Glial Cells of the Retina

Kolb H.

Publication Details

Three basic types of glial cell are found in the human retina: Muller cells, astroglia, and microglia. All were described for the retina by Cajal (1) more than 100 years ago in 1892.

Muller Cells

Muller cells are the principal glial cell of the retina. They form architectural support structures stretching radially across the thickness of the retina and are the limits of the retina at the outer and inner limiting membrane, respectively. A complete understanding of the shape of a Muller cell is best seen after Golgi staining, as shown originally by Cajal (1) below (Fig. 1).

Figure 1. Golgi-stained Muller cells.

Figure 1

Golgi-stained Muller cells. From Cajal (1).

Muller cell bodies sit in the inner nuclear layer and project irregularly thick and thin processes in either direction to the outer limiting membrane and to the inner limiting membrane. Muller cell processes insinuate themselves between cell bodies of the neurons in the nuclear layers and envelope groups of neural processes in the plexiform layers. In fact, retinal neural processes have direct contact, without enveloping Muller cell processes, only at their synapses.

A single progenitor cell gives rise to both Muller cells and retinal neurons (2), although apparently in two phases. The earliest phase neurons born at the apical margin of the neuroepithelium, adjacent to the pigment epithelium, produces primary neurons consisting of cone cells, horizontal cells, and ganglion cells. The second phase of cells, also born at the apical margins, produces Muller cells and rod photoreceptors, bipolar cells and amacrine cells (3). All of the developing neurons and the Muller cells have to migrate inward to their final position, and it is thought that the Muller cell processes and trunks guide much of the neuron migrations and direct the neurite differentiations (Fig. 2).

Figure 2. 3-D schematic drawing of the relationship between Muller cell and other retinal neurons.

Figure 2

3-D schematic drawing of the relationship between Muller cell and other retinal neurons.

The junctions forming the outer limiting membrane are between Muller cells and other Muller cells with photoreceptor cells as sturdy desmosomes' coronial adherents. In some species, gap junctions (specialized membrane associations and channels that allow passage of small molecules and ions) or tight junctions are part of these Muller cell junctions (4) but not so in mammalian species, where no dye coupling has ever been observed (3, 5). The surface of the Muller cell facing the pigment epithelium and subretinal space is expanded by many projections of the Muller cell membrane, known as apical villi. The inner limiting membrane, on the other hand, is formed by the conical endfeet of the Muller cell, but no specialized junctions are seen here. Muller cells also form endfeet on the large retinal blood vessels at the inner surface of the retina. The surface of the Muller cell membrane facing the vitreous is covered with a mucopolysaccharide material and thus forms a true basement membrane.

Muller cells contain glycogen, mitochondria, and intermediate filaments that are immunoreactive for vimentin and to some extent to glial fibrillary acidic protein (GFAP). The latter filaments are normally in the inner half of the Muller cells and their endfeet, but after trauma to the retina, such as retinal detachment, both vimentin and GFAP are massively upregulated and found throughout the cell (see below) (6, 7) (Fig. 3).

Figure 3. GFAP immunoreactivity in Muller cells.

Figure 3

GFAP immunoreactivity in Muller cells. From Fisher and Lewis (7).

Muller cells have a range of functions, all of which are vital to the health of the retinal neurons. Muller cells function in a symbiotic relationship with the neurons (for an excellent review, see Reichenbach and Robinson (3)). Thus, Muller cell functions include:


Supplying end products of anaerobic metabolism (breakdown of glycogen) to fuel aerobic metabolism in the nerve cells.


They mop up neural waste products, such as carbon dioxide and ammonia, and recycle spent amino acid transmitters.


They protect neurons from exposure to excess neurotransmitters, such as glutamate, using well-developed uptake mechanisms to recycle this transmitter. They are particularly characterized by the presence of high concentrations of glutamine synthase.


They may be involved in both phagocytosis of neuronal debris and release of neuroactive substances such as GABA, taurine, and dopamine.


They are thought to synthesize retinoic acid from retinol (retinoic acid is known to be important in the development of the eye and the nervous system) (8).


They control homeostasis and protect neurons from deleterious changes in their ionic environment by taking up extracellular K+ and redistributing it.


