). some other definitions of lambda based on empirical curve fitting of data have also been suggested ( 10, 171 ). for models based on electrical current flow in the horizontal - cell syncytium, receptive field size is directly related to lambda, and lambda is directly related to the membrane resistance of the horizontal cell, and inversely related to the coupling resistance between the horizontal cells. the space constant of the cone signal components in a cat a - type horizontal cell ( fig. 16a ) is 250 μm. the space constant for the rod signal component in the same cell is 200 μm ( fig. 16b ). this illustrates the point that even in the same cell, depending on what is being measured ; somewhat different receptive fields can be inferred. the concept of field size is not monolithic. the exceptional width of horizontal - cell receptive fields finds several uses. first, horizontal - cell actions on photoreceptors and bipolar cells, both of which are much narrower in receptive field centers than horizontal cells, can be seen in the distal limbs of area functions in these narrower - field neurons. second, horizontal cell types can be distinguished by the size and properties of receptive fields. in the turtle retina, two types of luminosity horizontal cells were early recognized ; l1 and l2 ( 53 ) or respectively, large receptive field ( lrf ) and small receptive field ( srf ) horizontal cells ( 81 ). 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 ( 172 ) and responsiveness to surround illumination ( 173 ). the anatomical stains of lrf and srf cells actually reveals that they are two, electrically isolated, parts of the same cell. lrf is the axon terminal of h1, and srf is the cell body ( fig. 2a ) ( 53 ). thus receptive field measurements add further evidence that a single horizontal cell may have 2 independent area summation regions. the horizontal cell syncytium cannot be fully described by static passive electrical models. the resistances within the horizontal cell layer change with illumination and time and therefore, the size of the receptive field ( magnitude of lambda, or the length constant ) changes also ( 169, 174, 175 ). in general, the size of the receptive - field


the horizontal cell layer change with illumination and time and therefore, the size of the receptive field ( magnitude of lambda, or the length constant ) changes also ( 169, 174, 175 ). in general, the size of the receptive - field length constant is related to the intensity of the light stimulus used to measure it ( 16, 167, 172, 176, 177 ). when the irradiance of the ambient illumination is increased, the length constant first increases to a peak value and then decreases ( 16, 169, 175 ). the spatial properties of c - type horizontal cells in the turtle retina depend upon the color of the light stimuli ( 91, 178 ). 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 ( 91 ). this is because depolarizing and hyperpolarizing mechanisms may differ in size. in isolated pairs of horizontal cells, coupling current decreases somewhat over time ( 179 ), potentially introducing another time - dependence in receptive fields. a further receptive field size dependency is introduced by neuromodulators such as dopamine ( see below ). effects on cone receptive fields horizontal cells are post - synaptic to photoreceptors, but are also pre - synaptic, forming a feedback loop. horizontal cells send wide - field visual signals back to the narrow center mechanism of cones through these feedback pathways ( 180 - 186 ). the effects of these pathways is revealed by adjusting the size, shape and color of the light stimuli used to evoke responses from cones. the effects of area and brightness on cone photoresponses from the retina of the tiger salamander are shown in figure 17 ( 183 ). 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 ( arrows in fig


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 ( arrows in fig. 17 ). this result appears independent of stimulus intensity. the late depolarizing potential reflects the activation of the negative feedback pathway from the horizontal cells to cones. feedback effects are particularly large when cone intracellular chloride concentrations are artificially elevated ( 183, 185 ). figure 17. the contribution of the feedback pathway from l - type horizontal cells to cone responses in the retina of the tiger salamander. cone photoresponses were elicited by light stimuli of different intensities covering a small or a large spot as indicated. the illustration is from lasansky, 1981 ( 183 ). in turtle retina, the feedback pathway from horizontal cells to cones can be revealed by experiments examining the effects of size and color on cone responses ( fig. 18 ). with small spots, red and green light stimuli can be adjusted in brightness until equal amplitude hyperpolarizations are elicited from red and green cones. with these small - spot stimuli, the photoresponses of the red cone are very similar in shape, regardless of wavelength ( upper pairs of responses ). however, when the same two wavelengths of light stimuli were increased in diameter, the excitatory input from the green cones to the l1 - type horizontal cells activated the feedback pathway, and caused the response of the red cone to the green light stimulus to become transient and biphasic ( fig. 18, lower left pair ). in the green cone, the contribution of the feedback pathway from the red - cone input to l1 - type horizontal cells is even more pronounced, and a depolarizing photoresponse is elicited in the green cone with a large diameter red - light stimulus ( fig. 18, bottom right pair ). blue cones also receive feedback signals from l - type horizontal cells ( 187 ) as shown in figure 18 ( right hand traces ). a large diameter red light stimulus was used to selectively isolate possible inputs that were mediated by these feedback pathways. 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 red cones ( l - cones ), a pure hyperpolarizing photores


