Chapter 99 – Structure and Function of the Neural Retina
HERMANN D. SCHUBERT
The primary purpose of the corneoscleral and uveal coats of the eye is to focus light on the retina; they also provide protection and nourishment and enable movement. The retina is derived embryologically from the optic vesicle, an outpouching of the embryonic forebrain. The bilayered neuroepithelial structure of the mature retina reflects the apex-to-apex arrangement of the original optic cup. It also forms the wall of a cavity, the vitreous cavity, which is filled with glycosaminoglycans and collagen. The ocular cavity is homologous to a leptomeningeal cistern, in that both vitreous and choroid are derived from mesenchyme that sandwiches the neuroepithelium on its path away from the brain. The ocular neuroepithelial cyst has two openings. Anteriorly lies the pupil, which is a full-thickness aperture, and posteriorly lies the optic nerve in which, similar to a coloboma, only derivatives of the inner retinal layers are found. Since the cell apices are oriented inwardly, the two layers of the optic cup and their derivatives are enveloped externally by basement membrane ( Fig. 99-1 ).
The relationship of the epithelial layers to each other is modified from anterior to posterior. Anterior to the ora serrata, the pigmented and nonpigmented epithelia of the iris and ciliary body are joined at their apices by a system of intercellular junctions ( Fig. 99-2 ), which is continuous with the external limiting layer of the neural retina and the apical junctional girdles of the retinal pigment epithelium (RPE; Fig. 99-3 ). At the ora serrata, the pigmented epithelium is continued as RPE; its basement
Figure 99-1 Apex-to-apex arrangement of müllerian glia and retinal pigment epithelial cells. Because the cell apices face each other, the neuroepithelia are enveloped externally by a basement membrane. Note that this basement membrane is elaborated by a single-layer neuroepithelium, with the exception of the internal limiting membrane, which is formed by Müller cells.
membrane becomes Bruch’s membrane. The nonpigmented epithelium of the ciliary body and pars plana is continued posteriorly as the neural retina; its basement membrane becomes the internal limiting membrane. The union of the epithelial layers delimits the anterior cul-de-sac of the subretinal space.
Figure 99-2 Apex-to-apex arrangement of retina and pigment epithelium. Apical attachments connect the iris and ciliary body epithelia (red line).
Figure 99-3 Transition of neural retina to nonpigmented epithelium at the ora serrata. The external limiting membrane, which consists of the attachment sites of photoreceptors and Müller cells, transforms into the apical junctional system of the pars plana epithelia. The internal limiting membrane becomes the basement membrane of the nonpigmented epithelium.
Figure 99-4 Structures of the retina that border the optic nerve head. The junctional system of the external limiting membrane connects with the apical junctional system of the retinal pigment epithelium and is supported by the intermediary border tissue of Kuhnt.
The apex-to-apex arrangement between the epithelia that clearly exists anterior to the ora is continued posteriorly by Müller cells that face and intermittently contact the RPE (see Fig. 99-1 ). Here, the contact is maintained not by apical junctions (even though an interreceptor matrix exists) but by the pressure of the vitreous and by suction forces of the RPE. Müllerian glia are the main structural cells of the neural retina and are found throughout the retina from the ora to the optic nerve head.
At the optic nerve head, the internal limiting membrane continues as the basement membrane of Elschnig, supported by the glial meniscus of Kuhnt ( Fig. 99-4 ). The (glial) external limiting membrane joins the apices of the RPE to form the posterior cul-de-sac of the subretinal space, which is supported by a glial border tissue, the intermediary border tissue of Kuhnt. This border tissue continues posteriorly at the choroidal level as the border tissue of Elschnig; both tissues separate the outer retina and choroid from the axons of the inner retina. The axons in turn fixate the posterior retina to the scleral lamina cribrosa and its glial system. The retina, therefore, is fixed to the choroid directly by the apical junctional system at the ora serrata (anterior cul-de-sac of the subretinal space) and indirectly, via the choroid and ciliary body, to its attachments at the scleral spur and sclera. At the nerve head, all neuroepithelial and choroidal layers are fixed by both the junctional tissues and the exiting axons. The corneoscleral coat protects, moves, and holds the retina in the appropriate position and allows the object of regard to be focused on the center of the retina.
CENTER OF THE MACULA: UMBO
The fovea represents an excavation in the retinal center and consists of a margin, a declivity, and a bottom ( Fig. 99-5 ). The bottom corresponds to the foveola, the center of which is called the umbo. The umbo represents the precise center of the macula, the area of retina that results in the highest visual acuity. Usually, it is referred to as the center of the fovea or macula. Although both terms are commonly used clinically, neither is a precise anatomical designation.
The predominant photoreceptor of the foveola and umbo is the cone. The foveal cones result from the centripetal migration of the first neuron and the centrifugal lateral displacement of the second and third neurons during foveal maturation, which occur 3 months before and 3 months after term. Although their individual
Figure 99-5 Foveal margin, foveal declivity, foveola, and umbo. The foveal diameter (from margin to margin) measures 1500?µm, and the foveola is 350?µm in diameter. The foveal avascular zone is slightly larger (500?µm) and is delimited by the capillary arcades at the level of the inner nuclear layer. The foveal excavation represents the fovea interna, which is lined by the internal limiting membrane. The fovea externa is represented by the junctional system of the external limiting membrane. Both Henle’s fibers and the accompanying glia assume a horizontal and radial arrangement in the fovea.
