S-Potentials and Horizontal Cells
Ido Perlman, Helga Kolb and Ralph Nelson
[History] [Morphology and Circuitry] [Physiological Types] [Rod and cone contributions] [Ionic conductances] [Gap junctions and spatial characteristics] [Feedback] [Modulation of physiology] [Functional Roles] [References]
Horizontal cells are the interneurons of distal vertebrate retina. They provide the pathways for both local and long range interactions between photoreceptors. These interactions are called feedback signals. Feedback signals adjust the gain of photoreceptor synaptic output, both as seen in the horizontal cells themselves and in the adjacent, proximally projecting bipolar cells. In forming a distal, lateral synaptic pathway, horizontal cells enrich not only their own physiology but that of photoreceptors and bipolar cells. They adjust both their own rod-cone balance and that of bipolar cells. They generate spatial opponency in photoreceptors and bipolar cells. They also generate color opponency in some photoreceptor and bipolar cell subtypes, as well as certain horizontal-cell subtypes. The actions of horizontal cells propagate forward in the retina, can be identified in the physiology of retinal ganglion cells, and in visual perception. These actions are in turn tuned by neuromodulators released by other retinal neurons.
1. History.
Horizontal cells provided the first intracellular, light-evoked responses recorded in the vertebrate retina. Before the morphological source of these responses became clear, they were called simply S-potentials (Svaetichin, 1953). As shown in figure 1, S-potentials are negative going changes in membrane potential that last for as long as the light stimulus is present. The graded character of the S-potential is evident in figure 1A. The brighter the stimulus, the larger the amplitude of the S-potential until a saturation level is reached. In figure 1B, the duration of a light stimulus of fixed intensity is altered in order to examine the effects of this parameter upon the S-potential. For long stimuli, the S-potential only changes in duration but the amplitude remains constant (2 leftmost responses in Fig. 1B). Further reduction in the stimulus duration causes a decrease in amplitude (Fig. 1B). This illustrates the temporal summation of the S-potential, following the psychophysical Bloch's law (Roufs, 1972). Up to certain stimulus durations (10 msec), the amplitude is directly related to the quantal content of the stimulus (quantal flux*duration), while for stimuli of longer duration, the amplitude is related to the quantal flux, that is, the rate of quantal absorption by photoreceptors. It is likely that S-potentials were named in honor of their discoverer, Gunnar Svaetichin, although 'slow potential' is another common interpretation.
S-potentials puzzled neurophysiologists of the late 1950s when they were first described. At that time, neurons were thought only to be depolarized (inside becoming more positive relative to outside) by excitatory synaptic inputs, thus having their inside-negative resting membrane potentials become reduced. If the depolarization was of sufficient amplitude, action potentials, or nerve spikes, were generated to transfer signals down the length of the axon. S-potentials, however, had neither light-induced depolarizations nor nerve impulses.
At first, the cell type of origin for S-potentials was not really known other than they were recorded somewhere in the outer retina. In fact, initially S-potentials were thought to arise from cones as revealed by the title of the article that was written by Gunar Svaetichin in 1953, The title was "The cone action potential". However, later intracellular marking techniques, in which dyes were injected from the electrode tips into the cytoplasm of the recorded neuron, revealed the horizontal cells were the source of the S-potentials (Werblin and Dowling, 1969; Kaneko, 1970). Since first described in fish retinas, S-potentials have been recorded from retinal horizontal cells in all vertebrate classes including cold-blooded vertebrates (Naka and Rushton, 1966; 1967; Norton et al., 1968; Byzov and Trifonov, 1968; Werblin and Dowling, 1969; Fuortes and Simon, 1974; Naka, 1976; Normann and Perlman, 1979; Itzhaki and Perlman, 1984), mammals (Steinberg, 1969a, b; Niemeyer and Gouras, 1973; Nelson et al., 1975; Nelson 1977; Bloomfield and Miller, 1982; Dacheux and Raviola, 1982) and primates (Dacheux and Raviola, 1990; Dacey et al., 1996; Verweije et al., 1999). Horizontal cells have now been studied by numerous investigators using anatomical, biochemical, pharmacological and electrophysiological techniques. In this chapter, we shall try to summarize our current knowledge of horizontal cells in the vertebrate retina.
2. Morphology and Circuitry.
Horizontal cells are second order neurons interconnecting photoreceptors laterally across the plane of the outer plexiform layer of the retina. These cell types were first described as huge brick-like structures occupying much of the inner nuclear layer in the fish retina (Yamada and Ishikawa, 1965). Early interpretations assumed these cells to be glial cells, mainly because they gave rise to hyperpolarizing slow responses to light (S-potentials) rather than true depolarizing spikes like 'real neurons'. Now we know horizontal cells to be true neurons that have synapses and exhibit most of the structural and ultrastructural characteristics of neurons. Through Golgi staining, intracellular marking and immunostaining techniques we have learned of the various morphologies horizontal cells can adopt, in the retinas of different vertebrate species (Fig. 2) (Cajal, 1892; Polyak, 1941; Gallego, 1986; Boycott and Dowling, 1969; Kolb, 1970; Stell and Lightfoot, 1975; Boycott et al., 1978; Wassle and Rieman, 1978; Leeper, 1978a,b; Sandmann et al., 1996a, b; Peichl et al., 1998).
There are two morphological types of horizontal cell in the majority of vertebrate retinas, B-Type cells with axons and A-Type cells that are axonless (Fig. 2). The dendrites of both B- and A-Types contact cones. In non-mammalian species, horizontal cells come in further axonless subtypes with color specific cone connections (Fig. 2, axonless). Figure 2 shows the morphologies of these different types of horizontal cells in different species indicated. Also shown are the spectral types of cone (red, blue and green dots) that connect with each type. Rod dominated non-mammalian retinas like fish, also have a horizontal cell type devoted only to the rods (not shown), while rod dominated mammalian retinas have adapted the axonal terminal portion of the B-type cell to connect purely with rods (Fig. 2, gray shaded areas over the axon terminals).
B-Type horizontal cells code changes in ambient light intensity but do not discriminate color or fine detail. They regulate adaptational and spatial responses of vertical pathway neurons. These are luminosity type horizontal cells that will be discussed later. B-Type cells can often be identified with antibodies against calcium binding proteins (Wassle et al., 1989; Wassle and Boycott, 1991; Cuenca et al., 2000) and some contain GABA neurotransmitters (Marc et al., 1978; Marc 1999; Cuenca et al., 2001). In turtle retina, acetylcholine has been located in H1 type horizontal cell dendrites where they invaginate the cone pedicles (Cuenca et al., 2000). H1 type cells of turtles are morphologically analogous to mammalian B-type cells. The dendrites of B-type horizontal cells in mammalian retinas are bushy and contact all cones in their dendritic field. An axon emerges from one of these dendrites. An axon terminal sprouts at its distal end to collect signals from large numbers of rods at some distance from the cone connecting dendritic field. The length and thinness of the axon is believed to electrically isolate one portion of the cell from the other, thereby, separating a cone photoreceptor-involved compartment of the cell from a rod photoreceptor-involved compartment (Nelson et al., 1975). In species where there are few rods (Fig. 2, Turtle) the B-Type cell's axon terminal has sparse contacts with red cones and the few rods present in this retina (Leeper, 1978a, b). In this case soma dendritic and axon terminal compartments also maintain physiological separation, as evidenced by different summation areas (Simon, 1973).
A-type horizontal cells in mammals are pure cone connecting (most species have only green and blue cones). They have no connections with rod photoreceptors at all The H2 cell of trichromatic primate retina is a kind of A-type cell. Even the H2 cell, where one or more dendrites are elongated and axon-like, connects only with cones. Interestingly enough, these longer dendrites contact principally blue cones. This may be a general theme for mammalian axonless horizontal cells that is only now being realized. In certain big cats (not yet confirmed in domestic cat), the elongated dendritic tips of A-type cells contact blue cones, while the dendrites closer to the cell body are in contact with both red cones and blue cones (Ahnelt et al., 2000). In horses the A-type cell is apparently only connected to blue cones (Fig. 2) (Sandmann et al., 1996a; Peichl et al., 1998).
