A2

s2

A13 diffuse

10 um

AII bistrat

A8 bistrat

FIGURE 4-10

Whole-mount view of amacrine cells. (From Kolb H: Amacrine cells of the mammalian retina: neurocircuitry and functional roles, Eye 11:904, 1997.)

between these layers (Figure 4-11), apparently providing feedback from inner to outer retinal layers.51,57 Some of their nerve endings are presynaptic and some are postsynaptic to amacrine processes or amacrine cell bodies in the inner plexiform layer. Interplexiform neurons are presynaptic to rod or cone bipolar cells in the outer plexiform layer.2,8,65

NEUROGLIAL CELLS

Neuroglial cells, although not actively involved in the transfer of neural signals, provide structure and support and have a role in the neural tissue reaction to injury or infection. Types of neuroglial cells found in the retina include Müller cells, microglial cells, and astrocytes.

Müller Cells

Müller cells are large neuroglial cells that extend through­ out much of the retina. There are 10 million Müller cells in the mammalian retina.66 They play a supportive role, providing structure. The apex of the Müller cell is in the photoreceptor layer, whereas the basal aspect is at the inner retinal surface. Cellular processes form a reticulum among the retinal cell bodies and fill in most of the space of the retina not occupied by neuronal elements

(Figure 4-12). Müller cells ensheathe dendritic processes within the synaptic layers, giving structural support, and their processes envelop most ganglion axons.67

Neuronal cell bodies and their processes appear to reside in tunnels within the Müller cell.52 Delicate apical villi, fiber baskets (of Schultze), terminate between the inner segments of the photoreceptors.1,29 On light microscopy, Müller cell processes can be seen passing through the layer containing the nerve fibers of the ganglion cells, perpendicular to the retinal surface. An expanded process, called the endfoot, along the basal aspect of the Müller cell contributes to the membrane separating the retina from the vitreous, and extensions of Müller cells wrap around blood vessels.1 The pervasiveness of the Müller cell results in very little extracellular space in the retina (see Figure 4-12). Besides providing structure, the Müller cell acts as a buffer by regulating the concentration of potassium ions (K+); they help maintain the extracellular pH by absorbing metabolic waste products68; they recycle GABA and glutamate, removing them from the extracellular space; and Müller cells metabolize, synthesize, and store glycogen.69-71

Microglial Cells and Astrocytes

Microglial cells are wandering phagocytic cells and might be found anywhere in the retina. Their number increases in response to tissue inflammation and injury.

Astrocytes are star-shaped fibrous cells found in the inner retina, usually in the nerve fiber and ganglion cell layers. These perivascular cells form an irregular supportive network that encircles nerve fibers and retinal capillaries.1 They may contribute to the internal limiting membrane as well as perform some of the same functions as the Müller cells.72

T E N R E T I N A L L A Y E R S

The “10-layered” arrangement of the retina is actually a remarkable organization of alternate groupings of the retinal neurons just described and their processes. Traditionally, descriptive names were given to these socalled layers, and these designations are still in use today (­ Figure 4-13).

1.Retinal pigment epithelium

2.Photoreceptor cell layer

3.External limiting membrane

4.Outer nuclear layer

5.Outer plexiform layer

6.Inner nuclear layer

7.Inner plexiform layer

8.Ganglion cell layer

9.Nerve fiber layer

10.Internal limiting membrane

Internal limiting membrane

Nerve fiber layer

Ganglion cell layer

Inner plexiform layer

Inner nuclear layer

Outer plexiform layer

Outer nuclear layer

External limiting membrane

Photoreceptor

layer

Retinal pigment epithelium

Ganglion

cell

Interplexiform

neuron

Amacrine

cell

Horizontal

cell

Bipolar

cell

Rod

Cone

FIGURE 4-11

Retinal cells and synapses. The 10 retinal layers are indicated.

RETINAL PIGMENT EPITHELIUM

The RPE consists of a single layer of pigmented cells, as previously discussed. There are 4 to 6 million­

RPE cells, and each cell interacts with 30 to 40 ­photoreceptors.37,73,74 There is little cell division in the layer. The RPE is an active area with several functions that will be described in a later section.

photoreceptor cells and between photoreceptors and Müller cells at the level of the inner segments. On light microscopy, the so-called membrane appears as a series of dashes, resembling a fenestrated sheet through which processes of the rods and cones pass. This band of zonula adherens has the potential to act as a metabolic barrier restricting the passage of some large molecules.8,75

PHOTORECEPTOR LAYER

The photoreceptor layer contains the outer and inner segments of rods and cones. Projections from the apical surface of Müller cells extend into the photoreceptor layer and separate the inner segments.

EXTERNAL LIMITING MEMBRANE

The external limiting membrane (ELM, outer limiting membrane) is not a true membrane but is actually composed of zonula adherens junctions between

OUTER NUCLEAR LAYER

The outer nuclear layer (ONL) contains the rod and cone cell bodies; the cone cell body and nucleus are larger than those of the rod. Cone outer fibers are very short, and therefore the cone nuclei lie in a single layer close to the external limiting membrane; cell bodies of the rods are arranged in several rows inner to the cone cell bodies. The ONL is 8 to 9 cells thick on the nasal edge of the optic disc and 4 rows thick at the temporal edge and is thickest in the fovea, where it contains approximately 10 layers of cone nuclei.2

Internal limitimg mem.

Nerve fiber l.