Figure 99-6 Umbo (center) and foveola. The outer nuclear layer is separated from the inner nuclear layer by the horizontal-oblique fibers of Henle. Umbo and foveola between few nuclei feature clear müllerian fibers (clear tissue), delimited by Henle’s fibers externally and by the internal limiting membrane internally. The central 150–200?µm represents the umbo, where cone concentration is maximal.
diameters are narrowed because of extreme crowding, central cones maintain their volume through elongation, up to a length of 70?µm. The central migration takes place in an area of 1500?µm diameter. The greatest concentration of cones is found in the umbo, an area of 150–200?µm diameter, referred to as the central bouquet of cones. Estimates of central cone density are 113,000 and 230,000 cones/mm2 in baboons and cynomolgus monkeys, respectively. For the central bouquet, the density of cones may be as high as 385,000 cones/mm2 . The inner cone segments are connected laterally by a junctional system, the external limiting membrane. Their inner fibers (axons) travel radially and peripherally as fibers of Henle in the outer plexiform layer ( Fig. 99-6 ). As a result of their high concentration and crowding, the central cones have their nuclei arranged in multiple layers in a circular shape, which resembles a cake (gateau nucleaire).
Cones, including their inner and outer segments, are surrounded and enveloped by the processes of müllerian glia, which concentrate on the vitreal side (tissu clair), just underneath the internal limiting membrane. Some glial cell nuclei are found in this inner layer, but most form part of the laterally displaced inner nuclear layer. Foveal development, therefore, involves the migration, elongation, concentration, and displacement of both neuronal cells and, most importantly, glial cells,
the main structural element of the retina. Radiating striae found in the foveal internal limiting membrane are related to Henle’s fibers but are probably mediated by glia that elaborate and are connected to the internal limiting membrane. The density of the foveal glia has been measured as 16,600–20,000 cells/mm2 . 
The bouquet of central cones is surrounded by the foveal bottom, or foveola, which measures 350?µm in diameter and 150?µm in thickness (see Fig. 99-5 ). This avascular area consists of densely packed cones that are elongated and connected by the external limiting membrane. As a result of the elongation of the outer segments, the external limiting membrane is bowed vitreally, a phenomenon that has been termed fovea externa. Both umbo and foveola represent the most visible part of the outer retina; however, to the level of the external limiting membrane, all cones and their axons are enveloped by the processes of Müller cells, which form the vitreal inner layer and elaborate and support the internal limiting membrane. Thus, the apex-to-apex arrangement of the optic cup is maintained by the processes of müllerian glia that face the apices of the pigment epithelial cells in the foveola. The high metabolic demands of central cones are met by direct contact with the pigment epithelium, as well as through the processes of glia whose nuclei lie more peripheral in the inner nuclear layer and closer to the perifoveal vascular arcades (see Fig. 99-6 ).
In pathological conditions, loss of the normal foveolar reflex may indicate a glial disturbance (acute nerve cell damage, cloudy swelling) either primarily or mediated by the vitreous, which is tightly adherent to the thin internal limiting membrane. Loss of the foveal reflex may thus indicate traction or edema of glial cells and, secondarily, of cones. The inner glial layer may separate from the nuclear layer, which results in cyst-like schisis.
The fovea consists of the thin bottom, a 22° declivity (the clivus), and a thick margin (see Figs. 99-5 to 99-7 ). The bottom, or foveola, was described earlier. The declivity of 22° denotes the lateral displacement of the second and third neurons in the inner nuclear layer, which includes most of the nuclei of its müllerian glia. The avascular foveola is surrounded by the vascular arcades, a circular system of capillaries. These vessels are located at the level of the internal nuclear layer and leave an avascular zone of 250–600?µm between them. The declivity also is associated with an increase in basement membrane thickness, which reaches a maximum at the foveal margin. Internal limiting membrane thickness and strength of vitreal attachment are inversely proportional; that is, adhesions are strongest in the foveola. Not surprisingly, the foveal center is most affected in traumatic macular holes in which glial opercula suggest anterior-posterior traction as the cause. The margin of the fovea (margo foveae) is often seen biomicroscopically as a ring-like reflection of the internal limiting membrane, which measures 1500?µm (disc size) in diameter and 0.55?mm in thickness (see Fig. 99-7 ).
The parafovea is a belt that measures 0.5?mm in width and surrounds the foveal margin (see Fig. 99-7 ). At this distance from the center, the retina features a regular architecture of layers, which includes 4–6 layers of ganglion cells and 7–11 layers of bipolar cells.
The perifovea surrounds the parafovea as a belt that measures 1.5?mm wide (see Fig. 99-7 ). The region is characterized by several layers of ganglion cells and six layers of bipolar cells.