In lower vertebrates with well developed color vision, typically there are two axonless horizontal cell types. Each of these connects selectively with a cone type. In turtles, birds, and fish, species with excellent color vision, type H2 and type H3 horizontal cells are large, stellate cells, lacking axons, and are concerned solely with cone pathways (Fig. 2, axonless, color-opponent types). These cells sense color. They respond to some colors with hyperpolarization, and to other colors with depolarization. Thus, in turtle (pentachromats) and fish (trichromats or tetrachromats), H2 horizontal cells connect to green and blue cones and H3 to blue cones (Fig. 2) (Miller et al., 1973; Lipetz, 1978: Fuortes and Simon, 1974; Stell and Lightfoot, 1975; Leeper, 1978a, b). In the turtle, which is tetrachromatic, ultraviolet-sensitive cones appear to connect only with H3 type horizontal cells, along with blue cones.
The C-type horizontal cells of the turtle can be labeled with antibodies to nitric oxide synthase and calcium binding proteins (Cuenca et al., 2000), suggesting a role for NO in their functioning (see later section).
Horizontal cells always interact with photoreceptor terminals at what are known as lateral elements at pre-synaptic ribbons (Fig. 3a, le, arrow). In fish retinas, the horizontal cell connections with cones at the lateral elements are characterized by minute projections called spinules (Fig. 3b). Spinules are dynamic and change shape with the level of illumination. During background illumination, the spinules are stimulated to form, while darkness causes contraction (Raynauld et al., 1979; Weiler and Wagner, 1984). These plastic spinules are known to contain the calcium binding protein caldendrin and CaMKII (Schultz et al., 2004). These spinules are also under an endogenous circadian control but need centrifugal control from the brain via FMR-amide-like and GnRH-like hormone releasing hormones (Munz et al., 1982; Stell et al. 1984) acting upon the dopaminergic interplexiform cell system in the retina (Zucker and Dowling, 1987; DeJuan and Garcia, 2001).
Retinal horizontal cells in all species, are connected to their homologous neighbors, by areas of gap junctions between their dendrites, their axon terminals and occasionally between their dendrites and cell bodies. These junctions are very selective, occurring only between cells of the same type (that is H1 to H1 etc). This selectivity even extends to axon terminals and dendrites of B-type horizontal cells. These cellular regions are also selectively interconnected, that is, cell body to cell body, and axon terminal to axon terminal (Kaneko, 1971; Mills and Massey, 1994). The gap junction can be extremely large, appearing as plaques of electrical junction (Fig. 3c). First described in fish retinas by Yamada and Ishikawa (1965), gap junctions were considered "fused membrane structures" specialized for electrical transmission of stimuli. Procion Yellow dye diffusion between morphologically similar horizontal cells was noted by Kaneko (1971) and indicated that the electrical junctions could pass small molecules freely through the so-called S-space of horizontal cells (Naka and Rushton, 1967). A further example of this can be seen in figure 8, where neurobiotin injected into a primate horizontal cell spreads into neighboring cells (Dacey, 1996).
Gap junctions are formed at closely applied plasma membranes (2-4 nm gap) of the two horizontal cell structures (Fig. 3c). Each half of the cell supplies connexons or hemichannels to complete the gap junction channel. These channels can consist of homomeric or heteromeric connexons thus, allowing a huge variety of gap junctions with slightly different properties to exist between various neurons of the nervous system. Each connexon channel contains six connexins (Cx) surrounding the channel pore. In fish and turtle retinas Cx43 and Cx26 (Fig. 3e) have been demonstrated to comprise the horizontal cell gap junction connexons (McMahon et al., 1989; Janssen-Bienhold et al., 2001). Not only dye molecules but also ion and cytoplasmic molecules of small size can pass through the connexon pores of the gap junction, so changing horizontal cells activities and ionic properties. These ionic conductances and patency to dye molecules are modulated by various agents such as dopamine, nitric oxide and retinoic acid and pH (Hampson et al, 1994).
3. Physiological Types.
The vertebrate retina contains a mosaic of rod- and cone-photoreceptors that serve for dark- and light-adapted vision respectively. Multiple cone types with visual pigments tuned to different regions of the visible spectrum provide vertebrates with the opportunity to discriminate colors. Most mammals are dichromats (having 2 different cone types) however, old world monkeys, humans, and many cold-blooded species are trichromats (3 different cone types) or even tetrachromats (4 different cone types). In the retinas of birds, fish and reptiles, a class of cones that are sensitive to ultraviolet light can also be found (Goldsmith, 1980; Robinson, 1993; Hughes et al, 1998; Ammermuller et al., 1998) in addition to the red, green and blue sensitive cones. Since rods and cones of different spectral types are directly connected to horizontal cells, it is of interest to explore how horizontal cells integrate and process this richness of spectral information.
Two physiological types of horizontal cell are known to exist: luminosity and chromaticity. These cell types can be identified by their photoresponses to lights of different wavelength. The luminosity (L-type) horizontal cells always respond with hyperpolarization to light stimuli of any wavelength within the visible range of the spectrum, while the chromaticity (C-type) horizontal cells respond with different polarity to light stimuli of different wavelengths (Svaetichin & MacNichol, 1958).
L-type horizontal cells are found in every retina that has been studied. Cold-blooded vertebrates, mammals and primates all exhibit cells with L-type physiology. Figure 4 shows the photoresponses of luminosity-type horizontal cells from the toad (A), rabbit (B) and monkey (C) retinas. These cells respond with graded hyperpolarizations to light stimuli of any wavelength. The amplitude and duration of the photoresponse depends upon the intensity and duration of the light stimulus. In some species, two classes of L-type horizontal cells can be distinguished according to their anatomical structure and physiological properties. In the turtle retina, the L1 and L2 types are similar in their spectral sensitivity but they differ in receptive field size and in the kinetics of their photoresponses to red and green light (Simon, 1973; Perlman & Normann, 1979). Anatomically, these two L-type horizontal cell physiologies are respectively the soma and axon terminal of the H1 horizontal cell (Fig. 2). In cat and rabbit retinas, type A and B type cells are both luminosity types. They differ in morphology and connectivity with rods and cones but respond only with hyperpolarizations to light stimuli (Nelson et al, 1975; Dacheux and Raviola, 1982; Bloomfield and Miller, 1982). Differences in A- and B-Type spectral properties have not yet been reported.
In 1958, Svaetichin and MacNichol first reported on wavelength-dependency of some S-potentials (Fig. 5). As shown in the figure, the photoresponses of this S-unit reversed in polarity at a wavelength of about 560 nm. Photoresponses to light stimuli of longer wavelength are depolarizing, while stimuli of shorter wavelengths elicit hyperpolarizing responses. These color opponent S-units are called chromaticity or C-type horizontal cells. C-type horizontal cells have been extensively studied in turtle and fish retinas (Naka and Rushton, 1966; Spekreijse and Norton, 1970; Saito et al., 1973; Fuortes and Simon, 1974; Yazulla, 1976; Kolb and Lipetz, 1991; Kamermans and Spekreijse, 1995; Ammermu_ller and Kolb, 1995; 1996, Asi and Perlman, 1998; Twig et al., 2001; 2002). Horizontal cells are named by the number of wavelengths at which response polarity reverses; no reversal - monophasic (or L-type) cells, one reversal - biphasic C-type cells, two reversals - triphasic C-type cells. The wavelength at which response polarity reverses is called the null wavelength. In fish retinas, two types of chromaticity horizontal cells have been described; biphasic and triphasic (Gottesman and Burkhardt, 1987; Kammermans and Spekreijse, 1995). In the bowfin retina, the null wavelength for the biphasic cells is around 640 nm, while null wavelengths of the triphasic cells are; one in the regions of 500-530 nm and the other in 650-670 nm (Gottesman and Burkhardt, 1987). The biphasic and triphasic C-type horizontal cells of the fish retina are identified morphologically as H2 and H3 types respectively (Fig. 2).
In the turtle retina, two classes of biphasic C-type horizontal cells have been identified (Fuortes and Simon, 1974; Asi and Perlman, 1998; Twig, et al., 2002). Typical photoresponses of L-type and C-type horizontal cells in the turtle Mauremys caspica to light stimuli of different wavelength and intensity are shown in figure 6. For each wavelength, a series of photoresponses to different intensities is shown (Fig. 6). The L-type horizontal cell (1st row in Fig. 6) responds to all stimuli with graded hyperpolarizations regardless of wavelength. The red/green biphasic C-type horizontal cell (2nd row, Fig 6) responds with graded depolarizations to red light stimuli and with graded hyperpolarizations to yellow, green and blue stimuli. The yellow/blue biphasic horizontal cell (3rd row, Fig. 6), responds with depolarizations to red and yellow light stimuli and with hyperpolarizations to blue light stimuli.
