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Kolb H, Fernandez E, Nelson R, editors. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-.

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Webvision: The Organization of the Retina and Visual System [Internet].

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Cone Pathways through the Retina

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Created: ; Last Update: July 1, 2009.

Circuitry for Cone Signals

Cone photoreceptors are the sensors of bright light and different wavelengths of light in the retina. They are sensitive in photopic (bright light) conditions and come in several types according to the structure of the visual pigments or opsins in their outer segment regions. In dichromatic animal species there are two types of visual pigments in two types of cone (most mammals): cones sensitive to blue light and cones sensitive to red-green light. In trichromatic animal species (some primates and man) there are three types of cone according to their visual pigments (see chapter on photoreceptors). These are long wavelength (red), medium wavelength (green) and short wavelength (blue) sensitive cones (Fig. 1).

Figure 1. Confocal micrograph to show the cones of the monkey retina.

Figure 1

Confocal micrograph to show the cones of the monkey retina. Monkey retinal sections were triple immnunolabeled with antibodies against alpha-synuclein in red, and arrestin and rhodopsin in green to show the entire morphology of cones (green, elongated (more...)

The circuitry whereby cone signals pass through the retina to the ganglion cells is rather different from that of the rod pathways. The first difference is at the outer plexiform layer. The cones synapse upon various cone bipolar types rather than on a single type like the rod system. Thus at the outer plexiform layer a choice of pathways is already installed for the cone system. As we have already mentioned (section on the OPL), cone bipolars come in varieties distinguished by the size of their dendritic field (midget, diffuse, and large-field diffuse) and by their different types of synaptic contact with the cone pedicles i.e. invaginating-ribbon synapses, semi-invaginating basal junctions or non-ribbon related basal junctions (see section on OPL).

Vertebrate photoreceptors are in a depolarized state in darkness and are hyperpolarized by light (1). Thus it is thought that the neurotransmitter glutamate is released continuously in the dark and is suppressed by light (Fig. 2).

Figure 2. Schematic drawing of the cone synapses to bipolar and horizontal cells.

Figure 2

Schematic drawing of the cone synapses to bipolar and horizontal cells.

Different glutamate receptor types appear on depolarizing ON- and hyperpolarizing OFF-center bipolar cells (2). The OFF-bipolar receptor appears to be related to the AMPA-kainate type and so is a common, excitatory, ionotropic glutamate receptor (iGluR). In contrast the ON-type bipolar cells have metabotropic receptors (mGluR) that bind selectively the glutamate agonist APB (or AP4, 2-amino-4-phosphonobutyrate), and are insensitive to AMPA-kainate ligands. Application of APB selectively hyperpolarizes their membrane potentials and suppress the light-responses of ON-center bipolar cells (3, 4). The receptor at the ON-bipolar cell is now thought to be mGluR6 (5, 6). Receptor-activated G-proteins, originally thought to mimic the cyclic-GMP cascade occurring in photoreceptors are the underlying mechanism of transduction in ON-center bipolar cells (7, 8). Most recently, good evidence has been provided for a subunit of the transducin molecule, GalphaO, to be the second messenger in the ON-center bipolar cell activation pathway (9, 10).

Thus, we know that the cone bipolar types that make central ribbon contacts or narrow-cleft, semi-invaginated contacts have the metabotropic glutamate receptors (Fig. 3) and will be ON-center (center-depolarizing) types (ON BC), while cone bipolar cells that make wide-cleft basal junctions (OFF BC) will have the ionotropic glutamate receptors (Fig. 3) and will respond to light like the photoreceptor itself, i.e. will be OFF-center (centre-hyperpolarizing) types (11) (see movie of the intracellular recordings).

Figure 3. Drawing of the organization of the photoreceptor synapse showing the different glutamate receptors that are presently known to be on the various postsynaptic dendrites.

Figure 3

Drawing of the organization of the photoreceptor synapse showing the different glutamate receptors that are presently known to be on the various postsynaptic dendrites.

Movie 1. A movie of the intracellular recordings.

Movie 1

A movie of the intracellular recordings.

Some years ago it was demonstrated by electron microscopy and 3-D reconstruction of cone bipolar profiles in the inner plexiform layer of the cat retina, that these bipolar axons make most of their ribbon output synapses to ganglion cell dendrites (12) (Fig. 4 and Fig. 5).