kainate membrane channels ( fig. 19b ), supporting the notion that horizontal cells are the source of the negative feedback input in cone photoreceptors. further, the characteristics of blue - cone feedback currents resemble those of calcium currents ( 185 ), supporting the long - held idea that horizontal - cell feedback to cones operates through a modulation of calcium channels ( 183, 189 ). figure 19. in monkey retina, inhibition of blue cones by long wavelength light is mediated by horizontal cell feedback. a. short - wavelength blue light evokes outward photocurrents in the blue cone, but long - wavelength yellow light evokes inward feedback currents. b. inward feedback currents elicited by long - wavelength stimuli are blocked by 20µm cnqx, a blocker of horizontal - cell light responses. blue cones are voltage clamped at - 40mv. the figure is adapted from packer et al., 2010 ( 185 ). thus, in primate retina there are color opponent blue cones, but not color opponent horizontal cells. the difference with other vertebrates would appear to reside with horizontal cell circuitry. while the h2 cell of primate retina is somewhat blue cone selective ( fig. 10 ), it apparently is not selective enough to reveal the blue - cone depolarizing feedback signals to red stimuli. the direct hyperpolarizing long - wavelength cone input to h2 cells may mask the blue - cone feedback response. the feedback synapse the negative feedback circuit from horizontal cells to cones is thought to occur at the horizontal - cell lateral elements that invaginate photoreceptor terminals at the triad ribbon synapses ( fig. 3a ). the problem has been that no images of a synapse with presynaptic vesicle clusters has ever been seen within the lateral elements, except for human retina ( 190 ), and there it was only noticed for axon terminal invaginations within rod spherules. however syntaxin - 4, a snare protein involved in fusion of synaptic vesicles to the plasma membrane, has been localized to the lateral elements of mouse horizontal cells in both cones and rods ( fig 20 ) ( 191 ), as has vgat, the vesicular gaba transporter ( fig. 21 ) ( 192 ). these molecules both suggest presynaptic activity in horizontal cells. further, fish retinas have distinctive spinules on the dendritic endings of the horizontal - cell lateral elements


159, 160, 203, 205 ). although these cells clearly have gaba uptake systems and accumulate gaba, the idea that gaba mediates the negative feedback of horizontal cells to cone photoreceptors has not received universal experimental validation. horizontal - cell gaba could still have a feed - forward action directly upon bipolar cell dendrites or other horizontal - cell processes ( 156, 205 ). alternatively gaba receptors on horizontal cells might simply serve the purpose of limiting transporter - generated membrane depolarizations in the presence of extracellular gaba. figure 21. electron microscopy shows immunolabeling ( dark granules ) for vesicular γ - aminobutryric acid transporter ( vgat ) in mouse ( a ) and rat ( b ) horizontal cell lateral elements ( arrow heads ) in rod spherules. rod synaptic ribbons are indicated by long arrows. the scale bars are 0. 5 μm. the illustration is from cueva et al., 2002 ( 192 ). a further feedback model proposes that elevated proton concentration in the synaptic cleft mediates feedback by inhibiting photoreceptor calcium channels ( 206 ). proton buffers, particularly amino sulfonates like hepes, block feedback ( 207 - 212 ). while there is general agreement that some ph buffers block feedback, there is currently disagreement whether alteration of ph in the synaptic cleft is the mechanism ( 213, 214 ). most feedback models propose that modulation of presynaptic calcium channels in the photoreceptor terminals is the key. using voltage - clamp recordings from cones during illumination with spots or annuli of light, verweij et al ( 1996 ) ( 215 ) suggest that feedback modulates the voltage - dependency of the calcium channels in the cone pedicles ( fig. 22a ). the explanation takes off from an old electrical model ( 5 ) and proposes that horizontal cells can initiate large extracellular current flow through hemi - gap - junction channels into the restricted extracellular space within the triad synapse of the cone ( fig. 22b ) ( 68, 70, 72, 189, 216 ). during light stimulation, the l - type horizontal cells hyperpolarize, increasing the magnitude of the inward flow of cations from extracellular space, through hemi - gap - junction channels, into horizontal cell lateral elements. this causes hyperpolarization of the extracellular space. such hemi - gap - junctions,


