anterior hyaloidal traction and horizontal traction of contractile ERM, respectively. The red arrows indicate anterior traction exerted by the stretched Müller cells of the foveal walls which causes a detachment of the central outer retina from the RPE. The development of DLH may be preceded by CME, which tractionally disrupts the foveal structure, or traction onto the fovea exerted by the partially detached posterior hyaloid and/or ERM which causes a stretching and thickening of the foveola associated with or not a detachment of the central fovea from the RPE. The traction may also produce foveal pseudocysts or macular pseudoholes (MPH). In addition, surgical treatment of TLH or FTMH may result in the development of DLH. A DLH may evolve into a FTMH. Scale bars, 200 μm. GCL, ganglion cell layer; NFL, nerve fiber layer. (Images are modified after Bringmann, A., Unterlauft, J.D., Wiedemann, R., Rehak, M., Wiedemann, P., 2020c. Morphology of partial-thickness macular defects: presumed roles of Müller cells and tissue layer interfaces of low mechanical stability. Int. J. Retina Vitreous 6, 28; Bringmann, A., Unterlauft, J.D., Wiedemann, R., Barth, T., Rehak, M., Wiedemann, P., 2020f. Degenerative lamellar macular holes: tractional development and morphological alterations. Int. Ophthalmol., in press and show unpublished data (A. Bringmann and P. Wiedemann, Leipzig).)

Fig. 7 Müller cells in thin (peripheral) retinal areas are optical fibers which guide the incoming light to photoreceptor cells. (A) Artist’s view of the optical path through the retina. Light arrives at the inner retinal surface where it hits the Müller cell endfeet. Then it propagates through the Müller cell stem processes (thus bypassing the light-scattering nerve fibers and synapses in the plexiform layers) until it arrives at photoreceptor cells. (B, C) Vertical (B) and horizontal (C) sections through the retina of a guinea pig ( Cavia porcellus ). Müller cells are immunolabeled for vimentin ( green ) and cones are red -stained. (B) The cone inner segments in the receptor segment layer (RSL) appear as continuous with the outer processes of Müller cells which envelop the cone cell perikarya in the outer nuclear layer (ONL). (C) The focus of the horizontal scan is on the outer plexiform layer. The number of cone pedicles ( red ) roughly equals that of Müller cell processes ( green ); often the two elements appear as pairs. Thus, each cone receives its part of the image of the outside world by its individual light-guiding Müller cell. (D) Every Müller cell illuminates a distinct group of photoreceptors (about 10 rods and one cone) in the guinea-pig retina. The focus of the horizontal scan is on the RSL. A laser beam was directed to the endfoot of one Müller cell; the laser-induced illumination of photoreceptor segments is shown in red . (E) Path of a thin laser light beam (diameter, 5 μm; arrows ) through a section of a guinea-pig retina. Laser light which is scattered within the tissue is shown in green . When the laser beam hits a Müller cell endfoot, light scatter within the retinal tissue is almost absent and a narrow light beam arrives at the photoreceptors ( left ). When the laser beam hits spaces between the endfeet/inner processes of Müller cells, considerable light scatter occurs within the retina and the light beam which arrives at the photoreceptors is large and blurred ( right ). GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer. (Images are modified after Reichenbach, A., Bringmann, A., 2013. New functions of Müller cells. Glia 61, 651–678; Reichenbach, A., Bringmann, A., 2017b. Cell biology of retinal glia. In: Schachat, A., Wilkinson, C., Hinton, D., Sadda, S., Wiedemann, P. (Eds.), Ryan's Retina. sixth ed., vol. 1, Part 2. Elsevier London, New York, pp. 451–487.)