Ganglion cell l.

Internal plexiform l.

Internal nuclear l.

External plexiform l.

a–Radial processes

b–Honeycomb meshwork

External nuclear l.

c–Horizontal fibers

d–Fiber baskets

External limiting mem.

FIGURE 4-12

Structure of the Müller cell (dark gray). mem., membrane; l., layer. (From Hogan MJ, Alvarado JA, Weddell JE: Histology of the human eye, Philadelphia, 1971, Saunders.)

OUTER PLEXIFORM LAYER

The outer plexiform layer (OPL; also outer synaptic layer) has a wide external band composed of inner fibers of rods and cones and a narrower inner band consisting of synapses between photoreceptor cells and cells from the inner nuclear layer. Rod spherules and cone pedicles synapse with bipolar cell dendrites and horizontal cell processes in the OPL. Many of these synapses consist of invaginations in the photoreceptor terminal; invaginations are deep in the spherule but more superficial in the pedicle.8 In these junctures the photoreceptor element contains a membranous plate, the synaptic ribbon8,59 (Figure 4-14). The invaginating synapse generally has three postsynaptic processes and is called a triad. The lateral elements are horizontal cell processes and are deep within the invagination, a bipolar dendrite is the center process (see Figure 4-6). Invaginating

Internal

limiting membrane Nerve fiber

layer Ganglion cell

layer

IPL

INL

OPL

ONL

External limiting membrane

Photoreceptor layer

Retinal pigment epithelium

FIGURE 4-13

Light micrograph of full-thickness view of the retina.

midget bipolar cells are involved in cone triads, and all cones have at least one invaginating midget bipolar and one flat midget bipolar contact.8

Synaptic contacts also occur outside invaginating synapses in the OPL. Horizontal cells make synaptic contact with bipolar dendrites and contact other horizontal cell processes via gap junctions.61,76 Bipolar dendrites synapse with photoreceptor cell endings; a single photoreceptor can have contact with more than one bipolar dendrite. The relatively long axon of the interplexiform neuron makes numerous synaptic connections with processes entering photoreceptor terminals.65,77

Desmosome-like attachments called synaptic densities are located within the arrangement of interwoven, branching, bipolar dendrites and horizontal cell processes in the OPL. These synaptic densities are seen as a series of dashed lines on light microscopy and resemble a discontinuous membrane, termed the middle limiting membrane. This “membrane” demarcates the extent of the retinal vasculature29 and may prevent retinal exudates and hemorrhages from spreading into the outer retinal layers.52

INNER NUCLEAR LAYER

The inner nuclear layer (INL) consists of the cell bodies of horizontal cells, bipolar cells, amacrine cells, interplexiform neurons, Müller cells, and sometimes displaced ganglion cells. The nuclei of the horizontal cells are located next to the outer plexiform layer, where their processes synapse. The nuclei of the amacrine cells are located next to the inner plexiform layer, where their processes terminate. The bipolar cell has its dendrite in the

FIGURE 4-14

Electron micrograph of cone pedicle. Note dark linear bodies (synaptic ribbons) in pedicle. (×20,000.) (From Leeson CR, Leeson ST: Histology, Philadelphia, 1976, Saunders.)

outer plexiform layer and its axon in the inner plexiform layer (Figure 4-15). The interplexiform neuron also has processes in both synaptic layers. It is thought to receive input in the inner plexiform layer and project it to the outer plexiform layer.65 The retinal vasculature of the deep capillary network is located in the inner nuclear layer.

INNER PLEXIFORM LAYER

The inner plexiform layer (IPL; also inner synaptic layer) consists of synaptic connections between the axons of bipolar cells and dendrites of ganglion cells. The IPL contains the synapse between the second-order and third-order neuron in the visual pathway (see Figure 4-15). Generally, the axon of the invaginating midget bipolar cell ends in the inner half of the IPL, and the axon of the flat midget bipolar cell ends in the

FIGURE 4-15

Arrangements of synaptic contacts found in vertebrate retinas.  In outer synaptic layer, processes from bipolar (B) and horizontal cells (H) penetrate into invaginations in receptor terminals (RT) and terminate near synaptic ribbons (lamellae) of receptor. Processes of flat bipolar cells (FB) make superficial contacts on bases of some receptor terminals. Horizontal cells make conventional synaptic contacts onto bipolar dendrites and other horizontal cell processes (not shown). Because horizontal cells usually extend farther laterally in outer synaptic layer than do bipolar dendrites, distant receptors presumably can influence bipolar cells via horizontal cells.

In the inner synaptic layer, two basic synaptic pathways are suggested. Bipolar terminals may contact one ganglion cell dendrite and one amacrine process at ribbon synapses (left side) or two amacrine cell (A) processes (right side). When the latter arrangement predominates in a retina, numerous conventional synapses between amacrine processes (serial synapses) are observed, and ganglion cells (G) are contacted

mainly by amacrine processes (right). Amacrine processes in all retinas make synapses of conventional type back onto bipolar terminals (reciprocal synapses). (From Dowling JE: Organization of vertebrate retinas, Invest Ophthalmol 9:655, 1970.)

outer half of the IPL.51,54 Synapses also occur between

(1) amacrine processes and bipolar axons, (2) amacrine processes and ganglion cell bodies and dendrites, (3) amacrine cells, and (4) amacrine cells and interplexiform neurons (Figure 4-16). The processing of motion