increasing the magnitude of the inward flow of cations from extracellular space, through hemi - gap - junction channels, into horizontal cell lateral elements. this causes hyperpolarization of the extracellular space. such hemi - gap - junctions, consisting of connexin cx55. 5, have been demonstrated anatomically in horizontal cell lateral elements in zebrafish retinas ( fig. 3d ). the extracellular hyperpolarization activates voltage dependent calcium channels which sense the change in the same way as intracellular depolarization, leading to calcium entry, and an increase in glutamate release. 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 ( 189, 204 ). figure 22. electrical feedback model. a. the activation range of calcium currents in cone synaptic terminals shifts towards more hyperpolarized values during surround stimuli that hyperpolarize horizontal cells. b. the electrical or ‘ ephaptic ’ feedback model argues that the voltage within the enclosed extracellular space surrounding horizontal - cell invaginated dendritic tips is influenced by horizontal - cell membrane polarization. with surround stimulation, these dendrites hyperpolarize, causing extracellular space to hyperpolarize also. this affects synaptic calcium channels in the same way as would intracellular depolarization of the cone terminal. the more hyperpolarized the horizontal cell dendrite, the more calcium enters the cone terminal, and the more neurotransmitter is released. the effect is opposite to the light - induced closing of cone outer segment cation channels that suppress neurotransmitter release. ( i ) calcium channels ( red ) are located on the cone presynaptic membrane, adjacent to the ribbon. gap junction hemichannels ( blue ), polarize adjacent extracellular space. extracellular current flow hyperpolarizes extracellular space to a greater extent in the light ( ii ) than in the dark ( i ) the illustration is from kamermans and fahrenfort, 2004 ( 216 ). further evidence for the importance of connexin 55. 5 and hemi gap - junctions for feedback comes from a genetic knockout in zebrafish. feedback to cones, behavioral contrast sensitivity, and horizontal - cell color opponency were all weakened in this knockout. as this connexin is only expressed in horizontal cells


hemi gap - junctions for feedback comes from a genetic knockout in zebrafish. feedback to cones, behavioral contrast sensitivity, and horizontal - cell color opponency were all weakened in this knockout. as this connexin is only expressed in horizontal cells, a perturbation of horizontal - cell circuitry is a likely cause. curiously the knockout effects were strongest when horizontal cells were in a hyperpolarized state, but were less evident when they were in a depolarized state ( 73 ). 9. modulation of physiology. the properties of horizontal cells are altered by a variety of humoral factors released by retinal cells during changing conditions of illumination. these chemicals, generally referred to as neuromodulators, are believed to adjust the modes of information processing in the retina in order to match retinal function to ambient condtions. neuromodulators reach horizontal cells either via direct synaptic interactions or by volume transmission. in the latter mode, inter - cellular communication is mediated by passive diffusion of the chemical following its release from the source cells into extracellular space. dopamine is the most extensively studied retinal neuromodulator, but in recent years nitric oxide and retinoic acid have been added to the list. in this section the actions of these neuromodulators on vertebrate horizontal cells is discussed. dopamine - containing neurons reside in the amacrine cell layer of the retina. in fish, where they were first discovered, dopaminergic cells are interplexiform cells ( ipcs ), having cell bodies in the amacrine cell layer and sending long processes to the outer plexiform layer where they arborize and synapse on horizontal cells. in other species ( e. g. turtle, most mammals ), the dopaminergic cells are amacrine cells with few, if any, processes extending to the outer plexiform layer ( 217 ), 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 and reviewed ( 218 ) and involves at least 4 distinct actions. ( 1 ) dopamine reduces the extent of gap - junction coupling, as shown by dye coupling experiments, by electrophysiological determination of receptive field size ( 119, 166, 176, 219 - 222 ), and by patch recordings from isolated cell pairs ( 69 ).


