General Characteristics

Today's research on the retina focuses a great deal of attention on neurotransmission between the neurons of the retina. Various techniques using autoradiography, immunocytochemistry and molecular biology are being used to mark neurons for neurochemicals, their synthesizing enzymes, calcium binding proteins and receptors and transporters of these neurochemicals. Cells immunostained with antibodies to the various neurotransmitter candidates give particularly spectacular images by confocal microscopy because they become stained to their finest dendrites and so can be readily classified against their Golgi-stained equivalents. Furthermore, the whole population of neurotransmitter specific neurons are stained so one can understand their topographical organization into mosaics across the entire retina. Some immunocytochemistry for the common neurotransmitter candidates has been performed on the human retina (1, 2) but most have been done in the cat, rabbit and mouse retinas and so far the findings are the same in general. The consistency of cell types staining across species boundaries, in mammals at least, suggest that most, with a few exceptions, of the neurotransmitters, neuromodulators and neuropeptides discovered in nonhuman retinas are present in human retina too.

The Neurotransmitter of Neurons of the Vertical Pathways through the Retina is Glutamate

Glutamate is the neurotransmitter of the neurons of the vertical pathways through the retina. All photoreceptor types, rods and cones, use the excitatory amino acid glutamate to transmit signals to the next order neuron in the chain (see chapter on glutamate and Massey (3) for review). There was originally some evidence for the closely related amino acid, aspartate, being present in rods but the later sophisticated techniques of demonstrating amino acid signatures in retinal neurons cannot confirm aspartate as a retinal neurotransmitter at all (4). Uptake, release and action of glutamate and agonists upon second-order neurons in slice preparations or isolated cells in tissue culture have also all confirmed glutamate to be the neurotransmitter acting at the first synapse in the retina (see Lasater and Lam (5) for review). The action of the photoreceptor neurotransmitter upon the second-order neurons is through two different types of sensory channels though. The one type of postsynaptic receptor type is the metabotropic glutamate channel (mGluR6) that involves a second messenger cascade and cyclic GMP for activation of the channel (in the ON-center bipolar cell) whereas the other is an ionotropic channel via at least two types of AMPA receptors and Na ions (OFF-center bipolar and horizontal cells) (6-9). Photoreceptors in most vertebrates including human, havea content of D2 dopamine receptors somewhere upon there surface (10).

Glutamate is also considered to be the neurotransmitter of all bipolar cells and most ganglion cells in the vertebrate retina including the monkey retina (Kalloniatis and Marc, personal communication and Marc et. al. (4)). In an immunocytochemical study of the human retina a similar conclusion was drawn by us. All the ganglion cells appeared to label strongly with antibodies to glutamate (2) (see Fig. 1).

Figure 1

Distribution of Glutamate immunoreactivity in human retina.

Bipolar cells have receptor channels that are either of the metabotropic type, mGluR6,(APB sensitive) or ionotropic type (AMPA) at their dendrites in the OPL, while their axonal ending in the IPL have channels and receptors for GABA (A, B and C types), D1 dopamine and glycine because, of course, all kinds of amacrine cells are presynaptic at these sites in the IPL neuropil. Ganglion cells are as diverse in receptor sensors as the bipolar cells with the addition of receptors to acetylcholine (11), and the first appearance in the retina of NMDA glutamate receptors that are typical in the brain (12, 13).

Amacrine cells

Recently an amacrine cell type has also been shown to contain the glutamate transporter, vesicular glutamate transporter 3, shortened to VGLUT3 (14, 15). VGLUTs are used to concentrate cystolic glutamate into the synaptic vesicles. Typically in the retina the VGLUT1 isoform is expressed in photoreceptors and bipolar cells and the VGLUT2 in ganglion cells. The amacrine cell type that can be immunostained to the antibody to VGLUT3 is found to be a small-field amacrine cell with varicose processes that are restricted in branching to the OFF laminae (S1 and S2) of the IPL (Fig. 2A). It is also immunoreactive to the transmitter glycine as seen in Fig. 2, B and C, but not reactive for GABA, dopamine (Fig. 3, A-C) or acetylcholine. Fig. 3, A-C, shows that the dopamine cell and its dendrites run above the branches of the VGLUT3 cell and indeed appear to be able to make synaptic contact with the cell bodies of the latter cell type, in the way we know dopamine cell processes do (see below and amacrine cell chapter). The VGLUT3 amacrines appear to be in a good position to interact with OFF center ganglion cell, stained for MAP-1, dendrites as shown in Fig. 3, D-F.