Figure 99-7 Normal fundus with macula encompassed by major vascular arcades. The macula, or central area, has the following components from center to periphery: umbo, foveola, fovea, parafovea, and perifovea.
MACULA, OR CENTRAL AREA
The umbo, foveola, fovea, parafovea, and perifovea together constitute the macula, or central area. The central area can be differentiated from the extra-areal periphery by the ganglion cell layer. In the macula, the ganglion cell layer is several cells thick; however, in the extra-areal periphery, it is only one cell thick. The macular border coincides with the course of the major temporal arcades and has an approximate diameter of 5.5?mm (see Fig. 99-7 ), which comprises the diameter of the fovea (1.5?mm), twice the width of the parafovea (2 × 0.5 = 1?mm), and twice the width of the perifovea (2 × 1.5 = 3?mm).
The peripheral retina is divided arbitrarily into belts of near, middle, far, and extreme periphery. The belt of the near periphery is 1.5?mm wide, and the belt of the middle periphery, or equator, is 3?mm wide. The far periphery extends from the equator to the ora serrata. The width of this belt varies, depending on ocular size and refractive error. The average circumference of the eye is 72?mm at the equator and 60?mm at the ora serrata, and the average width of this belt is 6?mm. Since peripheral retinal pathology is usually charted in clock hours, 1 clock hour corresponds to 5–6?mm of far peripheral circumference. Therefore, the far periphery of the retina may be divided into 12 segments that measure approximately 6 × 6?mm. As a result of the insertion of the posterior vitreous base, most peripheral pathology falls into these segments. The ora serrata and pars plana are referred to as the extreme periphery.
Figure 99-8 Neuronal connections in the retina and participating cells. The inner nuclear layer contains the nuclei of the bipolar cells (second neuron) and müllerian glia. The amacrine cells are found on the inside and the horizontal cells on the outside of this layer, next to their respective plexiform connections.
LAYERS OF THE NEURAL RETINA
With the exception of the fovea, ora serrata, and optic disc, the neural retina is organized in layers, dictated by the direction of the müllerian glia, its organizational backbone. Essentially, there is the photoreceptor layer plus the bipolar and ganglion cell layer, which represent the outer first neuron and inner second neuron of the visual pathway. The müllerian glia elaborate the internal limiting membrane as its basement membrane and extend to the external limiting membrane, where it communicates with the apices of the RPE ( Fig. 99-8 ).
The inner nuclear layer is home to the nuclei of the müllerian glia, the bipolar cells, and the horizontal and amacrine cells. The amacrine cells lie on the inside of the inner nuclear layer, and the horizontal cells lie on the outside (see Fig. 99-8 ). The inner nuclear layer has plexiform layers on either side, which connect it to the outer photoreceptor layer and the (inner) ganglion cell layer. From this simple anatomical consideration, it follows that rods and cones synapse with bipolar and horizontal cells in the outer plexiform layer. As a result of the increased length of Henle’s fibers, the junctional system (the middle limiting “membrane”) is found in the inner third of the outer plexiform layer, which is the only truly plexiform portion of this layer. The bipolar cells and amacrine cells of the inner nuclear layer synapse with the dendrites of the ganglion cells in the inner plexiform layer. In embryogenesis, müllerian glia, along with their internal limiting membrane and orientation, antedate photoreceptor differentiation; this is analogous to the rest of the central nervous system, in which structural development precedes individual cell differentiation.
PHOTOTRANSDUCTION AND VISUAL PROCESSING
The retina’s function is to both capture external light and process the resultant stimuli. Both these tasks are highly complex and incompletely understood. Despite its relatively small size and compact structure, the morphology of the neural retina is extraordinarily complicated, a reflection of the complexity of its basic tasks.
The capture of a photon of light and its conversion into an electrical signal is called phototransduction, and it is accomplished within the outer segments of the photoreceptors—the rods and cones. The photopigment molecules that are the biochemical basis for phototransduction reside in the membranes of the photoreceptors’ outer segment discs. In the rods, rhodopsin is the primary photopigment, and it best absorbs photons with a wavelength of 500?nm (blue–green). Cone pigments are referred to collectively as iodopsin; there are three types, with absorption peaks in the blue, green, and yellow parts of the spectrum. Each cone normally contains only one of the three varieties of pigment molecules. Various stimulatory combinations of these three types of pigments are responsible for color vision perception.
All the photoreceptor cells respond to the capture of light energy with a hyperpolarization. The bipolar and horizontal cells represent the site of second-order information processing and communicate with the photoreceptors via the exchange of chemical neurotransmitters. In the dark-adapted state, photoreceptors are depolarized and release neurotransmitters. Hyperpolarization brought on by the capture of light energy results in a reduction in the release of neurotransmitters. As in other parts of the central nervous system, glutamate represents the major excitatory neurotransmitter, but it is likely that many others exist.
Higher-order processing in the neural retina is accomplished via the ganglion cells, the dendrites of which connect to bipolar cells within the inner plexiform layer. Amacrine cells further process the signal. Neuromodulation is probably accomplished via extracellular influences of the Müller cells.
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