the extent of gap - junction coupling, as shown by dye coupling experiments, by electrophysiological determination of receptive field size ( 119, 166, 176, 219 - 222 ), and by patch recordings from isolated cell pairs ( 69 ). dopamine shrinks the receptive field, and reduces photoresponse amplitude in horizontal cells from intact fish retina ( fig. 23a ). 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 ( fig 23a ). 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 the horizontal cell network ( 220 ). gap junction conductance is reduced through activation of adenylate cyclase by dopamine d1 - type receptors ( 223 ). figure 23. dopamine affects synaptic gain and receptive fields in fish horizontal cells. a. photoresponses were recorded from a horizontal cell in the intact carp retina using light stimuli of fixed intensity but different diameter, under control conditions and after exposure to dopamine. the illustration is from mangel and dowling, 1985 ( 220 ). b. dopamine by itself did not elicit any current response in a horizontal cell isolated from white perch retina ( upper trace ). however in the presence of dopamine the inward current elicited by the ampa / kainate agonist kainic acid ( middle trace ) was significantly augmented ( bottom trace ). the illustration is from knapp and dowling, 1987 ( 227 ). by reducing gap - junction coupling, dopamine limits the spread of neurobiotin, a low - molecular weight ( 323 dalton ) tracer molecule, after injection of this molecule into a cell within the horizontal cell layer. in h1 cells of monkey retina the neurobiotin tracer field is maximal during dark adaptation ( fig. 24a ). the dopamine d1 agonist skf38393 reduces the size of the tracer field ( fig. 24d ), as does light adaptation ( fig. 24b ) and the gap junction blocking agent meclofenamic acid ( fig. 24c ). dark adapted space constants in monkey h1 cells are very large, in excess of 1000 μm ( 222 ). similar results are seen in mouse retina where additionally,


blocking agent meclofenamic acid ( fig. 24c ). dark adapted space constants in monkey h1 cells are very large, in excess of 1000 μm ( 222 ). similar results are seen in mouse retina where additionally, blockade of the dopamine d1 receptor with a d1 antagonist ( sch23390 ) widens the area of tracer spread, and the camp analogue 8 - bromo cyclic gmp reduces the spread of the tracer. all observations are consistent with a d1 receptor, camp - mediated mechanism ( 224 ). figure 24. modulation of horizontal - cell coupling in monkey retina. a. neurobiotin tracer reveals maximal coupling - field occurs in h1 horizontal cells under dark adaptation. b. mesopic ( 500 nm ) background illumination shrinks the coupling field. c. meclofenamic acid, a gap junction blocking agent, prevents tracer spread. d. the dopamine d1 receptor agonist skf38393 greatly reduces the spread of tracer. the scale bars are 100 μm. the illustration is from zhang, jacoby and wu, 2011 ( 222 ). receptive field modulation by dopamine varies somewhat with species. neurobiotin spread between rabbit a - type cell bodies is highly ph sensitive ( 165 ), in fact only observable at ph 7. 2 + / - 0. 05. nonetheless, a particularly striking modulation of receptive field size occurs in the axon terminal systems of rabbit b - type horizontal cells ( 233 ). modulation of tracer coupling by dopamine is robust in mouse retina ( 224 ) and in monkey retina ( fig. 24 ) ( 222 ). tracer coupling between the rod - driven horizontal cells of skate retina was dopamine insensitive ( 234 ). in isolated horizontal cell pairs dopamine uncouples gap junctions ( 69 ). in this preparation the biophysics of gap junction coupling and its modulation by dopamine can be examined in detail. in zebrafish the unitary conductance of a gap - junction channel is 50 - 60 ps and the open time is ~ 10 msec. dopamine reduces the open time and the frequency of opening of these channels for a net reduction of 2 - 3 fold ( 235 ). the action is mediated through a d1 agonist and is mimicked by the camp analogue 8 - bromo - camp, suggesting an intracellular mechanism that involves increases in camp, a common action