Figure 2

VGLUT3 immunostaining (A, red) shows a small-field amacrine cell. It also Immunostains for glycine (B,C).

Figure 3

A-C, VGLUT3 cell has dendritic branching in S1 and S2. Dopamine cells branch above the main plexus of the VGLUT3 cell. D-F, The MAP-1 ganglion cells (red) branch in the same layers as the dendrites of the VGLUT3 cell.

Electron microscopy of VGLUT3 dendrites in the IPL, indicate that they are postsynaptic to OFF cone bipolar cell axons (Fig. 4B) and presynaptic to OFF ganglion cell dendrites (Fig. 4A).

Figure 4

Electron microscopy of VGLUT3 immunostained processes in the IPL of the rat retina.

Recent evidence from the metabolic mapping technique of Marc and Jones (16) indicates that a dopaminergic amacrine cell type also has a content of glutamate. However, from the above evidence on VGLUT3 immunostaining it is clear that the dopaminergic type 1 cell does not use that particular vesicular glutamate transporter.

Gamma Aminobutyric Acid

The classical inhibitory neurotransmitter gamma aminobutyric acid (GABA) occurs in many different varieties of amacrine cells, and in one or more classes of horizontal cell in most vertebrate retinas (4). There is still some controversy over whether GABA is contained within horizontal cells in monkey and human retina.

In this figure (Fig. 5a) taken from human peripheral retina, it can be seen that there is heavy staining with antibodies to GABA in the inner plexiform layer (three heavier bands can be discerned) and in about half of the amacrine cell bodies in the lower row of amacrine cells in the inner nuclear layer. Some displaced amacrines and interplexiform cells are also revealed with GABA immunocytochemistry (2). However, the horizontal cells are not stained at all in peripheral retina although they are in foveal retina apparently (Cuenca, personal communication).

Figure 5a

Expression pattern of GABA immunoreactivity in human retina.

A valuable identification of individual cell types that contain GABA has come from double staining techniques upon Golgi stained cell types (17). The amacrine cell that are contain GABA are all of the large-field types. Thus we know now that A10, A13, A17, A19, and the interplexiform cell accumulate GABA and probably use it as their primary neurotransmitter (Fig. 5b). Many large field amacrine cells also colocalize GABA with another neurotransmitter. Thus the GABAergic A17 colocalizes serotonin, the acetylcholine (starburst amacrine) colocalizes GABA and so does the dopamine A18 cell (18). Neuropetides (see later) are also commonly colocalized with GABA i.e. substance P in A22 is almost certainly the secondary transmitter to GABA as the primary. GABAergic amacrine cells and IPCs act upon bipolar, amacrine and ganglion cell processes or cell bodies in the neuropils of the retina via all the three varieties of GABA receptors (a, b and c types). It appears clear that A17 type or the type that makes reciprocal synapse with the rod bipolar axon terminal uses a GABAc receptor (see chapter by Haohua Qian) (19). However, for most amacrine cells, what GABA receptors are associated with which morphological or physiological subtype of amacrine cell, still need more elucidation.

Figure 5b

Large-field amacrine cells in all retinas use gabaergic transmission. Illustration of large-field cell types in cat retina.

Glycine

The other classic inhibitory neurotransmitter glycine, accounts for most of the small-field types of amarine cell. All amacrine cells in the vertebrate retina can be accounted for by the two inhibitory neurotransmitters GABA and glycine (4). In addition one or more types of bipolar cell are also thought to contain glycine in mammalian retinas including monkey and human.

In Fig. 6 it can be seen that the immunostaining for glycine is just as strong in the inner plexiform layer as GABA staining. About the same number of amacrine cells are revealed. However there is an addition of some small bipolar cell bodies in the inner nuclear layer and the occasional large cell body of a ganglion cell type in the ganglion cell layer (2).