In order to define the spectral properties of the horizontal cells, monochromatic light stimuli of dim intensities are used to elicit small amplitude (<1mV) photoresponses. These photoresponses are within the linear range of the cells and can be used to calculate light sensitivities. The relationship between light sensitivity and wavelength is the action spectrum of the cell and describes the threshold spectral properties. Figure 7 shows the action spectra of 8 L-types, 7 red/green types and 6 yellow/blue types of horizontal cell (A, B and C respectively) from the turtle Mauremys caspica. These spectra clearly demonstrate that the L-type horizontal cells are most sensitive to long-wavelength stimuli as expected since their major excitatory input is from red cones (Fuortes and Simon, 1974; Asi and Perlman, 1998). These cells receive additional excitatory input from green cones and to a lesser extent from blue cones (Asi and Perlman, 1998). The red/green C-type horizontal cells are characterized by reversal of response polarity around 600 nm (Fig. 7B). These cells receive excitatory input from green and blue cones and inhibitory input from red cones (Fuortes and Simon, 1974; Asi and Perlman, 1998). The yellow/blue C-type horizontal cells receive inhibitory green and red wavelength input and excitatory input from blue cones (Fuortes and Simon, 1974; Asi and Perlman, 1998) and interestingly, also from UV cones (Ammermuller et al., 1998; Zana et al, 2001). Consequently, their photoresponses reverse in polarity around 540 nm (Fig. 7C).
Given the horizontal cell diversity from lower vertebrates, where the axonless types are chromatically opponent, and axon-bearing types are not, it is surprising that in mammalian retinas, where the axonless horizontal cell type is also present, only luminosity-type horizontal cell responses can be recorded (Steinberg, 1969a, b; Niemeyer and Gouras, 1973; Nelson, 1985). For example, both cat A- and B-Types are luminosity sorts (Fig. 9). Although dominated by red-cone input, low-level synergistic input from blue cones can be seen when tested using specific spectral stimulating and adapting conditions (Nelson, 1985).
In primate retina, horizontal cells also only occur as luminosity types (Dacheux and Raviola, 1990; Dacey et al., 1996). Some of these cells receive synergistic signals from long- and medium-wavelength cones (red and green cones), while others receive synergistic input from all three spectral types of cones; long- medium- and short-wavelength (red, green and blue cones) as shown in figure 8. Anatomically H1 type horizontal cells tend to avoid the pedicles of blue cones (Fig. 8, left) (Ahnelt and Kolb, 1994a, b; Dacey et al., 1996) and are therefore, not responsive to blue selective stimuli (E in Fig. 8 left). On the other hand, large numbers of H2 dendrites contact blue cone pedicles (outlined clusters, Fig. 8 right) (Kolb and Ahnelt, 1994a,b; Dacey et al., 1996). The H2 cell is indeed very sensitive to the blue end of the spectrum (E in Fig. 8 right). Yet, the responses of both horizontal cell types are only hyperpolarizing to the three wavelengths (Dacey et al., 1996). Thus, it appears that subsets of mammalian and primate L-type horizontal cells are devoted primarily to processing of either red green and blue signals or red and green signals, but spectral opponency is not part of the processing regime.
4. Rod and cone contributions and passive electrical models.
Steinberg (1969a; b) was the first to record S-potentials in a mammalian retina. He made intracellular recordings from horizontal cells in the cat retina and saw the typical graded hyperpolarizing responses that depended upon the intensity of the light stimulus. However, unlike the responses seen in non-mammalian retinas, Steinberg's S-potential recordings revealed distinct rod and cone contributions to the response. A very slow phase of membrane repolarization seen after termination of the light stimulus was identified as the rod contribution based on spectral adaptation. Steinberg called this the rod after effect (Fig. 9). The difference in offset kinetics for rod and cone signal components provides a convenient assay for rod and cone signal composition of S-potentials in rod-dominated mammalian retinas (Nelson, 1977). In Figure 9, typical mixed rod and cone signals of all three horizontal cell structures in cats are shown (Nelson, 1977). In A- and B-type horizontal cell bodies, rod and cone signals are about equal in amplitude, whereas in the axon terminal of the B-type cell, the response has only the slowly recovering waveform, characteristic of rod signals. Rod and cone signals appear about equally mixed in cat horizontal cell bodies, but only rod signals are seen in the axon terminals. The "rod after effect" is most evident with bright light stimuli (Fig. 9, bottom).
Further evidence for the mixing of rod and cone inputs to horizontal cells is seen during adaptation to background lights. When retinas are light adapted by steady background lights, rod function saturates and rod contributions to the horizontal cell photoresponses vanish. Meanwhile, the cones adapt to the conditions of ambient illumination and their input grows and remains robust. These properties of rod and cone inputs are easily seen in the photoresponses of mammalian horizontal cells. The rod-dominated photoresponses of B-type horizontal cell axon terminals are virtually abolished by light adaptation. In the horizontal cell bodies (A and B types) that receive mixed rod and cone inputs, light adaptation selectively reduces the rod contribution but large cone signals remain and therefore, these horizontal cell elements continue to respond well in the presence of background lights (Nelson, 1977).
Axon terminals of the axon-bearing horizontal cells in the cat receive an excitatory feed-forward input from rods but the cell bodies of A-type and B-type cells contact only cones. So where does the large rod component of the S-potential in these structures of horizontal cells comes from? Electron microscope observations show that small gap junctions link rod and cone photoreceptors in the outer plexiform layer (Raviola and Gilula, 1975; Kolb, 1977). These electrical synapses introduce rod signals into cones and thence into horizontal cells. This rod/cone mixing in the photoreceptors is now considered a major pathway whereby rod driven inputs pass to horizontal cells and to all subsequent second and third order cells in the retina (Smith et al., 1986; Sterling, 1990).
In other species, similar characteristics of rod-cone mixing can be found in horizontal cells. In the rabbit retina, as in the cat retina, rod-dominated input to the axon terminal is identified by waveform, sensitivity and after-potentials (Dacheux and Raviola, 1982; Massey and Miller, 1987). Also in primate retina, the axon terminals of the axon-bearing H1-type horizontal cells produce rod signals while the cell bodies produce cone or mixed rod-cone signals (Dacheux and Raviola, 1990; Dacey, 1996; Verweij et al., 1999). Similar to other mammalian retinas, the somata of primate H1-type horizontal cells receive rod input indirectly via gap junctions between rods and cones (Verweij et al., 1999).
Horizontal cells in cold-blooded vertebrate are also characterized by mixing of rod and cone signals. In the retina of the turtle Chelydra serpentina, the photoresponses of H1 axon terminals contain slow, low-amplitude components that are contributed by rod photoreceptors, despite the major excitatory input being from long-wavelength sensitive cones. The cell bodies of the same H1 horizontal cells receive input only from long- and medium-wavelength sensitive cones (Leeper and Copenhagen, 1979).
Passive electrical models
All vertebrate retinas contain at least one horizontal cell type that is an axon-bearing cell (Fig. 2, B-type). The axon terminal and the somata of this horizontal cell type are connected by a long thin axon, but both parts behave as isolated physiological units. In the turtle Pseudemys scripta elegans, both axon terminal and somata receive excitatory input mainly from red cones but they are characterized by different spatial properties and different kinetics to red and green stimuli (Simon, 1973; Perlman and Normann, 1979). In another turtle species, Chelydra serpentina, the axon terminal receives excitatory input from red cones and rods while the cell body dendrites contact red and green cones (Leeper and Copenhagen, 1979). In mammals (cat, rabbit) and in primates (monkey), the dendrites of the cell body receive input from cones while the terminals of the axon contact thousands of rods. No evidence has been found to indicate any synaptic or electrical interaction between the axon terminal and the soma of the same cell in any of these cases.
Where horizontal cell types have the dendritic portion of the cell much distant from the axonal ending (Fig. 2, B-cells), calculations based on the anatomical dimensions and geometry of the neuron, and ohmic linear properties of cell membrane and cytoplasm, indicate that the axons are too long and thin to allow passive electrotonic spread of signals from one end of the cell to the other (Nelson et al, 1975; Leeper, 1978a, b; Leeper and Copenhagen, 1979). Such models tell us that signals in cell bodies of horizontal cells reflect the local synaptic inputs from cones while signals in axon terminals reflect the local synaptic inputs from rods. Indeed, the two portions of the same cell act as independent units (Nelson et al., 1975), in clear violation of neuron theory.