net reduction of 2 - 3 fold ( 235 ). the action is mediated through a d1 agonist and is mimicked by the camp analogue 8 - bromo - camp, suggesting an intracellular mechanism that involves increases in camp, a common action of d1 receptors ( 179 ). a parallel study in isolated catfish horizontal - cell pairs yielded similar results. dopamine d1 receptors raised intracellular camp, closing gap junctions. further, intracellular ph and ca2 + ions were ruled out as mediators ( 236 ). ( 2 ) dopamine induces the formation of spinules in fish horizontal cells in a manner similar to that seen with bright - light background illumination ( 193, 225 ). ( 3 ) in fish retina, dopamine reduces the amplitude of horizontal - cell photoresponses ( 220, 226 ), as shown in figure 23a. this phenomenon is attributed to dopamine modulation of the interaction between l - glutamate and ampa / ka receptors on the horizontal cell membrane. dopamine increases the binding of l - glutamate to horizontal - cell - membrane receptors ( 227 ), as illustrated in figure 23b. dopamine by itself evoked no current in the isolated horizontal cell ( fig. 23b, upper trace ), but it significantly augmented the kainate - induced glutamate - receptor current ( fig. 23b, lower traces ). further studies show that this dopamine action is dependent on extracellular magnesium ions ( 228 ). 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 at light onset 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 ( 229 ). pflug et al ( 229 ) suggest that the dopamine - induced increase in glutamate binding by horizontal cells may induce a maintained depolarized bias that shifts cone calcium activation through feedback interaction towards more depolarized levels, tending to facilitate dim - stimulus synaptic transmission, while truncating


increase in glutamate binding by horizontal cells may induce a maintained depolarized bias that shifts cone calcium activation through feedback interaction towards more depolarized levels, tending to facilitate dim - stimulus synaptic transmission, while truncating bright - stimulus transmission ( 229 ), an elaboration of the ideas put forward by mangel and dowling ( 230 ). in other species this appears not to be the case. such modulations are not clear in the turtle retina ( 176, 221 ). ( 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. this action is thought to depend on different dopamine sensitivities of ampa / ka receptors postsynaptic to rods and cones ( 231, 232 ). involvement of nitric oxide ( no ) in physiolological regulation of retina is indicated by the presence of cells containing the enzyme nitric oxide synthase ( nos ) that synthesizes no from l - arginine ( 237 ). immunoreactivity to nos isoforms or demonstration of nadph - diaphorase activity has been seen in every vertebrate retina studied ( 238 ). in all species nos occurs in some types of amacrine cells, but reports of nos in photoreceptors, horizontal cells, bipolar cells and muller cells have also been published. in fish retinas, evidence for nos in horizontal cells has been demonstrated by immunostaining and nadph diaphorase histochemistry ( 239 - 241 ). in the turtle retina, n - nos has been reported in horizontal cell processes at 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 ( 47, 242 - 244 ). in the rabbit retina, nadph diaphorase activity, an indicator for nos presence 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 ( 245 ) or by the activation of ampa / ka type receptors ( 246 ). indeed nitric oxide has been suggested as a player in horizontal - cell feedback mechanisms ( 247 ). regardless of the exact cellular source of


the dark - adapted state ( 245 ) or by the activation of ampa / ka type receptors ( 246 ). indeed nitric oxide has been suggested as a player in horizontal - cell feedback mechanisms ( 247 ). 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, the substrate for its synthesis, reduces the size of the horizontal cell receptive field ( 177, 248, 249 ). this effect reflects direct action of no on the gap junctions between adjacent horizontal cells. it is thought to be mediated through cgmp - dependent protein kinase pathways ( 249, 250 ), in a pathway parallel to camp, dopaminergic modulation. no modifies the photoresponses of both a - type and b - type horizontal cells in the rabbit retina ( fig. 25 ). these responses were elicited by a series of disks of fixed intensity and different radii, both in control conditions and during exposure to snap ( an no donor ). for every light stimulus, the photoresponse is larger during snap application as compared to control conditions ( gray vs black responses, fig. 25 ). this is illustrated graphically in figure 25b and 25d where the peak responses of photoresponses shown in parts a and c respectively are plotted as a function of stimulus diameter. snap clearly causes augmentation of the photoresponses to large diameter stimuli. no acts in the distal rabbit retina to augment the photoresponses of the horizontal cells and to reduce the receptive field size ( 249 ). figure 25. the actions of nitric oxide ( no ) upon the physiology of horizontal cells in the rabbit retina. a. & c. the effects of no were tested by adding snap, an no donor, and observing the effects upon photoresponses that were elicited by disks of fixed intensity but different diameters. b. & d. the relationship between response amplitudes and stimulus diameters indicates that no augments the photoresponses of both a - type and b - type horizontal cells and reduces their receptive field sizes ( black traces, control ; gray traces, snap ). the illustration is from xin and bloomfield, 2000 ( 249 ). a similar augmentation of horizontal - cell responses by no has been seen in l - type horizontal cells of carp ( 177 ) and turtle retinas