Figure 6

Expression pattern of glycine immunoreactivity in human retina.

Pourcho and Goebel (20) showed quite clearly that tritiated glycine accumulated in Golgi stained AII, A4, and A8 cells in cat retina. More recently as many as 10 different morphological types of small field amacrine cells have been demonstrated by immunocytochemistry and GFP (green fluorescent protein) staining in mouse retina (21, 22). The A8 cell was the most strongly glycinergic of the small field amacrine cells according to Pourcho and Goebel, with the rod amacrine AII cell being also very clearly glycinergic. Fig. 7 shows the commonest glycinergic amacrine cells present in the mouse retina (22). These cells are presumably also so in the cat and primate retinas.

Figure 7

Expression of glycine immunoreactivity in small-field amacrine cells of mouse retina. A-B, aII amacrine cells; C, Type 2 cell (A2 cell); D, Type 3 cells (A4 cell); E, Type 4 cell (A6 cell); F, Type 7 cell (A9? cell): G, A8 cell (Kolb et al. (24)). (Adapted (more...)

Glycine receptors are found on all the neurons that are postsynaptic to these glycinergic (all small-field) amacrine cells. Thus receptors are found on certain bipolar cell axons, and on many amacrine and ganglion cell dendrites. Again like for the GABA receptors, linking receptor type to morphological type of postsynaptic cell is still a hot topic for research in the retina (22, 23).

Dopamine Is Present in Amacrine Cells in the Mammalian Retina

The neuromodulator dopamine is found in one or more types of amacrine cell in the mammalian retina. The most robustly stained dopaminergic cell after immunocytochemistry to the rate limiting enzyme of dopamine synthesis, tyrosine hydroxylase (Toh), is recognized as an A18 cell of the Golgi descriptions (24, 25) (Fig. 8).

Figure 8

Immunostaining with antibodies to TOH. A18 amacrine cells stain and have overlapping dendrites that form into rings.

It is very characteristic in wholemount appearance, with a large cell body and a dense plexus of dendrites in stratum 1 of the inner plexiform layer. Holes or "rings" in the plexus of criss-crossing stained dendrites are sites of amacrine cell bodies or large amacrine dendrites (see chapter on amacrine cells) on which the processes of the Toh stained plexus synapse. The Type 1 dopamine cell (A18) is known to synapse upon the AII rod amacrine cell and possibly also upon A8 and A17 cells (26-29).

A second type of dopamine amacrine cell has also been described in the monkey and human retinas (2, 30). The Type 2 CA cell has dendrites stratifying in stratum 3 of the IPL and in vertical views of Toh processed human retinas these dendrites can be seen quite clearly below those of the Type 1 (A18) dendritic plexus in stratum 1 (orange arrows, Fig. 9).

Figure 9

Vertical section of a type 1 TOH+ amacrine cell.

Type 1 dopamine cells provide ascending processes to the outer plexiform layer (see above) which are known to synapse on the GABAergic interplexiform cell (see previous chapter on feed-back loops).GABA and dopamine colocalize to the A18 cell type (Type 1 CA cell) and serotonin has also been found to co-exist in in the same amacrine cells in cat retina (31).

Both D1 and D2 receptor types have been found on neurons of the inner and outer retina in many vertebrates. It is thought that the D1 receptor is particularly associated with cells that are coupled by gap junctions, because of dopamine's known action in cyclic AMP regulation of gap junction channels (32). Thus D1 receptors have been demonstrated in association with horizontal cells of the OPL and some amacrine cells of the IPL. D1 receptors are robust on ganglion cell bodies as well (personal observations), despite the fact that the dopamine amacrine cell is not known to make direct synapses upon ganglion cells. D2 receptors are also found in the retina associated with photoreceptors in the outer nuclear layer, outer limiting membrane and retinal pigment epithelium even. Also they are present in the IPL but the target cells in this neuropil are not well understood yet.