5. Ionic conductances.
Ligand-gated channels
Photoreceptors make excitatory (sign conserving) synapses onto horizontal cells. In darkness, the photoreceptors continuously release an excitatory neurotransmitter that opens cation channels with a depolarized reversal potential. Therefore, the horizontal cells are maintained at a relatively depolarized potential in darkness. When the photoreceptors are hyperpolarized by a light stimulus, transmitter release is reduced, the post-synaptic ligand-gated channels close and horizontal cells hyperpolarize. Transmitter release from photoreceptor terminals is calcium dependent. Thus, exposing the retina to solutions that interfere with calcium influx through voltage-dependent calcium channels, causes block of transmitter release and horizontal cell hyperpolarization (Dowling and Ripps, 1973; Cervetto and Piccolino, 1974; Kaneko and Shimazaki, 1975).
Early experiments in intact retinas pointed to the excitatory amino acids L-glutamate and L-aspartate as putative candidates for the photoreceptor neurotransmitter (Cervetto and MacNichol, 1972; Marshall and Werblin, 1978; Negishi and Drujan, 1979; Bloomfield and Dowling, 1985; Normann et al., 1986). Exposing the retina to either L-glutamate or L-aspartate caused depolarization of the horizontal cells and loss of their photoresponses as shown in figure 10A for rabbit horizontal cells in the intact retina (Bloomfield and Dowling, 1985). In the experiment described in figure 10A, 15mM solutions of L-aspartate or of L-glutamate were needed to induce depolarization of rabbit horizontal cells and loss of their photoresponses. These observations are consistent with the notion of an excitatory amino acid neurotransmitter being continuously released by the photoreceptors in the dark, and that light-induced electrical activity in the horizontal cells reflects the removal of the neurotransmitter from the synaptic cleft. Accordingly, exogenously applied neurotransmitter saturates the receptor sites in the horizontal cells causing further depolarization. Since the horizontal cells are saturated with the neurotransmitter, modulation of endogenous transmitter release by light stimuli have no effect on membrane potential and the photoresponses are eliminated. In the experiment described in figure 10A, 15mM solutions of L-aspartate or of L-glutamate were needed to induce depolarization of rabbit horizontal cells and loss of photoresponses. These and other studies also raised two major questions. (1) Why relatively high concentrations (millimolar range) of excitatory amino acids were needed to exert the effects shown in figure 10A? (2) Which of the two excitatory amino acids was the real neurotransmitter?
The first question was answered by the identification of efficient uptake systems for excitatory amino acids in retinal cells (Eliasof et al., 1998; Rauen et al., 1998). These uptake mechanisms remove excitatory amino acids from extracellular space, thereby greatly reducing the applied concentrations reaching the cone-to-horizontal cell synapses. Retinal glutamate transporters are elsewhere reviewed in Webvision by V. P. Connaughton. When non-transportable agonists of excitatory amino acids are used, considerably lower concentrations are needed to exert effects on horizontal cells (Massey and Miller, 1987; Yang and Wu, 1991). This is illustrated in figure 11 where 10 mM L-glutamate (A) is compared to 0.1 mM kainic acid (B). Kainic acid, an agonist for AMPA-kainate-type glutamate receptors in vertebrate horizontal cells, exerts similar effects to those of L-glutamate at a concentration lower by 100 fold. In both cases horizontal cells are depolarized and photoresponses lost. In further support of the glutamate receptor hypothesis, kynurenic acid, a non-selective antagonist of excitatory amino acids receptors (Mayer and Westbrook, 1987) hyperpolarizes horizontal cells, also with loss of photoresponse (Fig, 11 C).
The exact identity of the neurotransmitter was a subject of debate for more than a decade. A variety of experiments in intact retinas were designed to decide between L-glutamate and L-aspartate as candidates for photoreceptor neurotransmitter. Conflicting conclusions were achieved. It was not until the development of the isolated cell preparation that a clear answer to this question was obtained. Lasater and Dowling (1982), in their pioneering work, isolated horizontal cells from the carp retina and recorded their membrane potentials with sharp microelectrodes. These cells were separated from all other influences of retinal circuitry. With the loss of photoreceptor stimulation, isolated horizontal cells in culture were characterized by hyperpolarized resting potentials (close to the potassium equilibrium potential). Application of L-glutamate, but not of L-aspartate or D-glutamate, induced depolarization, indicating that specific receptors for L-glutamate existed in the horizontal cell membrane (Fig. 10B). With this experimental approach, a low concentration of L-glutamate was sufficient to induce effects, because in this preparation, removal of extracellular L-glutamate by uptake systems is negligible.
Voltage- and current-clamp techniques have been applied to isolated horizontal cells from a variety of species, in order to reveal the properties of the glutamate-gated channels. These channels have a reversal potential around 0 mV, depending upon the composition of the intra-pipette and extracellular solutions (Tachibana, 1985; Hals, et al., 1986; Perlman et al., 1989; Yang and Wu, 1991). Pharmacological analysis of the properties of the glutamate-gated channels in horizontal cells, using specific agonists and antagonists, revealed them to be of the AMPA/KA type. They are specifically activated by a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainic acid (KA) and are antagonized by 6-cyano-7-nitroquinoxaline (CNQX) or cis-2,3-piperidine-dicarboxylic acid (PDA) (reviews in Wu, 1994; Peng et al., 1995). When these ion channels are activated by the agonist kainic acid, the induced currents are considerably larger than those elicited by L-glutamate, even at higher concentrations (Perlman, et al., 1989; O'Dell and Christensen, 1989). This effect has been attributed to fast desensitization of the AMPA/KA type channels by L-glutamate but not by kainic acid (Schmidt et al., 1994; Eliasof and Jahr, 1997). More recently, selective blockers of the glutamate-induced desensitization (e.g. cyclothiazide) have shown that the glutamate-induced currents are increased by several fold, thereby thereby buttressing the conclusion that horizontal cells express largely AMPA-type glutamate receptors (Yang et al, 1998; Shen et al, 1999; Blanco and de la Villa, 1999). Catfish horizontal cells, which express NMDA receptors in addition to AMPA/KA receptors, appear to be the lone exception to the above general conclusion (O'Dell and Christensen, 1989).
Metabotropic glutamate effects
Glutamate also influences horizontal cells through metabotropic pathways. Unlike ionotropic AMPA-glutamate responses, metabotropic actions do not spread globally through membrane voltage changes within the horizontal cell network, but remain local, influencing only nearby cytoplasmic chemistry. DL-AP4, a glutamate analogue selective for type III metabotropic glutamate receptors, suppresses nearby voltage sensitive potassium channels (Dixon and Copenhagen, 1997). Similarly, group I and group III metabotropic glutamate receptors increase the amplitudes of nearby voltage-gated calcium currents in horizontal cells (Linn and Gafka, 1999). Glutamate provides further metabotropic regulation of calcium and potassium channels through modulation of cytoplasmic pH (Takahashi and Copenhagen, 1996). NMDA receptors on catfish horizontal cells have been observed to down-regulate voltage dependent sodium and calcium channel activity through a calmodulin-dependent mechanism, also a type of metabotropic effect (Davis and Linn, 2003). Furthermore sodium entry through stimulated AMPA-glutamate channels stimulates local activity of Na+K+ ATPase. This in turn appears important in setting membrane potential (Nelson et al, 2003). Thus horizontal cells rely on photoreceptor glutamate to regulate a variety of cellular and membrane functions in addition to causing the light response itself.
Voltage- and time-dependent conductances
The photoresponses of horizontal cells from cold-blooded, as well as warm-blooded mammalian retinas, are shaped by voltage- and time- dependent ionic conductances in their plasma membrane (Lasater, 1986; 1991; Ueda et al., 1992; Lohrke and Hofmann, 1994). Five types of ionic currents; a sodium current, a calcium current and three types of potassium current have been identified in isolated horizontal cells of goldfish (Tachibana, 1983), catfish (Shingai and Christensen, 1986), white perch (Lasater, 1986), skate (Malchow et al., 1990), turtle (Golard et al., 1992), rabbit (Lrke and Hofmann, 1994) and cat (Ueda et al., 1992).