traces, snap ). the illustration is from xin and bloomfield, 2000 ( 249 ). a similar augmentation of horizontal - cell responses by no has been seen in l - type horizontal cells of carp ( 177 ) and turtle retinas ( 251 ). the no effect in horizontal cells can reflect either no action upon the phototransduction process in the photoreceptor outer segments ( 251, 252 ) or upon the neurotransmitter release from the photoreceptors ( 253 ). furthermore, no can modulate the interaction between l - glutamate and its receptors on the horizontal cell membrane ( 254 ), and thus can alter the responsivity of horizontal cells independently of effects upon phototransduction. in order to distinguish the above possibilities, the influence of no - related drugs on the transfer function between cone photoreceptors and l1 - type horizontal cells ( l1 - hc ) were studied in the turtle eyecup preparation as shown in figure 26 ( 251 ). in the dark - adapted state ( fig. 26a ), the cone to l1 - hc synapse is non - linear and is characterized by high amplification for dim light stimuli that elicit low amplitude cone photoresponses. reducing the retinal level of no by adding l - name, increased this non - linearity, while raising retinal no level by adding either l - arginine or snp, reduced the non - linearity and linearized the cone - to - horizontal cell transfer function. in the light - adapted state ( fig. 26b ), the cone to l1 - hc transfer function was linear under control conditions consistent with high no level. further increase of retinal no ( adding l - arginine or snp ) did not change the transfer function or synaptic amplification, while lowering retinal level of no ( adding l - name ) changed the transfer function into a non - linear one with high amplification for small amplitude cone photoresponses. what is clear in figure 26 is a direct effect on synaptic transfer from cones to horizontal cells. this may include neurotransmitter release and / or neurotransmitter interactions with its post - synaptic receptors. figure 26. the effects of nitric oxide ( no ) upon transfer function and synaptic amplification between cone photoreceptors and l1 - type horizontal cells in the turtle


recently a further role for retinoic acid has been proposed ; that of a neuromodulator linked to background adaptation, affecting horizontal cells in particular ( 64, 65, 261 ). retinoic acid is produced in the pigment epithelium as a side effect of the rhodopsin transduction process in bright illumination. retinoic acid induces synaptic plasticity at the terminal dendrites of horizontal cells and promotes the growth of spinules in fish horizontal cells, in a pattern similar to that induced by background lights ( 64, 65 ). 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 ( 261, 262 ) as shown in figure 27. 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 ( fig. 27a ), in a manner similar to that seen during background illumination. 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. 27b ). the responses to stimulation with bright light annuli are reduced by retinoic acid, and those to spot illumination are increased ( fig. 27c ). 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. figure 27. the effects of retinoic acid upon the physiology of horizontal cells in different species. a. in carp, rabbit and mouse retinas, retinoic acid added in the dark - adapted state reduced the extent of dye coupling. b. retinoic acid added in the dark - adapted state exerts effects similar to those of light adaptation by augmenting the photoresponses of fish horizontal cells. c. retinoic acid, like background illumination, reduces the response to an annulus stimulus and augments that to a spot stimulus in fish horizontal cells. the illustration is from weiler et al., 2001 ( 261 ). 10. functional roles. the major functional roles of horizontal cells in the vertebrate retina are 1 ) initiating the organization of spatially opponent receptive fields for second and third order


is from weiler et al., 2001 ( 261 ). 10. functional roles. the major functional roles of horizontal cells in the vertebrate retina are 1 ) initiating the organization of spatially opponent receptive fields for second and third order neurons in the retina, 2 ) modulation of the photoreceptor signal with different lighting conditions and 3 ) adjustment of synaptic gain. these roles represent both neuronal signal processing and neuronal adaptation at the first synaptic level in the retina. in the half century since svaetichin ( 80, 263 ) 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 nitric 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 under the influence of centrifugal neuromodulatory control from both within the retina and even from the brain itself. photoreceptor synaptic modulation calcium entry into synaptic structures induces the release of neurotransmitter by promoting fusion of neurotransmitter - laden synaptic vesicles with the presynaptic membrane. calcium enters through specialized membrane channels regulated by voltage, by second messengers, and by neurotransmitters. in the ephaptic model for horizontal cell modulation of gain at cone synapses ( 189, 215, 216 ), 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 ( fig. 22b ). background illumination hyperpolarizes horizontal cells, increases the extracellular currents, shifts the voltage dependency of the calcium channels in the cone terminals to more hyperpolarized levels