Acetylcholine

The classic fast excitatory neurotransmitter of the peripheral nervous system, acetylcholine (ACh), is found in a mirror symmetric pair of amacrine cells in the vertebrate retina. In the rabbit such cells have been named starburst cell (33, 34). One of the mirror pair occurs in the amacrine cell layer with dendrites in sublamina a (OFF sublamina of the IPL). The other of the pair has its cell body displaced to the ganglion cell layer and its dendrites stratify in sublamina b (ON sublamina of the IPL).

These ACh containing amacrine cells are common to almost all vertebrate retinas and have been described morphologically in human retina too (25, 35) (see previous chapter on amacrine cells). Both muscarinic and nicotinic receptors have been demonstrated in the mammalian retina, particularly associated with transient phasic ganglion cells (Y cells) (36, 37) and effects of ACh and antagonists on ganglion cell responses are documented but not well understood (Fig. 10).

Figure 10

ACh containing amacrine cell stained with Lucifer yellow.

Serotonin

There are two types of serotonin-accumulating amacrine cell in the rabbit retina (38). One of these is almost certainly the A17 cell or the reciprocal amacrine cell of the rod system in the rabbit (see previous chapters) (Fig. 11). However, in cat retina, a completely different amacrine cell type stains with antibodies against serotonin. One cell type in cat is similar to the wide-field cell A20, while the other may be the A18 or dopamine cell (31). Even where serotonin is strongly demonstrated in these amacrine cells in rabbit retina, it is not thought to be the neurotransmitter.

Figure 11

Serotonin accumulating amacrine cells in rabbit retina known as A17 GABAergic cells in cat and primate retinas.

Serotonin co-exists with GABA, in the A17 cell and the latter is thought to be the releasable transmitter (18, 39). A few cold-blooded vertebrates have a bistratified amacrine cell and a bipolar cell type that immunostain for serotonin (40, 41).

Adenosine May Be a Retinal Neurotransmitter

The purine nucleotide, adenosine may be a neurotransmitter or neuromodulator in the mammalian retina. Autoradiography and immunocytochemistry for adenosine has revealed cell bodies in the amacrine and ganglion cell layers (42). Probably most of these cells are amacrine cells but some in the ganglion cell layer may be true ganglion cells. In human retina additional cells that could be bipolar or horizontal cell label too. K+ and light evoked release of adenosine can be measured in rabbit and chick retinas. And the vertical pathway neurotransmitter glutamate can induce adenosine release from [³H]-adenosine preloaded rabbit retina. Additionally some effects of adenosine on the ERG generated in the retina and on the activity of ganglion cell terminals in the superior colliculus have been recorded and the information points to the strong likelihood that adenosine does play a neurotransmitter role in the vertebrate retina (See review by Blazynski and Perez (42)). Adenosine colocalizes with GABA, acetylcholine and serotonin in various retinas. Much more research is needed in this area.

Substance P Occurs in an Amacrine Type and a Ganglion Cell Type

Substance P (SP) is a neuropeptide belonging to the tachykinin family that include neurokinin A, neuropeptide K and neurokinin B, as well. Substance P is thought to be a neurotransmitter or neuromodulator in the vertebrate retina (See Kolb et al. (43) for a review).

SP-IR amacrine cells appear to be of a single type in the human retina (Fig. 12). They are large-field cells with large cell bodies (16 um diameter) lying in normal or displaced positions on either side of the inner plexiform layer (IPL).

Figure 12

Substance P containing amacrine cell in human retina.

Their sturdy, spiny and appendage-bearing dendrites stratify in stratum 3 (S3) of the IPL, where many overlapping fine dendrites intermingle to form a plexus of stained processes. Either cell bodies or primary dendrites emit "axon-like" process which divides typically into two long, fine processes that run in opposite directions for hundreds of microns in S5 and S3 before disappearing as distinct entities in the stained plexus in S3. Long fine dendrites also pass from the dendritic plexus to run in S5 and down to the nerve fibre layer to end as large varicosities at blood vessel walls. In addition fine processes are emitted from the dendritic plexus that run in S1, and some pass up to the outer plexiform layer (OPL) to run therein for short distances. The SP-IR amacrine cell has many similarities to thorny type 2 amacrine cells described in Golgi studies. SP amacrine cells co-localize GABA as a neurotransmitter (44).