Figure 12 shows the current responses to voltage steps for two types of horizontal cells from the cat retina (A) and four types of horizontal cells that were isolated from the retina of the white perch (B). In cat horizontal cells, the inward sodium current is clearly evident during the first 10 ms of the current responses while at the steady state, a sustained outward potassium current is seen (Fig. 12A). The fish horizontal cells exhibit a more complex array of currents as evident from the current pulses and transient and sustained I-V curves (Fig. 12B). Basically all four types of fish horizontal cells exhibit similar ionic currents but they differ in relative magnitude. The sodium current is inward going and is seen during the initial 10ms of the current pulses that are recorded when the horizontal cells are depolarized from a negative holding potential (about -70mV) to around 0mV. It is very similar to the regenerative sodium current typical of spiking neurons. The physiological role of this current in horizontal cells is not known since these cells do not exhibit action potentials. Three types of potassium channel have been identified by their voltage- and time-dependency and by their sensitivity to specific blockers. The inwardly rectifying channels conduct an inward current when the cells are hyperpolarized below potassium equilibrium potential. In some species, extracellular sodium ions influence the reversal potential of these channels making the currents functional at physiological potentials (Pfeiffer-Linn et al., 1995). The sustained outward potassium current (delayed rectifier) is activated at potentials more depolarized than the resting, dark potential of the horizontal cells. The outward transient potassium current (IA), is activated upon fast depolarization from negative potentials. In the intact turtle retina, the outward transient potassium current is activated upon termination of a bright light stimulus, speeding the recovery of the L-type horizontal cell from the depolarizing overshoot at light offset back to the dark level. This effect allows the L-type horizontal cells to follow fast flickering stimuli and thus, improves the frequency response curve of the cells (Perlman et al., 1993).
L-type calcium responses are a prominent feature of isolated horizontal cells. Prolonged activation of these channels results in long duration spikes and persistent depolarized states (Tachibana, 1981; Shingai and Christnesen, 1986, Ueda et al, 1992; Nelson et al, 2003) (Fig 12.1). Outward potassium currents appear in themselves too weak to inactivate calcium currents in these cells (Sullivan and Lasater, 1990). Calcium currents contribute to oscillations in the light responses of horizontal cells (Akopian et al, 1997).
6. Gap junctions and spatial characteristics
Gap junctions
In all vertebrate retinas including mammals, horizontal cells are characterized by large-surface-area gap junctions (Fig. 3c and e) between each others' dendrites (Witkovsky and Dowling, 1969; Kolb, 1977). These junctions allow lateral flow of small molecules and ions within the horizontal cell network. Gap-junction-permeant tracers such as Lucifer yellow or Neurobiotin that are injected into one horizontal cell in the layer spread to hundreds of neighboring cells, forming striking images of the interconnected horizontal cell network (Fig. 13a, b) (Kaneko, 1971; Teranishi et al., 1983; Bloomfield and Miller, 1982; AmmermŰller and Kolb, 1996; Mills and Massey, 1994; Vaney, 1994 ). Gap junctions are formed only between neighboring horizontal cells of the same physiological type as shown in figure 13a, b. Networks of turtle H2 cells (Fig. 13b, A, left) and of rabbit A-type cells (Fig. 13b, A, right) are demonstrated by neurobiotin injection into one cell of the network. The conductance of the gap junctions between horizontal cells and therefore, dye coupling, is influenced by the intracellular and extracellular milieu and by chemicals such as dopamine, retinoic acid, nitric oxide or hydrogen ions that are released by other retinal cells (see later section).
Receptive field properties
The gap junctions between horizontal cells are highly permeable to small ions and therefore, serve as low-resistance pathways for electrical signals to spread laterally within the horizontal cell layer. Thus, horizontal cells receive excitatory input via chemical synapses from photoreceptors and via gap junctions from neighboring horizontal cells. The physiological consequence of the gap junctions between horizontal cells is a very large receptive field that spreads out to retinal regions beyond the range of their immediate dendritic fields (Naka and Rushton, 1967; Kaneko, 1971).
Different procedures have been used to characterize the receptive fields of horizontal cells. The most common experimental procedures have been (1) the application of a series of concentric spots of increasing diameter but fixed intensity, or (2) moving a narrow slit of light across the retina. In either case horizontal-cell light responses can be modeled, at least to first order, by differential equations describing current flow in a resistive plane, or by passive networks of resistors. An experiment in which an L-type horizontal cell in the retina of the turtle Pseudemys scripta elegans was stimulated with a series of concentric spots of fixed intensity is shown in figure 13b, B. The first photoresponse to the left was elicited with a stimulus of super-saturating intensity that illuminated the entire receptive field of the cell. This is the maximal photoresponse of the cell. A series of 6 photoresponses that were elicited by light stimuli of fixed intensity and wavelength (650 nm) but different diameters are shown. The amplitudes of the photoresponses gradually decrease as the size of the illuminated retinal area is reduced (Fig. 13C). This reduction of amplitude is not due to diminution of photoreceptor input to the recorded cell, but to shunting of the direct input to the horizontal cell by neighboring horizontal cells. With full-field illumination, all the horizontal cells are evenly illuminated and are equipotential. Therefore, no current flows between them. With small spot illumination, the membrane potential of non-illuminated horizontal cells is different from that of illuminated cells causing electrical currents to flow between them and thus, to shunt the responses of the illuminated cells.
The dimension of the horizontal cell receptive field can be quantified by the diameter of the spot that elicits a response that does not differ from that elicited by a full field illumination or by the length constant lambda. The mathematical definition of lambda and the ways of measuring it vary (Lamb, 1976; Nelson, 1977; Owen and Hare, 1989; Nelson et al, 1990; Lankheet et al., 1990; Kamermans et al., 1996). However, it is generally agreed that the receptive field size is directly related to lambda and that lambda is directly related to the membrane resistance of the horizontal cell, and inversely related to the coupling resistance between the horizontal cells.
Another common method for determining the length constant is to measure the photoresponses that are elicited by long narrow slits of light that are presented at different distances from the recorded horizontal cells (Nelson, 1977). The relationship between response amplitude and distance of the slit from the cell can be described by an exponential function. For slit stimuli much smaller than the length constant, the length constant is approximately the distance between the slit of light and the recorded cell when a response of 1/e of maximal is elicited. Horizontal cells have been classified according to spectral or morphological type (sections 2, 3), but also according to the size and properties of receptive fields. In the turtle retina, two types of luminosity horizontal cells have been described; L1 and L2 (Simon, 1973) or respectively large receptive field (LRF) and small receptive field (SRF) horizontal cells (Perlman and Normann, 1979). The L1 (LRF) cells are characterized by receptive fields of large diameter (>3 mm) while the L2 (SRF) cells have a receptive field diameter of about 2 mm. These two L-type horizontal cells also differ with regards to spectral properties (Perlman et al., 1985) and responsiveness to surround illumination (Piccolino et al., 1981). The spatial properties of C-type horizontal cells in the turtle retina also depend upon the color of the light stimuli (Kato, 1979; Twig et al., 2002). The waveform of the photoresponses of C-type horizontal cells may change dramatically when the spatial pattern of the light stimulus is changed, especially when the wavelength of the light is close to the zone where response polarity reverses (Twig, et al., 2002).
The horizontal cell syncytium cannot be fully described by static passive electrical models. The resistances of the horizontal cell layer change with illumination and time and therefore, the size of the receptive field (magnitude of length constant) changes with light intensity also time (Byzov and Shura-Bura, 1983; Kamermans et al., 1996; Borenstein, 1999). In general, the diameter of the receptive field (length constant) is directly related to the intensity of the light stimulus used to measure it (Lamb, 1976; Perlman et al., 1985; Perlman and Ammermuller, 1994; Pottek et al., 1997). When the irradiance of the ambient illumination is increased, the length constant first increases to a peak value and then decreases to a steady state value (Nelson, 1977; Kamermans et al., 1996; Borenstein, 1999).
7. Feedback.
Horizontal cells are post-synaptic to photoreceptors and but in certain cold-blooded species they are also pre-synaptic to the photoreceptors. Horizontal cells send visual information back to cones through feedback pathways (Baylor et al., 1971; Fuortes et al., 1973; O'Bryan, 1973; Burkhardt, 1977; Lasansky, 1981; Wu, 1991). The effects of these pathways can be revealed by adjusting the size and shape of the light stimuli. Cone photoresponses from the retina of the tiger salamander are shown in figure 14 (Lasansky, 1981). Each pair of responses was elicited by light stimuli of the same intensity but different size. The early ON-phase of each pair of photoresponses (initial hyperpolarization) is identical regardless of the size of the stimulus, but the later phases are considerably affected by the stimulus size. With a small spot stimulus, following the initial hyperpolarization, the cell slightly recovers towards the dark potential but the membrane potential is maintained at a hyperpolarized level for the entire duration of the stimulus. When a large spot stimulus is used, a significant depolarization is seen after the initial hyperpolarizing phase despite continuous illumination (arrows in Fig. 14). This result appears independent of stimulus intensity. This late depolarizing potential reflects the activation of the negative feedback pathway from the horizontal cells.