rate of neurotransmitter release ( fig. 22b ). background illumination hyperpolarizes horizontal cells, increases the extracellular currents, shifts the voltage dependency of the calcium channels in the cone terminals to more hyperpolarized levels ( fig. 22a ), and increases the rate of transmitter release for a given potential of the cone as compared to the rate of release in the absence of horizontal cell feedback. light - evoked hyperpolarization of horizontal cells increases neurotransmitter release from cones, while light evoked hyperpolarization of cones depresses the same release. horizontal - cell feedback modulation of horizontal cells horizontal - cell modulation of transmitter release from cones serves to complete a negative feedback loop between horizontal cells and cones. this in turn 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. thus horizontal cell membrane potential becomes controlled by the network, rather than strictly by factors intrinsic to the cell itself. horizontal cells do not express overt center - surround organization of their receptive fields ; however, they do express color opponency, a very likely result of their own feedback. this is discussed in the section physiological types above. horizontal - cell receptive fields also show evidence of spatial effects from their own feedback circuitry. small spot responses from horizontal cells are increased in amplitude and quickened in time course when a feedback - stimulating annular background is added ( fig. 28 ). in the illustration ( 264 ) small - spot, white - noise stimuli are used to calculate impulse functions under conditions where the spot is presented either with, or without an annulus. the white noise impulse function provides a very accurate depiction of changes in response dynamics. it is clear that the gain of the small spot response is increased, and the temporal tuning of the response is changed to higher frequencies and shorter latencies in the presence of the feedback - stimulating annulus. the increased gain agrees with the idea that an inhibitory feedback influence on photoreceptor synaptic transmission has been removed by the annulus causing greater transmitter release, and consequently greater modulation of that release by light. the change in dynamics is not yet modeled, but it would appear that clearance of glutamate from the photoreceptor synaptic cleft has been accelerated through feedback also. figure 28. the


modulation of that release by light. the change in dynamics is not yet modeled, but it would appear that clearance of glutamate from the photoreceptor synaptic cleft has been accelerated through feedback also. figure 28. the effects of feedback on horizontal - cell gain and speed. using small - spot, white - noise stimuli, impulse functions were calculated for horizontal - cell light responses. s is the impulse function for the spot stimulus alone. s / a is the impulse function for the spot stimulus with additional maintained annular stimulation in the surround to stimulate feedback. in the presence of an annulus the peak time of the spot impulse function shortens, the amplitude increases, and the shape becomes biphasic or differentiating. a. turtle horizontal cells. b. catfish horizontal cells. in each case results are superimposed for 4 different horizontal cells. the illustration is from chappell, et al., 1985 ( 264 ). the illustrated effect ( fig. 28 ) is shown for turtle and catfish horizontal cells ( 264 ), but has also been reported in xenopus, mudpuppy and cat horizontal cells ( 168, 265, 266 ). in these latter species horizontal cell responses contain mixed rod and cone signals. in these species it is particularly rod - selective wide - field stimuli that are effective in increasing the amplitudes of cone - driven spot responses and shortening their latencies ( 168, 265, 266 ). the effect is thought to be analogous to ‘ suppressive rod cone interaction ’ ( srci ), a behavioral paradigm where dim rod backgrounds make flickering, cone - selective, small spots more visible ( 267 ). these observations suggest that feedback provides more than just wide field inhibition of cones, it also regulates synaptic gain and response dynamics. bipolar cell receptive fields bipolar cells respond with opposite voltage polarity to light stimuli illuminating either the center or the surround ( 4, 268 ). bipolar cells perceive horizontal - cell negative feedback and synaptic gain modulation as spatial opponency. this is true for both on - and off - center bipolar cells. the increase in photoreceptor transmitter release caused by horizontal cell hyperpolarization due to annular light stimuli is just the reverse of the decrease in transmitter release that occurs as cones are hyperpolarized by small spots of light. thus through horizontal cell feedback onto cones, for bipolar cells, wide field annular stimuli have just the opposite effect as small spot stimuli. feedback also provides synaptic gain in bipolar cells. small