In addition to the SP-IR amacrine cells, a ganglion cell type is immunostained with SP (Fig. 13). Its 20- 22 um cell body gives rise to a radiate, sparsely-branched, wide-spreading dendritic tree running in S3. Its dendrites and cell body become enveloped by the more intensely SP-IR processes and boutons from the SP-IR amacrine cell type (Fig. 13, fine arrows). The SP-IR ganglion cell type most resembles G21 of a Golgi study. A ganglion cell type in rabbit retina has definitely been proved to contain substance P. Such ganglion cells almost certainly colocalize a more standard neurotransmitter like glutamate too (45).

Figure 13

Substance P containing ganglion cell in human retina.

Other Neuropeptides

Immunostaining with antibodies against somatostatin has revealed a small population of neurons in the ganglion cell layer in the rabbit retina (46). They are distributed only in the inferior retina and in the far peripheral circumference of the retina. However, in the monkey and human retinas these amacrines are more uniformly distributed. The somatostatin-IR amacrines have long fibers that distribute across the entire retina running in three plexuses in the middle and outer and inner strata of the inner plexiform layer (Fig. 14, from Marshak (47)). In the human and monkey most of the somatostatin-IR cells have their cell bodies in the ganglion cell layer (Fig. 14) and they emit fibers or axon-like processes that can be measured running 20 mm across the entire retina (48). Because these axon like processes stay within the retina, not passing to the optic nerve, the somatostatin-immunoreactive cells are likened to the associational neurons of Cajal (49).

Figure 14

Somatostatin-IR amacrine cells of the monkey retina (47).

Corticotropin releasing factor (CRF) is contained within a population of wide-field tristratified amacrines with long axon like processes, very similar in morphology to those containing somatostatin (Fig. 15) (47). Colocalization of the two peptides has not been attempted yet but it seems probably that they are one and the same cell type.

Figure 15

Vertical section of CRF-IR amacrine cells are probably the same type as those labelling with somatostatin (47).

Vasoactive Intestinal peptide (VIP) immunostains a population of amacrine cells that can be normally place in the INL or displaced to the ganglion cell layer (Fig. 16). They appear to have a medium size dendritic field and dendrites that branch diffusely through the middle strata of the IPL. They may be equivalent to the A12 type of Mariani (50).

Figure 16

Vasoactive Intestinal peptide-IR amacrine cells of the monkey retina (47).

Amacrine cells that immunostain for neuropeptide Y are quite regularly stained in the primate and rodent retina. These amacrine cells have a characteristic sparsely branched wide-field dendritic tree with dendrites running in stratum 1 of the IPL (Fig. 17) (47). Recent research wherby NPY amacrine cells can be selectively ablated indicates that these cells have a role in low spatial frequency tuning of certain large ganglion cell types (51). Both ON and OFF center ganglion cell types are said to be equally affected by loss of NPY amacrine cells, which is a strange finding considering the OFF stratum branching of these particuar amacrine cells. Presumably another chain of amacrine cells is involved in spatial tuning of ganglion in addition to the NPY type.

Figure 17

Vertical section of neuropeptide Y-IR amacrine cells are wide-field and unistratified in stratum 1 of the IPL (47).

Using antibodies to the glycine extended form of cholecystokinin, Marshak and colleagues were able to demonstrate the presence of two different morphological types of amacrine cell and a single morphological type of bipolar cell in the monkey retina (47, 52). The amacrines come as pairs that are either bistratified in the strata 2 and 4 and a larger bodied monstratified pair, again branching in either stratum 2 or 4 (Fig. 18). The blue cone specific bipolar cell is well characterized by CCK immunostaining and its distribution, contact with blue cones specfically and its probably ON center physiology is now well known (52, 53) (see chapter on S-cone pathways).

Figure 18

Two type of amacrine (1 and , ) and a type of bipolar cell known to contact blue cones is immunostained with the peptide cholecystokinin (47).