In turtle retina, the feedback pathway from horizontal cells to cones can be revealed by experiments using different sizes and colors of the stimulus (Fig. 15). Red and green light stimuli of different diameters were used to excite a red cone and a green coneWith small field stimuli, the photoresponses of the red cone are very similar in shape (upper left pair of responses). However, with large field stimuli, the excitatory input from the green cones to the L-type horizontal cells activates the feedback pathway, and causes the response of the red cone to the green light stimulus to become transient and biphasic (Fig. 15, lower left traces). In the green cone, the contribution of the feedback pathway from the L-type horizontal cells is more apparent and a depolarizing photoresponse is elicited with a large diameter red light stimulus (Fig. 15, bottom traces). Blue cones also get feedback pathways from L-type horizontal cells (Itzhaki et al., 1992) as shown in figure 15 (right hand traces). A large diameter red light stimulus was used to selectively isolate possible inputs that were mediated by feedback pathways from L-type horizontal cells to blue cones. In the dark-adapted state, a small depolarizing after potential is seen following the initial hyperpolarizing phase (trace 1). During a red background light, that selectively desensitized the L-cones, a pure hyperpolarizing photoresponse was elicited by the red light stimulus (trace 2), while a blue background augmented the relative contribution of the feedback pathway and therefore a depolarizing photoresponse was obtained (trace 3). These and other anatomical and physiological studies have been the basis for proposing that a feedback model between cones and horizontal cells could underlie color opponency in non-mammalian retinas (Stell and Lightfoot, 1975; Witkovsky et al., 1995; review in Piccolino, 1995; Kamermans and Spekreijse, 1995).
The negative feedback circuit from horizontal cells to cones is thought to take place through the horizontal cell lateral elements invaginating the photoreceptor terminal at the triad ribbon synapse (Fig. 3). The problem has been that no images of a synapse with presynaptic vesicle clusters within the lateral elements have ever been seen except for human retina (Linberg and Fisher, 1988). Fish retinas have distinctive spinules on the dendritic endings of the horizontal cells lateral elements in cone pedicles (Fig. 3b). Spinules may be the sites of feedback from horizontal cells to cones because they change shape and enlarge during background illumination when the effects of negative feedback are most apparent (Raynauld et al., 1979; Wagner, 1980; Weiler and Wagner, 1984; Djamgoz et al., 1989; Downing and Djamgoz, 1989; Kirsch et al., 1990).
GABA is a the candidate for the inhibitory feedback neurotransmitter between H1 cells and photoreceptors in some species (Marc et al., 1978; Cuenca et al., 2000). GABA-induced currents can be recorded from the terminals of red-sensitive and green-sensitive cones isolated from the turtle retina (Tachibana and Kaneko, 1984). Color opponency in fish C-type horizontal cells is eliminated upon exposure to GABA or its antagonists (Murakami et al., 1982a; b). However, studies in other species have failed to show GABA effects that are supportive for a role of GABA as the inhibitory neurotransmitter of the horizontal cell (Stone et al., 1990; Perlman and Normann, 1990). In L-type horizontal cells of turtle, GABA and related drugs induce depolarizations that are consistent only with the activation of electrogenic GABA transporters in the horizontal cell membrane (Malchow and Ripps, 1990; Perlman and Normann, 1990; Kamermans and Werblin, 1992; Cammack and Schwartz, 1993; Dong et al, 1994). These cells clearly have GABA uptake systems. However, the idea that GABA mediates the negative feedback of horizontal cells to cone photoreceptors has gone out of favor in the last years, although GABA could still have a feedforward action directly upon bipolar cell dendrites or other horizontal-cell processes.
A different approach to the question of horizontal cell feedback has been taken recently (Verweij et al., 1996). Using voltage-clamp recordings from cones during illumination with spots or annuli of light, these authors have suggests that negative feedback modulates the voltage-dependency of the calcium channels in the cone pedicles. The idea takes off from an old electrical model (Byzov and Trikonov, 1968) and proposes that horizontal cells can initiate large extracellular current flow through hemi-gap junction channels at the lateral element synapse into the intercellular space at the triad synapse of the cone (Fig. 3d) (Kamermans et al., 2001; Janssen-Bienhold et al., 2001). During light stimulation, the L-type horizontal cells hyperpolarize and the magnitude of the extracellular current is reduced so affecting the transmembrane potential of the synaptic terminal and its voltage dependent calcium channels. The idea finds some support because when the hemi-channels are blocked with carbenoxolone (a specific gap junction blocker), the feedback signal in the cone is eliminated (Kamermans et al., 2001; Verweij et al, 2003).
8. Modulation of physiology.
The properties of horizontal cells can be altered by a variety of chemicals that are released by retinal cells during changing conditions of illumination. These chemicals are generally referred to as neuromodulators. They are believed to adjust modes of information processing in order to match retinal function to new states of adaptation. These chemicals reach the horizontal cells either via direct synaptic interactions or by volume transmission. In the latter mode, inter-cellular communication is mediated by release of the substance into the extracellular space and passive diffusion to the target. Dopamine is the most extensively studied retinal neuromodulator, but in recent years nitric oxide and retinoic acid have been added. In this section, effects of these neuromodulators on vertebrate horizontal cells will be discussed.
Dopamine
Dopamine-containing neurons reside in the amacrine cell layer of the retina in most species. In fish, where they were first demonstrated, dopaminergic cells are interplexiform cells (IPCs). Interplexiform cells send long processes to the outer plexiform layer to synapse on horizontal cells. In other species (e.g. turtle), the dopaminergic cells are amacrine cells and therefore, dopamine has to reach the horizontal cells by volume diffusion through the inner nuclear layer. The action of dopamine upon vertebrate horizontal cells has been extensively studied (see reviews in Witkovsky and Dearry, 1991; Dowling, 1991).
In cold-blooded vertebrates, dopamine has several influences on horizontal cells. (1) The extent of gap-junction coupling is reduced as shown by dye coupling experiments and by electrophysiological determination of receptive field size (Negishi and Drujan, 1979; Teranishi et al., 1983; Piccolino et al., 1984; Mangel and Dowling, 1985; Dong and McReynolds, 1991; Perlman and AmmermŰller, 1994). This effect reflects a reduction of gap junction conductance induced by activation of adenylate cyclase by dopamine at D1-type receptors (Dowling, 1991 for review). (2) Dopamine induces the formation of spinules in fish horizontal cells in a manner similar to that seen with bright light background illumination (Weiler et al., 1988; Djamgoz et al., 1989). (3) In goldfish cone horizontal cells, the interaction between L-glutamate and its receptors on the horizontal cell membrane is modulated by dopamine so that the amplitude of the photoresponse is reduced to any given light stimulus (Mangel and Dowling, 1985; Yang et al., 1988). In other species this appears not to be the case. Such modulations are not clear in the turtle retina (Piccolino et al., 1984; Perlman and Ammermu_ller, 1994). (4) Dopamine changes the balance between rod and cone inputs to horizontal cells in Xenopus retina, in order to augment the rod contribution in the dark-adapted state and the cone contribution in the light-adapted state (Witkovsky et al., 1989).
Figure 16 demonstrates the effects of dopamine on horizontal cell light responses in the intact fish retina (A) and contrasts them to dopamine effects on horizontal cell glutamate responses in isolated horizontal cells (B). Dopamine changed the receptive-field size of a horizontal cell measured in situ. Light stimuli of constant intensity but different diameters were used in order to study the effects of dopamine upon the receptive field size in the intact retina (Fig. 16Aintensity but different diameters were used in order to study the effects of dopamine upon the receptive field size in the intact retina (Fig. 16A). Photoresponses that were recorded during superfusion with dopamine solutions were larger in amplitude with small spot stimuli than those recorded with the same stimuli under control conditions. The increase in the response to spot stimuli indicates less shunting by neighboring non-illuminated horizontal cells and is consistent with the notion that dopamine uncouples horizontal cells from the network (Mangel and Dowling, 1985). In these experiments another effect of dopamine is a reduction in the maximum amplitude of the photoresponses that are elicited by stimulation of the entire receptive field (Fig. 16A). This was explained by the observation that dopamine modulated the interaction between L-glutamate and its receptors on the horizontal cell membrane itself (Knapp and Dowling, 1987). In figure 16B, the effect of dopamine upon the inward current elicited by a dose of kainic acid is shown. Dopamine by itself evoked no current in the horizontal cell (Fig. 16B, upper trace), but it significantly augmented the kainate-induced current (Fig. 16B, lower trace). Further studies show that dopamine increases the affinity of the glutamate-gated channels on the horizontal cell membrane to its agonist (Knapp et al, 1990), and that this dopamine action is dependent on extracellular magnesium ions (Schmidt, 1999). In the intact retina, the photoresponses of horizontal cells reflect the unbinding of glutamate from its receptors. If dopamine increases the affinity of glutamate for its receptors on the horizontal cell membrane, then unbinding during a light stimulus will be at a slower rate. The flicker photoresponses of cat and rabbit horizontal cells were in fact phase-delayed by both D1 and D2 selective dopamine agonists, in agreement with the idea of slower unbinding of glutamate. In these species flicker photoresponses increased in amplitude with dim lights, but decreased with bright lights (Pflug and Nelson, 1994). Similarly, while dopamine increased the amplitudes of horizontal cell cone photoresponses in Xenopus retina (Witkovsky et al, 1989), it decreased them in goldfish retina (Mangel and Dowling, 1985). Evidently the tighter binding of glutamate by dopamine stimulated glutamate receptors allows no firm conclusion about changes in light response amplitude. This depends on the shapes of modified and unmodified binding curves, and the intersections of these curves with light and dark glutamate levels.