are hyperpolarized by small spots of light. thus through horizontal cell feedback onto cones, for bipolar cells, wide field annular stimuli have just the opposite effect as small spot stimuli. feedback also provides synaptic gain in bipolar cells. small - spot center responses of bipolar cells, as well as small - spot responses of horizontal cells, are amplified by feedback ( 265, 269 ). 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. typical chemical synapses from horizontal to bipolar cells have been described in non - mammalian retinas ( 270, 271 ). in one study, in the presence of 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 input, possibly from horizontal cells ( 123 ). the best candidate for the feed - forward neurotransmitter is gaba, as seen in experiments on salamander retina ( 272 ). horizontal cells make the gaba synthetic enzyme gad in one of two isoforms, gad 65 or gad 67 ( 273 ) ; and further, in some species, they express uptake systems for gaba ( 51, 161 ). 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 ( 274, 275 ). 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. the transporter kcc2 localized on the dendritic tips of off - center bipolar cells, probably maintains a chloride gradient suitable for gaba inhibition ( 276 ). on bipolar cell dendrites express the chloride transporter nkcc, as do horizontal cells, setting 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 ( 161, 162 ),


center or depolarizing on - center bipolar cells to provide the opponent on - or off - surround respectively. in ( b ), the same mechanism can be used to model the generation of color opponent responses in bipolar cells. the drawing illustrates the manner in which biphasic ( bi ) chromaticity horizontal cells and monophasic ( mono ) luminosity horizontal cells can feed back through a single cone type to give the opponent color surround to a red off bipolar cell. in the lower cartoon, red cones provide excitatory input and green cone inhibitory input to produce a red off, green on center double opponent bipolar cell. the red on and green off surround is added by the chromatic ( bi ) and luminosity ( mono ) horizontal cells. the model is adapted from kamermans and spekreijse, 1995 ( 86 ). in the double opponent bipolar cell ( fig. 29b, bottom ), the bipolar cell responds in its center with hyperpolarizations to red light stimuli and with depolarizations to green and blue light 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. indeed in the retina of giant danio a color opponent cone bipolar cell with bistratified axonal morphology has been found to respond to both ampa / kainate agonists ( off type receptors ) and to eaat agonists ( on type receptors ) suggesting both on and off dendritic input from spectrally distinct cones ( 289 ). if the monophasic and the biphasic horizontal cells feed back onto both spectral types of cone ( 86 ), 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. horizontal cells influence ganglion - cell discharge in experiments where horizontal - cell membrane potentials are directly polarized by injections of current through intracellular microelectrodes ( fig. 30 ), gang


both horizontal cells to the bipolar cell itself. horizontal cells influence ganglion - cell discharge in experiments where horizontal - cell membrane potentials are directly polarized by injections of current through intracellular microelectrodes ( fig. 30 ), ganglion cell discharges characteristic of ‘ surround responses ’ or ‘ large - spot responses ’ are evoked ( 284, 290 ). a hyperpolarizing current step injected into a rabbit horizontal cell depresses the firing rate in an on - center ganglion cell, but increases the firing rate in an off - center ganglion cell ( fig. 30 ). both actions resemble surround responses. this current - evoked response reflects 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 - 4 phosphonobutyrate ( apb ), a selective blocker for transmission between cones and on - center bipolar cells, blocks the light responses of on - center ganglion cells, and also the ‘ surround - like ’ responses evoked by injection of current into horizontal cells ( 290 ). moreover, sub - millimolar concentrations of cobalt ions selectively block the feedback pathway from horizontal cells to cone photoreceptors. in turtles this results in the absence of surround components in ganglion cells in proximal retina ( 291 ). similarly the feedback blocker hepes, a cationic buffer which selectively attenuates horizontal - cell area effects in cone responses, blocks the surround responses of parasol ganglion cells in monkey ( 209 ). this evidence suggests that a major influence of horizontal cells at the ganglion cell level is through interactions with photoreceptors, that this interaction influences the discharge patterns of ganglion cells, and by extension, plays a very important role in vision and visual perception. figure 30. retinal ganglion cells are influenced by current injection into horizontal cells. horizontal cells were penetrated with intracellular electrodes while extracellular spikes were recorded from ganglion cells close to the horizontal cell recording site. the firing rate of an on - center ganglion cell was reduced by hyperpolarizing current injection, and increased by depolarizing currents ( red, above ). the firing rate of an off - center ganglion cell was increased by hyperpolarizing currents, and slightly decreased by depolarizing currents ( blue, below ). the actions mimicked ganglion - cell


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