1.1: Light guidance through Müller cells

Two retinal adaptations to minimize the retinal light scattering developed during the evolution of the vertebrate eye. It was shown for the retinas of spectacled caimans (Caiman crocodilus fuscus) and nonprimate mammals (Franze et al., 2007; Agte et al., 2011, 2018; Labin et al., 2014), and proposed for the human and avian retina (Labin et al., 2014; Zueva et al., 2014), that Müller cells act as living optical fibers which guide the light with minimal intensity loss through the inner retinal layers toward the photoreceptor cells (Fig. 7A, D). When confocal images are recorded in the reflection mode from freshly isolated wholemounts of the guinea-pig retina or the peripheral human retina, Müller cells remain dark whereas neuronal and vascular elements are visible as bright structures (Fig. 1A, B); this shows that the light goes through Müller cells but back-scattered by neuronal elements (Franze et al., 2007; Prasse et al., 2013). In freshly isolated sections of the guinea-pig retina, projection of a thin laser light beam to sites between Müller cell processes at the inner (vitreal) side of the retina results in light scattering within the IPL and OPL, whereas projection of the beam to Müller cell processes does not cause intraretinal light scattering (Fig. 7E) (Agte et al., 2011). Light scattering increases the size of the receptor field illuminated by the light transmitted through the neuroretina, and decreases the maximum intensity of the transmitted light, while light guidance through Müller cells decreases the size of the illuminated receptor field and increases the maximum intensity of the transmitted light (Fig. 7E) (Agte et al., 2011). These observations suggest that light guidance through Müller cells increases the amount of photons which reach certain photoreceptors and results in an improvement of the signal-to-noise ratio; these effects increase both the sensitivity and acuity of vision (Franze et al., 2007; Agte et al., 2011).

Müller cells, the principal macroglial cells of the vertebrate retina (Müller, 1851; Bringmann et al., 2006; Reichenbach and Bringmann, 2010), are specialized radial glial cells which span the whole thickness of the neural retina, from the internal limiting membrane (ILM) at the vitreal surface to the subretinal space (Figs. 8A and 9C) (Müller, 1856; Reichenbach and Bringmann, 2017a). The somata of Müller cells are located in the INL between the amacrine cell layer (ACL) and bipolar cell layer (BCL); two main (stem) processes radiate from the soma in opposite directions (Figs. 8A, B, 9A, C, and 10A, D). The inner main process ends with a funnel-shaped endfoot or several endfeet if this process split into several branches as in the cone-dominant retinas of many birds and reptiles. The vitreous-facing endfoot membranes of Müller cells together with the basal lamina at the inner retinal surface form the ILM (Retzius, 1871; Wolff, 1937; Pedler, 1961; Heegard et al., 1986). (In clinical studies, only the basal lamina is termed ILM.) Tight-like junctions between Müller and photoreceptor cells constitute the ELM (Fig. 11Jc) (Omri et al., 2010; Matet et al., 2015; Daruich et al., 2018). The ELM is a diffusion barrier for subretinal space-derived proteins with a Stokes’ radius greater than 36 Å (Bunt-Milam et al., 1985). Lateral processes of Müller cells expand into the plexiform layers, where they form sheaths around synapses, and into the nuclear layers where they embed neuronal perikarya (Figs. 8A and 9B, F) (Ramón y Cajal, 1972; Reichenbach et al., 1988a, 1989).