In the mammalian retina a similar but lesser magnitude of uncoupling of horizontal cells due to dopamine has been reported (Bloomfield et al. 1995; Mills and Massey, 1994). Similar to the findings in cold-blooded vertebrates, horizontal cell uncoupling in the mammalian retina is mediated by activation of cyclic AMP synthesis through the interaction of dopamine with D1-type receptors (Hampson et al., 1994).
Nitric oxide
Involvement of nitric oxide (NO) in physiological mechanisms is indicated by the presence of cells containing the enzyme nitric oxide synthase (NOS) that synthesizes NO from L-arginine (Nathan, 1992). Immunoreactivity to NOS isoforms or demonstration of NADPH-diaphorase activity has been seen in some populations of cells in every retina studied (Koistinaho and Sagar, 1995). In all species NOS occurs in amacrine cells, but reports of NOS in photoreceptors, horizontal cells, bipolar cells and Mller cells have also been published. In fish retinas, evidence for NOS in horizontal cells has been demonstrated by immunostaining and NADPH diaphorase histochemistry (Weiler and Kewitz, 1993; Liepe et al., 1994; Ostholm et al., 1994). In the turtle retina, n-NOS has been reported in horizontal cell processes at the photoreceptor ribbon synapses and in the inner segments of the photoreceptors, and e-NOS has been seen in the H1 cell axon terminals and in Muller cells (Haverkamp and Eldred, 1998; Haverkamp et al., 1999; Cuenca et al., 2000). In the rabbit retina, NADPH diaphorase activity in horizontal cells has been shown to depend upon the state of adaptation and the activity of glutamatergic pathways. It is increased in the dark-adapted state (Zemel et al., 1996) or by the activation of AMPA/KA type receptors (Zemel et al., 2001).
Regardless of the exact cellular source of NO, this molecule exerts profound effects on the physiology of horizontal cells. Raising NO level by either exogenous application (NO donors) or by adding L-arginine, reduces the size of the horizontal cell receptive field (Miyachi et al., 1990; Pottek et al., 1997; Xin and Bloomfield, 2000). This effect reflects direct action of NO on the gap junctions between horizontal cells. It is thought to be mediated through cGMP-dependent protein kinase pathways (DeVries and Schwartz, 1989; Lu and McMahon, 1997; Xin and Bloomfield, 2000).
Figure 17 shows the effects of NO on A-type (A and B) and B-type (C and D) horizontal cells in the rabbit retina. The photoresponses were elicited by a series of light stimuli of fixed intensity and different radii, in control conditions and during exposure to SNAP (an NO donor). For every light stimulus, the photoresponse is larger during SNAP application (gray responses). This is better illustrated in figure 17 B and D where the peak amplitudes of the photoresponses are plotted as a function of stimulus diameter. SNAP clearly causes augmentation of the photoresponses to large diameter stimuli. Thus, NO acts in the distal rabbit retina to augment the photoresponses of the horizontal cells and to reduce the receptive field size (Xin and Bloomfield, 2000).
A similar augmentation of horizontal cells responses by NO has been seen in L-type horizontal cells of both the carp (Pottek et al., 1997) and turtle retinas (Levy, 2001). The NO effect can either reflect an action directly upon the phototransduction process in the outer segments of the photoreceptors (Tsuyama et al., 1993; Levy, 2001) and/or upon the neurotransmitter release from the photoreceptors (Kurenny, et al., 1994). Furthermore, NO can modulate the interaction between L-glutamate and its receptors on the horizontal cell membrane (McMahon and Ponomareva, 1996) and thus, can alter the responsivity of horizontal cells independently of effects upon the photoreceptors (Levy, 2001). In contrast to dopamine, NO does not influence the process of spinule formation during exposure to background lights (Pottek et al., 1997).
Retinoic acid
Retinoids are of great importance in the eye having roles in both the photopigment cycle and in development of the eye. Retinoic acid is produced in the pigment epithelium as a side effect of the rhodopsin transduction process in bright illumination. In the form of a retinaldehyde, it is the chromophore of the rhodopsin molecule, the visual pigment of the vertebrate photoreceptors (Wald, 1935; Dowling and Wald, 1960), and in the form of retinoic acid, it activates transcription factors which are important in the development of the eye (Wagner et al. 1992; Hyatt et al, 1992; Marsh-Armstrong et al, 1994; Drager and McCaffery, 1997). Most recently a third role for retinoic acid has been proposed; that of a neuromodulator linked to background adaptation affecting horizontal cells in particular (Weiler et al., 1998; Pottek and Weiler, 2000; Weiler et al., 2001).
Retinoic acid induces synaptic plasticity at the terminal dendrites of horizontal cells and promotes the growth of spinules in a pattern similar to that induced by background lights (Weiler et al., 1998; Pottek and Weiler, 2000). It exerts a pronounced effect on the electrical coupling between horizontal cells in mammalian and non-mammalian retinas and reduces the receptive fields of the horizontal cells (Weiler and Vaney, 1999; Weiler et al., 2001) as shown in Figure 18. Adding retinoic acid to retinal preparations of carp, rabbit and mouse, reduces the conductance of the gap junctions between neighboring horizontal cells thus reducing the degree of dye coupling in a manner similar to that seen during background illumination (Fig. 18a). Intracellular recordings in horizontal cells also show that retinoic acid produces effects similar to those of light adaptation. The amplitudes of the horizontal cell photoresponses to full field stimuli are increased by retinoic acid (Fig. 18b). The responses to stimulation with light annuli are reduced by retinoic acid, and those to spot illumination are increased (Fig. 18c). Thus, retinoic acid, like dopamine and nitric oxide, seems to modulate the physiological properties of vertebrate horizontal cells in order to adjust their function during changing conditions of ambient illumination.
9. Functional Roles.
The major functional roles of horizontal cells in the vertebrate retina are 1) creating spatially opponent receptive field organization for second and third order neurons in the retina, and 2) modulation of the photoreceptor signal under different lighting conditions: a form of neuronal adaptation at the first synaptic level in the retina.
Spatial surround organization
Bipolar cells are the first visual neurons exhibiting spatial organization of their receptive fields. These cells respond with opposite voltage polarity to light stimuli illuminating either the center or the surround (Werblin and Dowling, 1969; Dowling, 1970). The interactions between horizontal cells and photoreceptors that underlie this spatial opponent organization are illustrated in figure 19A (after Werblin and Dowling, 1969). Specifically, direct input from photoreceptors is believed to contribute to the central response of bipolar cells while the horizontal cells form the surround component through modulation of photoreceptor synaptic output. In experiments where horizontal cell membrane potentials are directly polarized by injections of current through an intracellular microelectrode, ganglion cells discharges characteristic of "surround responses" or "large-spot responses" are evoked (Naka, 1971; Mangel, 1991). This current-evoked response could reflect the negative feedback pathway from horizontal cells to cones and/or direct input from the horizontal cells to bipolar cells. Evidence for both possibilities has been reported. The glutamate agonist 2-amino-4phosphonobutyrate (APB), selective for transmission between cones and ON-center bipolar cells, blocks the light responses of ON-center ganglion cells and also the responses evoked by injection of current into horizontal cells (Mangel, 1991). Moreover, sub-millimolar concentrations of cobalt ions selectively block feedback pathway from horizontal cells to cone photoreceptors and this results in the absence of surround components in ganglion cells in proximal retina (Vigh and Witkovsky, 1999). This evidence suggests that the main influence of horizontal cells on proximal retinal neurons is through interactions with photoreceptors.