Figure 4

Figure 4

Electron micrograph of a cone bipolar axon terminal

Figure 5. Reconstructions from electron microscopy of ON- and OFF- center beta cells of cat area centralis.

Figure 5

Reconstructions from electron microscopy of ON- and OFF- center beta cells of cat area centralis.

Bipolar cell axons that terminated in sublamina a of the inner plexiform layer (closer to the amacrine cell bodies) made ribbon synapses exclusively with dendrites of ganglion cells that had dendrites in this sublamina. In fact, such bipolar cell axons did not even reach down far enough to contact ganglion cells in sublamina b of the IPL. The ganglion cells branching in sublamina a were known from Nelson and coworkers findings (13) to give OFF-center responses to light flashes.

Conversely the cone bipolar cells with axons in sublamina b of the inner plexiform layer (closer to the ganglion cell bodies) made ribbon synapses only upon the dendrites of ganglion cells that branch in sublamina b. Again, Nelson et al. (13) had shown that such ganglion cells were ON-center in response to light flashes (Fig. 6) (see the movie of the intracellular recordings).

Figure 6. Intracellular responses of ON-center and OFF-center ganglion cells.

Figure 6

Intracellular responses of ON-center and OFF-center ganglion cells.

Movie 2. A movie of the intracellular recordings.

Movie 2

A movie of the intracellular recordings.

In the human retina the common cone bipolar cells are, like the cat, classified not only by the nature of their synapses with cone pedicles, but also by which sublamina of the IPL their axons terminate in. Thus, some of the cone bipolar types send axons to sublamina a (fb types) and others to sublamina b (ib types) of the IPL.

We expect that like the cat, human cone bipolar cells with axons in sublamina a will connect to OFF-center (center-hyperpolarizing) ganglion cells and bipolar cells with axons in sublamina b will connect to ON-center (center-depolarizing) ganglion cells (Fig. 7).

Figure 7. Schematic drawing of the cone bipolar subtypes.

Figure 7

Schematic drawing of the cone bipolar subtypes.

Thus a major difference in the circuitry of the cone compared the rod pathways in the mammalian retina is that cone bipolar cells make direct synapses with ganglion cell dendrites, without the need for intermediate amacrine cell circuitry as occurs in the rod pathway (see previous chapter). The cone pathways are, therefore, both more direct and more narrow-field and convergent than the rod pathways. Fewer cones converge onto cone bipolars than rod to rod bipolars and then only a relatively small number of cone bipolar cells converge onto their ganglion cells. The ultimate in low convergence ratio is the midget system in the human and primate retina, which we shall deal with separately in another section (Fig. 8).

Figure 8. Convergence of cones and bipolar cells upon ON- and OFF- center beta cells.

Figure 8

Convergence of cones and bipolar cells upon ON- and OFF- center beta cells.

Cone Pathways Mediate Successive Contrast (ON and OFF Pathways)

Cone pathways in mammalian and human retinas run as two parallel streams of information directly from the cone photoreceptor to the ganglion cell through the straight pipe-line, the cone bipolar cell. What is the reason for two parallel channels for the cone system when the rod system had only one? The answer is that this organization allows one channel to provide information to the ganglion cell concerning brighter than background stimuli (the ON-center channel) and the other, darker than background stimuli (the OFF-center channel) as first demonstrated by Kuffler (14) in 1953 from recordings of ganglion cells in the cat retina.

As we have seen above the anatomical substrate for the origins of these two important ON-center and OFF-center channels in the bipolar cell is in the types of synaptic contacts cone bipolar cells make with cone pedicles in the mammalian retina (see above) (11, 12, 15). The hyperpolarizing bipolar types are the start of OFF-center channels and the depolarizing types are the start of ON-center channels through the retina (Fig. 9.).

Figure 9. Stimuli for ON and OFF center channels.

Figure 9

Stimuli for ON and OFF center channels.

The ribbon synapse of the cone bipolar cells to the ganglion cell dendrites in the IPL, is considered to be an excitatory synapse and so, the type of signal in the ganglion cell, (either ON- or OFF-center) is essentially determined by the nature of the cone bipolar cells contacting it. Thus the complete circuit to carry the message concerning brightness and darkness through the retina in the cat is shown below (Fig. 10) (see an animation of the cone circuits.).

Figure 10. Circuits concerning brightness (left) and darkness (right) processing through the retina.

Figure 10

Circuits concerning brightness (left) and darkness (right) processing through the retina.

Movie 3. An animation of the cone circuits.