Fig. 8 Glia of the primate retina. (A) Cellular constituents of the retina. Müller cells (M) span the entire thickness of the neuroretina. The perikarya of the cells are localized in the inner nuclear layer (INL). Two stem processes, which originate at the perikaryon, draw in opposite directions to the inner and outer surfaces of the neuroretina. The end of the inner stem process forms a funnel-shaped endfoot in the ganglion cell layer (GCL). In the outer (OPL) and inner plexiform layers (IPL), side branches which form perisynaptic membrane sheaths originate at the stem processes. In the outer nuclear layer (ONL), the outer stem process of Müller cells forms membrane sheaths which envelop the perikarya and axons of rod (R) and cone (C) cells. Microvilli of Müller cells extent into the subretinal space which surround the inner photoreceptor segments (PRS). Both astroglia (AG) and Müller cells contact the blood vessels (BV) of the superficial vascular plexus and the basal lamina of the internal limiting membrane. Microglia (MG) are located in the GCL and plexiform layers. (B) Freshly isolated human Müller cells in suspensions of dissociated retinal cells. The cells were immunostained for aquaporin-4 ( red ; left ) and the α 1C subunit of voltage-gated calcium channels ( red ; right ), respectively. Arrows , cell endfeet. Arrowheads , cell somata. (C, D) Sections through the peripheral retina of a post-mortem human donor without apparent eye disease (C) and a human donor eye which was excised because of the presence of uveal melanoma (D). Cell nuclei are blue -stained. In the healthy retina (C), glial fibrillary acidic protein (GFAP) is expressed by astrocytes localized in the nerve fiber layer and GCL, and around the blood vessels in the GCL and at the IPL-INL interface. In the retina of the melanoma eye (D), astrocytes in the nerve fiber layer (NFL) and astrocytes which surround the vessels of the superficial vascular layer (*) strongly express GFAP. Perivascular astrocytes do not express cellular retinal binding protein (CRALBP). In contrast to the healthy retina, Müller cells express GFAP because they are gliotic due to the melanoma-induced tissue inflammation and retinal detachment. (E) Supervision on the astrocytic network in the NFL/GCL of the peripheral retina of a rhesus macaque ( Macaca mulatta ). Astrocytes are immunolabeled for both vimentin and GFAP; colabeling yielded a yellow merge signal. (F) Supervision on astrocytes and Müller cell endfeet in the NFL/GCL of a peripheral rhesus macaque retina. Astrocytes express GFAP, and Müller cell endfeet express glutamine synthetase (GS), but not GFAP. (G) Vimentin labeling of a section of the peripheral macaque retina. Note the labeling of horizontal Müller cell processes in the OPL. A, amacrine cell; B, bipolar cell; ELM, external limiting membrane; G, ganglion cell; H, horizontal cell; RPE, retinal pigment epithelium. Scale bars, 20 μm. (Images are modified after Goczalik, I., Ulbricht, E., Hollborn, M., Raap, M., Uhlmann, S., Weick, M., Pannicke, T., Wiedemann, P., Bringmann, A., Reichenbach, A., Francke, M., 2008. Expression of CXCL8, CXCR1, and CXCR2 in neurons and glial cells of the human and rabbit retina. Invest. Ophthalmol. Vis. Sci. 49, 4578–4589; Grosche, A., Pannicke, T., Karl, A., Iandiev, I., Francke, M., Wiedemann, P., Reichenbach, A., Bringmann, A., 2012. Physiological properties of Müller cells from human eyes affected with uveal melanoma. Invest. Ophthalmol. Vis. Sci. 53, 4170–4176; Bringmann, A., Syrbe, S., Görner, K., Kacza, J., Francke, M., Wiedemann, P., Reichenbach, A., 2018. The primate fovea: structure, function and development. Prog. Retin. Eye Res. 66, 49–84; Reichenbach, A., Bringmann, A., 2020. Glia of the human retina. Glia 68, 768–796.)

Fig. 9 Müller cells of the mammalian retina. (A) A Golgi-stained Müller cell of a peripheral human retina. The main subcellular compartments are marked. (B) Müller cells ( blue ) envelop retinal neurons ( green ) and retinal capillaries (Cap). (C) Section through the retina of a guinea pig ( Cavia porcellus ). Müller cells are green -stained; photoreceptor segments (PRS) and synapses are blue -stained. The arrowhead indicates Müller cell somata. (D) Supervision onto the inner plexiform layer (IPL) of a guinea-pig retina, illustrating the regular pattern of profiles of Müller cell stem processes ( green ). Synaptic structures are red -stained. (E) View onto the nerve fiber (NFL)/ganglion cell layers (GCL) of the retina of a rat ( Rattus norvegicus domestica ). The superficial vessels of the retina are surrounded by perivascular glial membranes which contain aquaporin-4 water channels ( red ). Blood vessels are blue -stained. (F) Section through the retina of a domestic pig ( Sus scrofa domestica ). Müller cells and some photoreceptor cell nuclei in the outer nuclear layer (ONL) are green -stained. The yellow arrowheads indicate Müller cell somata, the red arrowhead Müller cell endfeet. Note the multitude of glial membrane sheaths which surround the synapses in the IPL. (G) A section of a porcine retina immunostained against the glial marker glutamine synthetase ( green ) and the glial potassium channel Kir4.1 ( red ). Cell nuclei are blue . The somata of Müller cells lie in the mid portion of the inner nuclear layer (INL) ( yellow arrowhead ). The arrows indicate perivascular Kir4.1. The blue arrowhead indicates Kir4.1 localized to vitreous-abutting enfeet membranes of Müller cells. Kir4.1 is also localized to the microvilli extending into the subretinal space in situ . (Images are modified after Bringmann, A., Pannicke,