Cone Pathways Through the Retina
[Circuitry for cone signals]
[ON and OFF pathways]
[Simultaneous contrast]
[References]
1. 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. Figure 01 shows cone photoreceptors stained throughout with an antibody to alpha-synuclein and arrestin so they clearly visible in section of the monkey retina (courtesy of Professor Nicolas Cuenca, University of Alicante, Spain).
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 (Trifonov, 1968). Thus it is thought that the neurotransmitter glutamate is released continuously in the dark and is suppressed by light.
Fig. 1. Schematic drawing of the cone synapses to bipolar and horizontal cells (59 K jpeg image).
Different glutamate receptor types appear on depolarizing ON- and hyperpolarizing OFF-center bipolar cells (Miller and Slaughter, 1986). 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 (Slaughter and Miller, 1981; Nawy and Copenhagen, 1987). The receptor at the ON-bipolar cell is now thought to be mGluR6 (Numura et al. 1994; Vardi et al. 1997). 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 (Nawy and Jahr, 1990; Shiells and Falk, 1990). 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 (Nawy, 1999; Dhingra et al. 2000).
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. 2) 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. 2) and will respond to light like the photoreceptor itself, i.e. will be OFF-center (centre-hyperpolarizing) types (Nelson and Kolb, 1983).
CLICK HERE to see a movie of the intracellular recordings (103 K quicktime movie)
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 (Kolb, 1979).
 Fig. 3. Electron micrograph of a cone bipolar axon terminal (59 K jpeg image) |
 Fig. 4. 3-D reconstruction of cone bipolar terminals (59 K jpeg image) |
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 (Nelson et al., 1978) 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. (1978) had shown that such ganglion cells were ON-center
in response to light flashes.
Fig. 5. Intracellular recordings of ON-center and OFF-center ganglion cells (59 K jpeg image)
CLICK HERE to see a movie of the intracellular recordings
(297 K quicktime movie)
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. 6. Schematic drawing of the cone bipolar subtypes (59 K jpeg image)
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.
2. 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 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) (Kolb, 1979; Nelson and Kolb, 1983; Cohen and
Sterling, 1990). 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. 8. Stimuli for ON and OFF center channels (59 K jpeg image)
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.
CLICK HERE to see an animation of the cone circuits
(449 K quicktime movie)
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.
3. 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 (1940) 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. 10. Center-surround receptive fields (59 K jpeg image)
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 (Baylor et al., 1971; Kaneko, 1970; Werblin and Dowling, 1969).
The wiring responsible appears to start at the small local circuit we saw in
the cone triads at the ribbon synapses (see chapter on the outer plexiform
layer).
Fig. 11. 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 (Naka, 1976). This concentric organization is then transmitted to the bipolar cells making contact with the cone (Toyoda, 1972) and thence to the ganglion cell that the cone bipolar cell contacts.
The diagram below 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 (Werblin and Dowling, 1979;
Werblin, 1991).
In mammalian retinas, surround responses are not as strong a component of
bipolar cell receptive field as they are in cold-blooded vertebrate bipolars
(Nelson and Kolb, 1983). Compare for instance the bipolar responses from a
Turtle retina (Ammermüller and Kolb, 1995) with those of a cat retina
(Nelson and Kolb, 1983) in the figure below.
 Fig. 13. Bipolar cell recordings in turtle retina (59 K jpeg image) |
 Fig. 14. Bipolar cell recordings in cat retina (59 K jpeg image) |
We know from intracellular and extracellular recordings of cat and monkey ganglion cells (Enroth-Cugell and Robson, 1966; Kuffler, 1953; Levick, and Thibos, 1983; Gouras, 1968; Shapley and Perry, 1986) 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. 15).
4. References.
Ammermüller, J. and Kolb, H. (1995) The organization of the turtle inner
retina I. On- and off-center pathways. J. Comp. Neurol. 358, 1-34.