Horizontal cell feedback is not necessarily the only way of influencing bipolar cell receptive field architecture. Horizontal cells can impinge directly on bipolar cells, feeding visual information forward to these second-order retinal neurons, Direct horizontal to bipolar synapses have been described in several mammalian and non-mammalian retinas (Dowling, 1970; Fisher and Boycott, 1974; Kolb and Jones, 1984). In one study using APB to block synaptic transmission from photoreceptors to ON-center bipolar cells, the light stimulus induced a hyperpolarizing response in the bipolar cell thus supporting the idea of a direct excitatory input, possibly from horizontal cells (Yang and Wu, 1991). The best candidate for the feed-forward neurotransmitter is GABA (Wu, 1986). Horizontal cells make the GABA synthetic enzyme GAD in one of two isoforms, GAD 65 or GAD 67 (Vardi, 1995); and further, they express uptake systems for GABA (Marc et al, 1978; Malchow and Ripps, 1990). GABAA receptors are found postsynaptic to horizontal cells on the dendritic tips of both flat and invaginating bipolar cells in cat, macaque, and human retinas (Vardi et al, 1992; Vardi and Sterling, 1994). While GABA inhibition from horizontal cells might serve for the antagonistic surround of OFF bipolar cells, GABA excitation would be required for ON-bipolar cells. GABA responses are mediated by the chloride gradient in post-synaptic bipolar cells. This gradient is governed in part by the actions of chloride transporters. Vardi et al (2000) find the transporter KCC2 is located on the dendritic tips of OFF type bipolar cells. This maintains a chloride gradient suitable for GABA inhibition. ON bipolar cell dendrites express the chloride transporter NKCC, as do horizontal cells. This transporter sets up a chloride gradient suitable for GABAergic excitation. A further potential excitatory pathway for GABA in the distal retina might be provided by GABA transporters. These induce sodium entry, depolarizing, at least, horizontal cells (Malchow and Ripps, 1990), but possibly bipolar cells as well.
There are exceptions to every model though. Not all bipolar cells exhibit spatial antagonism. The ON-bipolar for the rod system and some OFF-center cone bipolar cells in cat retina appear to lack surrounds (Nelson and Kolb, 1983; Bloomfield and Xin, 2000). Regardless of the exact neuronal pathway, whether feedforward or feedback, it is generally accepted that horizontal cells play an important role in spatial information processing in retinal neurons in the distal retina (Werblin and Dowling, 1969; Kaneko, 1970; Naka, 1971, 1976; Lasansky, 1978; Marchiafava and Weiler, 1980; Saito et al., 1979, 1981; McReynolds and Lukasiewicz, 1989; Ammermuller and Kolb, 1995, 1996; Hare and Owen, 1990).
Horizontal cell feedback to bipolar cells probably also serves to generate color opponency in bipolar cells and therefore contribute to the physiology of color-opponent ganglion cells also. Figure 19B summarizes, in a cartoon form, the manner in which single and double opponent bipolar cell receptive fields could be formed in the fish retina according to the cascade model of color opponency (Stell and Lightfoot, 1975; Stell, 1976; Kamermans and Spekreijse, 1995). The opponent surround of the single opponent cell is easy to model (Fig. 19B, top). This bipolar cell receives an excitatory input from red cones only and therefore, is defined as a red OFF-center cell. The negative feedback from the monophasic and biphasic horizontal cells oppose each other in the red range of the spectrum and strengthen each other in the green and blue range. If the degree of feedback from both horizontal cells is the same, then the bipolar surround will be of an ON pattern with spectral sensitivity highest in the green range of the spectrum. If the feedback from the monophasic horizontal cell is weaker compared to that of the biphasic horizontal cell, then the spectral response of the bipolar cell to surround illumination will be hyperpolarizing for red light and depolarizing for green light (R+G-) (Kamermans and Spekreijse, 1995).
In the double opponent bipolar cell (Fig. 19B, bottom), the bipolar cell responds in its center with hyperpolarizations to red stimuli and with depolarizations to green and blue stimuli. This central color opponency is generated by different types of inputs from different types of cones; excitatory input from the red cones and inhibitory input from the green cones. If the monophasic and the biphasic horizontal cells feedback onto both spectral types of cones (Kamermans and Spekreijse, 1995), then the feedback through the green cones would work against the feedback through the red cones because of the different synaptic interactions. When the feedback pathways from each horizontal cell onto the red and green cones differ, then color opponency can be generated by the feedback pathways. However, when the strength of the feedback from each horizontal cell to both types of cones is equal, the surround response could be achromatic. Under these conditions, color opponency in the surround of the bipolar cell can occur only through direct input from one or both horizontal cells to the bipolar cell itself.
Photoreceptor modulation under different lighting conditions
Calcium entry into synaptic structures induces the release of neurotransmitter by promoting fusion of neurotransmitter-laden synaptic vesicles with the presynaptic membrane. Calcium entry occurs thorough specialized membrane channels regulated both by voltage and by second messengers. In a simple model of horizontal cell modulation of gain at cone synapses (Verweije et al., 1996; Kamermans et al., 2001), depolarized, dark-adapted horizontal cells produce an electrical gradient in the extracellular space that reduces the rate of calcium entry into cone terminals. This in turn, reduces the rate of neurotransmitter release. Background illumination, which hyperpolarizes horizontal cells, alters the extracellular currents thereby shifting the voltage dependency of the calcium channels in the cone terminals and increasing the rate of transmitter release for a given potential of the cone.
This modulation also serves to complete the negative feedback loop between horizontal cells and cones, which regulates the horizontal cell membrane potential. When horizontal cells become depolarized, calcium influx into the cone synapse is reduced, as is transmitter efflux from the synapse. The effect sends horizontal cell membrane potential in a hyperpolarized direction. The horizontal cell membrane potential becomes controlled by the network, rather than by factors intrinsic to the cell. Interestingly, bipolar cells perceive this negative feedback effect and synaptic gain modulation as a further spatial opponency effect. This is true for both ON- and OFF-center bipolar cells. The increase in transmitter release caused by horizontal cell hyperpolarization is just the reverse of the decrease in transmitter release that occurs as cones are hyperpolarized by small spots of light.
When horizontal cells are hyperpolarized by wide field stimuli, cone signals evoked by small spots increase in amplitude and become quicker in time course. This is true not only in the horizontal cells themselves, but in bipolar cells also. Such effects are commonly observed when small spots are flashed in the presence of large background fields (Chappell et al, 1985). In dark adapted conditions wide field rod signals, that induce hyperrpolarizations in horizontal cells, increase the sensitivity to narrow-field cone stimulation. It appears that the wide field integration of photic signals in horizontal cells acts to increase the gain for transmitter release at the cone synapse. Such horizontal cell modulatory effects on the cone signals can be seen in human pschophysics and utilized at the clinical level in human patients. The effect is known as suppressive rod-cone interaction (SRCI) (Goldberg et al, 1983). In the SRCI, large, dim green stimuli, seen only by rods, cause observers to perceive focal, red stimuli, seen only by cones, as being brighter. Analogous physiological effects involving rod and cone signals occur in horizontal cells and bipolar cells (Frumkes and Eysteinsson, 1987; Pflug et al, 1990; Nelson et al; 1990). Flickering cone signals are evoked in cat horizontal cells by flickering red stimuli of various sizes. When the stimuli are small, flicker amplitudes can be increased and phase advanced by superimposing steady blue backgrounds, which selectively excite rods. Thus the amplitude of the cone flicker signals is modulated by wide-field, rod driven horizontal cell stimulation, probably through increased gain at cone to horizontal cell synapses. P>
In the half century since Svaetichin first described S-potentials in the vertebrate retina, we have made progress in our understanding of the many ways that horizontal cells can influence the kinetics and spatial organization of the photoreceptor response, and as a consequence, the physiology of all downstream retinal neurons. These include rod-cone balance changes, distal color opponency, center surround opponency, and gain regulation at the photoreceptor synapse. Further, the horizontal cell itself is under neuromodulatory control, and reorganizes its synaptic connections, glutamate sensitivity, and receptive field under the influence of dopamine, retinoic acid and nitrous oxide. The horizontal cell forms an important link between inner and outer retina because this cell type controls distal retinal signal processing, while being itself very likely under the influence of centrifugal neuromodulatory control from both within the retina and even from the brain itself.
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