NADPH-Diaphorase Staining and the Possibility That There are Nitric Oxide Containing Neurons in the Retina

Nitric oxide is formed in many nerve cells of the peripheral and central nervous system. It is known to play a role in second messenger cascades by activating guanylyl cyclase and elevating cyclic GMP levels. Since many neurotransmitters and transduction events utilize cyclic GMP in the retina (notable phototransduction in the photoreceptors and activation of metabotropic glutamate receptors) the idea that nitric oxide might play a key role in retinal neurotransmission has been forwarded. Nitric oxide synthase the enzyme required for synthesis of nitric oxide requires NADPH as a cofactor in the cell. Thus the simple histochemical technique to reveal NADPH in a cell by the reduction of tetrazolium salts has proved to be a good marker of neurons that contain NADPH-diaphorase and hence possibly also nitric oxide synthase. An antibody has been made against the synthase but staining and identification of morphological cell types that contain this enzyme have been unsatisfactory to date for the retina. Thus the NADPH-diaphorase histochemical technique is still more reliable.

In monkey retina, three types of amacrine cell and one type of ganglion cell appear clearly stained with NADPH-diaphorase. The commonest type is the one shown above (Fig. 19 and Fig. 20) and occurs at a maximum density of 280 cell/mm2 at 1 mm from the fovea (Cuenca, personal communication). It has a large cell body that lies either in the amacrine cell layer or can be displaced to the ganglion cell layer. The dendrites radiate out from the cell body like the spokes of a wheel, contain, many fine spines, and lie on one plane in stratum 3 of the IPL. Fine axon like processes arise from the main dendritic tree that is about 300 um in diameter to run for mm in all directions. The cell is probably the equivalent of a spiny amacrine described by Mariani (50) and a cell type stained by Dacey as axon bearing (54).

Figure 19

NADPH-diaphorase histochemical staining of an amacrine cell in monkey retina.

Figure 20

Drawing from wholemount retina stained with NADPH-diaphorase of the commonly stained amacrine cell.

Amacrine Cell Populations and Mosaics Arrangements Are Revealed by Neurotransmitter Immunocytochemistry

Table 1 lists the amacrine cell types that have now become associated with particular neurotransmitter substances in the mammalian retina. The list is compiled primarily from data of cat and rabbit retinas. However, some clearly recognizable amacrine cell types of the monkey and human retina have been included. The list is as yet incomplete concerning an exact classification of each cell type by neurotransmitter signature because of the difficulty of agreeing on correspondence between different authors classification schemes and making cross species comparisons. The review article by Vaney (18) is the most comprehensive treatment on the subject of the differences between cat and rabbit retina in this regard.

Table 1

Common neurotransmitter substances found in mammalian amacrine cells

Immunocytochemical staining of amacrine cells, when done on wholemounts of retina, can reveal every cell of the population that are immunoreactive to the antibody used. Thus we are increasingly acquiring population maps and distribution maps of all the different types of amacrine cells according to neurotransmitter content. Most amacrine types are arranged in regular mosaics and the individual cells have certain overlap characteristics that can be calculated from nearest neighbor statistics. The cat and monkey amacrine mosaics peak in cell density with closest packing of their smallest dendritic trees in the fovea or area centralis. Then from center to periphery the neurons distribute evenly in concentric rings of decreasing density and increasing dendritic field sizes. The rabbit amacrine mosaics peak along the horizontally-organized visual streak and fall off therefrom linearly into superior and inferior retina (18). Some of the more sparsely distributed neurotransmitter types, have unique distributions. For example, the somatostatin-immunoreactive associational neurons in rabbit retina are located almost exclusively in inferior retina.

The commonest amacrine cell type of the cat and rabbit retina is the glycinergic AII amacrine (estimated 512,000 total in cat retina) followed by the serotonin-accumulating amacrines (between 170,000 and 230,000 cells in rabbit), cholinergic cells (approximately 130,000 in rabbit retina) and substance P-containing cell types (39,000 cells in cat retina). Dopaminergic amacrine cells are some of the lowest density populations of cells (3-5,000 in cat; 6-8,000 in rabbit). Somatostatin occurs in a small population of only 1000 cells in rabbit retina (Fig. 21).

Figure 21

Summary diagram of the organization of neurotransmitters in the retina.

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