Baylor, D.A., Fuortes, M.G.F. and O'Bryan, P.M. (1971) Receptive fields of the
cones in the retina of the turtle. J. Physiol. (Lond.) 214, 265-294.
Cohen, E. and Sterling, P. (1990) Demonstration of cell types among cone
bipolar neurons of cat retina. Phil. Trans. R. Soc., B 330, 305-322.
Dhingra,A., Lyubarsky, A., Jiang, M., Pugh, E.N., Birnbaumer, L., Sterling, P. and Vardi, N. (2000) The light response of ON bipolar neurons requires Gao. J. Neurosci. 20, 9053-9058.
Enroth-Cugell, C. and Robson, J. G. (1966) The contrast sensitivity of retinal
ganglion cells of the cat. J. Physiol. (Lond.) 187, 517-552.
Gouras, P. (1968) Identification of cone mechanisms in monkey ganglion cells.
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Hartline, H. K. (1940) The receptive fields of optic nerve fibers. Am. J.
Physiol. 130, 690-699.
Kaneko, A. (1970) Physiological and morphological identification of horizontal,
bipolar and amacrine cells in goldfish retina. J. Physiol. (Lond) 207,
623-633.
Kolb, H. (1979) The inner plexiform layer in the retina of the cat: electron
microscopic observations. J. Neurocytol. 8, 295-329.
Kuffler, S.W. (1953) Discharge patterns and functional organization of
mammalian retina. J. Neurophysiol. 16, 37-68.
Levick, W.R. and Thibos, L.N. (1983) Receptive fields of cat ganglion cells:
classification and construction. Prog. Ret. Res. 2, 267-320.
Miller, R.F. and Slaughter, M.M. (1986) Excitatory amino acid receptors of the
retina: Diversity and subtype and conductive mechanisms. TINS 9,
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Nelson, R. and Kolb, H. (1983) Synaptic patterns and response properties of
bipolar and ganglion cells in the cat retina. Vision Res. 23,
1183-1195.
Naka, K.-I. (1976) Neuronal circuitry in the catfish retina. Invest. Ophthal.
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Nawy, S, (1999) The metabotropic receptor mGluR6 may signal through Go, but not phosphodiesterase, in retinal bipolar cells. J. Neurosci. 19, 2938-2944.
Nawy, S. and Copenhagen, D.R. (1987) Multiple classes of glutamate receptor on
depolarizing bipolar cells in retina. Nature 325, 56-58.
Nawy, S. and Jahr, C.E. (1990) Supression by glutamate of cGMP activated
conductance in retinal bipolar cells. Nature 346, 269-271
Nelson, R., Famiglietti, E. V. and Kolb, H. (1978) Intracellular staining
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Numura, A., Shigemoto, R., Nakamura, Y., Okomoto, N., Mizumo, N, and Nakanishi, S. (1994) Developmentally-regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells. Cell 77, 361-369.
Shapley, R. and Perry, V.H. (1986) Cat and monkey retinal ganglion cells and
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Slaughter, M.M. and Miller, R.F. (1981) 2-amino-4-phosphonobutyric acid: A new
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Toyoda, J.-I. (1972) Membrane resistance changes underlying the bipolar cell
response in the carp retina. Vision Res. 12, 283-294.
Trifonov, Y.A. (1968) Study of synaptic transmission between the photoreceptor
and the horizontal cell using electrical stimulation of the retina. Biofizika
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Vardi, N., Morigawa, K. (1997) ON cone bipolar cells in rat express the metabotropic receptor mGluR6. Vis. neurosci. 14, 789-794.
Werblin, F.S. (1991) Synaptic connections, receptive fields, and pattens of
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Werblin, F.S. and Dowling, J.E. (1969) Organization of the retina of the mudpuppy, Necturus maculosus. II. Intracellular recording. J. Neurophysiol. 32, 339-355.
[Circuitry for cone signals]
[ON and OFF pathways]
[Simultaneous contrast]
[References]
Updated April 2001