Movie 3

An animation of the cone circuits.

Cones hyperpolarize to light but two bipolar channels, one carried by a depolarizing bipolar (orange cell and light response) and the other by a hyperpolarizing bipolar (yellow cell and light response), split the original cone signal into lightness or ON-center and darkness or OFF-center. These bipolar responses are transmitted directly to ganglion cells architecturally separated to the different sublaminae of the inner plexiform layer, resulting in one channel of ganglion cells with dendrites in proximal retina (sublamina b) becoming ON-center and the other types with dendrites only in distal retina (sublamina a) becoming OFF-center.

Cone Pathway Circuits Mediate Simultaneous Contrast (Center-Surround Receptive Fields)

Information concerning the overall brightness or darkness of the image is of primary importance for visual sensation, but putting these two informations in simultaneous contrast to each other greatly improves the resolution of the image.

Simultaneous contrast is achieved by lateral inhibition where a dark boundary inhibits a light area or vice versa. In the retina, an important finding by Hartline (16) from frog optic nerve recordings first described retinal ganglion cell receptive fields as concentric with a response of opposite sign to the center found in a surround of the receptive field (Fig. 11).

Figure 11. Center-surround receptive fields.

Figure 11

Center-surround receptive fields.

It is thought that horizontal cells at the OPL provide, through a mechanism of lateral inhibition, a surround arranged around the receptive field center of firstly the photoreceptor itself and then the bipolar cell contacting the photoreceptor (17-19). The wiring responsible appears to start at the small local circuit we saw in the cone triads at the ribbon synapses (see the chapter on the outer plexiform layer) (Fig. 12).

Figure 12

Figure 12

Electron micrograph of a cone triad (59 K jpeg image)

Thus, the negative feedback synapse of the horizontal cell to the cone photoreceptor at the ribbon triad synapse allows the larger receptive field of the horizontal cell network (horizontal cells are coupled in a syncytium across the retina by electrical synapses between neighboring cells. Like horizontal cells are coupled to each other) to provide a surround to the narrow central cone response (20). This concentric organization is then transmitted to the bipolar cells making contact with the cone (21) and thence to the ganglion cell that the cone bipolar cell contacts (see the movie of the mechanism of lateral inhibition on a stimulated cone).

Movie 4. A movie of the mechanism of lateral inhibition on a stimulated cone.

Movie 4

A movie of the mechanism of lateral inhibition on a stimulated cone.

The diagram in Fig. 13 summarizes the architecture for center surround organization by means of horizontal cell to cone bipolar cell circuits in the cone bipolar system of the mammalian retina. The center pathway is created by the cone to bipolar to ganglion cell through-channel, while the injection of horizontal cell information provides an antagonistic surround to the center: an OFF-surround for the ON-center channel (horizontal cell and orange bipolar, left hand pathway) and an ON-surround for the OFF-center channel (horizontal cell and yellow bipolar, right hand pathway (19, 22) (see the animation of the formation of surrounds for cone bipolar and ganglion cells).

Figure 13. Diagram of organization of center-surround circuits using horizontal cell circuitry.

Figure 13

Diagram of organization of center-surround circuits using horizontal cell circuitry.

Movie 5. An animation of the formation of surrounds for cone bipolar and ganglion cells.

Movie 5

An animation of the formation of surrounds for cone bipolar and ganglion cells.

In mammalian retinas, surround responses are not as strong a component of bipolar cell receptive field as they are in cold-blooded vertebrate bipolars (11). Compare for instance the bipolar responses from a Turtle retina (23) with those of a cat retina (11) in Fig. 14 and Fig. 15.

Figure 14. Bipolar cell recordings in turtle retina.

Figure 14

Bipolar cell recordings in turtle retina.

Figure 15. Bipolar cell recordings in cat retina.

Figure 15

Bipolar cell recordings in cat retina.

We know from intracellular and extracellular recordings of cat and monkey ganglion cells (14, 24-27) that the commonest mammalian ganglion cells have a strong center surround organization. Thus, it is possible that additional surround antagonism to the bipolar driven center response of a ganglion cell, is constructed by certain, as yet not fully understood, amacrine cell networks in the inner plexiform layer (Fig. 16).

Figure 16. Diagram of the organization of center-surround circuits using both horizontal cells and amacrine cells.

Figure 16

Diagram of the organization of center-surround circuits using both horizontal cells and amacrine cells.

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