They contribute to the generation of the electroretinogram (ERG) b-wave (4, 9), the slow P3 component of the ERG (10), and the scotopic threshold response (STR) (11). They do so by regulation of K+ distribution across the retinal vitreous border, across the whole retina, and locally in the inner plexiform layer of the retina (see figure below from Reichenbach and Robinson (3), adapted from Newman (12)) (Fig. 4).

Figure 4. Regulation of K+ by Muller cells in Muller cells.

Figure 4

Regulation of K+ by Muller cells in Muller cells.


Astrocytes are not glial cells of the retinal neuroepithelium but enter the developing retina from the brain along the developing optic nerve (13, 14). They have a characteristic morphology of a flattened cell body and a fibrous series of radiating processes. Intermediate filaments fill their processes, and thus they stain dramatically with antibodies against GFAP (15). Astrocyte cell bodies and processes are almost entirely restricted to the nerve fiber layer of the retina. Their morphology changes from the optic nerve head to the periphery: from extremely elongated near the optic nerve to a symmetrical stellate form in the far peripheral retina (15) (Fig. 5 and Fig. 6).

Figure 5. Astrocytes in peripheral retina.

Figure 5

Astrocytes in peripheral retina.

Figure 6. Astrocytes in central retina.

Figure 6

Astrocytes in central retina. From Schnitzer (15).

In Golgi and immunocytochemical staining, they look like cell bodies with fibrous tangles aligned along the ganglion cell axons coursing through the nerve fiber layer. In distribution, astrocytes reach their peak on the optic nerve head and have a fairly uniform decline in density in radiating rings from the nerve head. They are not present in the avascular fovea or ora serrata (Fig. 7).

Figure 7. HRP staining of astrocytes in the ganglion cell layer.

Figure 7

HRP staining of astrocytes in the ganglion cell layer.

Thick and thin astrocytes have been distinguished on the basis of staining with antibodies to GFAP (16). Thus, astrocytes are arranged over the surface of the ganglion cell axon bundles as they course into the optic nerve head, forming a tube through which the axons run. Gap junctions and zonula adherens junctions have been described between astrocytic processes in cat retina (17).

The blood vessels running in and among the ganglion cell bundles are also covered by both processes and even an occasional cell body of an astrocyte. The function of astrocytes enveloping ganglion cell axons and the relationship to blood vessels of the nerve fiber layer suggest they are axonal and vascular glial sheaths and part of a blood-brain barrier. Similar to Muller cells, they are known to contain abundant glycogen, and they may form a nutritive service in providing glucose to the neurons. In addition, they probably serve a role in ionic homeostasis in regulating extracellular potassium levels and metabolism of neurotransmitters like GABA (Fig. 8).

Figure 8. 3-D block of astrocytes arranged over the surface of ganglion cell axon bundles.

Figure 8

3-D block of astrocytes arranged over the surface of ganglion cell axon bundles. From Trivino et al. (16).

Microglial Cells

The third glial cell type is supposedly of mesodermal origin and thus, strictly speaking, are not neuroglial as the astrocytes and Muller cells are. They enter the retina coincident with the mesenchymal precursors of retinal blood vessels in development (14). Microglial cells are ubiquitous in the human retina, being found in every layer of the retina.

In Golgi-stained retina, they look like strange, multipolar forms with small cell bodies and irregular short processes. In fact, in Golgi preparations they have sometimes been mistaken for nerve cells, particularly when they lie in a nuclear layer with a single orientation of their processes in the plexiform layer (Fig. 9).

Figure 9. Golgi staining of microglial cells.

Figure 9

Golgi staining of microglial cells.

Microglial cells may be of two types. One form is thought to enter the retina at earlier stages of development from the optic nerve mesenchyme and lie dormant in the retinal layers for much of the life of the retina. The other form of microglia appear to be blood-borne cells, possible originating from vessel pericytes (18, 19). Both types can be stimulated into a macrophagic function on trauma to the retina, and then they engage in phagocytosis of degenerating retinal neurons (Fig. 10).

Figure 10. Lectin-stained microglial cell.

Figure 10

Lectin-stained microglial cell. From Chan-Ling (14).


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