Localization and function of dopamine in the adult vertebrate retina.

Dopamine (DA) has satisfied many of the criteria for being a major neurochemical in vertebrate retinae. It is synthesized in amacrine and/or interplexiform cells (depending on species) and released upon membrane depolarization in a calcium-dependent way. Strong evidence suggests that it is normally released within the retina during light adaptation, although flickering and not so much steady light stimuli have been found to be most effective in inducing endogenous dopamine release. DA action is not restricted to those neurones which appear to be in "direct" contact with pre-synaptic dopaminergic terminals. Neurones that are several microns away from such terminals can also be affected, presumably by short diffusion of the chemical. DA thus affects the activity of many cell types in the retina. In photoreceptors, it induces retinomotor movements, but inhibits disc shedding acting via D2 receptors, without significantly altering their electrophysiological responses. DA has two main effects upon horizontal cells: it uncouples their gap junctions and, independently, enhances the efficacy of their photoreceptor inputs, both effects involving D1 receptors. In the amphibian retina, where horizontal cells receive mixed rod and cone inputs, DA alters their balance in favour of the cone input, thus mimicking light adaptation. Light-evoked DA release also appears to be responsible for potentiating the horizontal cell-->cone negative feed-back pathway responsible for generation of multi-phasic, chromatic S-potentials. However, there is little information concerning action of DA upon bipolar and amacrine cells. DA effects upon ganglion cells have been investigated in mammalian (cat and rabbit) retinae. The results suggest that there are both synaptic and non-synaptic D1 and D2 receptors on all physiological types of ganglion cell tested. Although the available data cannot readily be integrated, the balance of evidence suggests that dopaminergic neurones are involved in the light/dark adaptation process in the mammalian retina. Studies of the DA system in vertebrate retinae have contributed greatly to our understanding of its role in vision as well as DA neurobiology generally in the central nervous system. For example, the effect of DA in uncoupling horizontal cells is one of the earliest demonstrations of the uncoupling of electrotonic junctions by a neurally released chemical. The many other, diverse actions of DA in the retina reviewed here are also likely to become model modes of neurochemical action in the nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)     

Taurine blocks spontaneous cone contraction but not horizontal cell dark suppression in isolated goldfish retina

The objective of this study was to investigate the effects of taurine on cone retinomotor movements and the responses of cone-driven horizontal cells in dark-adapted teleost retina. In isolated goldfish retina preparations maintained in the dark, cones spontaneously contracted, and the responses of horizontal cells were suppressed. Addition of 5 mM taurine to the physiological solution blocked the spontaneous contraction of cones in the dark but did not block the dark-suppression of horizontal cell responses. These results indicate that the mechanism that leads to horizontal cell dark suppression is not sensitive to taurine. Although both cone retinomotor position and horizontal cell responsiveness are known to be modulated by dopamine, the present results do not support the hypothesis that taurine inhibits dopamine release in the dark because only spontaneous cone contraction was affected by taurine. These results also indicate that spontaneous cone contraction in the dark is not the cause of horizontal cell dark suppression because, in the presence of taurine, cones were elongated yet horizontal cell responses were still suppressed. Consequently, these results make it clear that horizontal cell dark suppression is not an artifact produced by incubating isolated teleost retina preparations in taurine-free physiological solution.     

Dopaminergic interplexiform cells contact photoreceptor terminals in catfish retina

Summary Dopaminergic interplexiform cells in retinae of glass catfish were investigated using an antiserum against tyrosine hydroxylase and peroxidase-anti-peroxidase (PAP) visualization. In whole-mount preparations, we observed a homogeneous distribution of cell bodies throughout the retina without any indication of regional specializations. At the ultrastructural level, we studied the morphology of labelled telodendria within the outer plexiform layer. Apart from contacts with horizontal cells and bipolar cell dendrites, we report for the first time direct contacts with cone pepdicles and rod spherules. Quantitative evaluation of short series of sections showed that all cone pedicles, and a major part of the rod terminals, were approached in this way. The dopaminergic pathway terminating on photoreceptors is discussed in the context of pharmacological effects of this transmitter in the distal retina during light adaptation, i.e., cone contraction, spinule formation and horizontal cell coupling.     

Regulation of Dopamine Release from Interplexiform Cell Processes in the Outer Plexiform Layer of the Carp Retina

The gamma-aminobutyric acid (GABA) antagonists bicuculline and picrotoxin stimulate a four- to fivefold increase in endogenous dopamine release from isolated intact carp retina. The release evoked by these agents is Ca2+ dependent, a finding suggesting a vesicular release. Using light microscopic autoradiography, we have localized the sites of dopamine release to the dopaminergic interplexiform cell processes of the outer plexiform layer, which synapse onto horizontal cells. Our findings support previous suggestions that the dopaminergic interplexiform cells receive GABAergic inhibitory input and that the effects of GABA antagonists on horizontal cells are mediated by dopamine release from the interplexiform cells.     

Light-adaptive role of nitric oxide in the outer retina of lower vertebrates: a brief review

The role of nitric oxide (NO) as a novel neurochemical mechanism controlling light adaptation of the outer retina is discussed by considering mainly published results. The emphasis is on the retinae of fishes and amphibia, but some data from the mammalian (rabbit) retinae have also been included for completeness. In the fish retina, application of NO donors in the dark caused light-adaptive photomechanical movements of cones. The normal effect of light adaptation in inducing cone contractions was suppressed by pretreatment of retinae with an NO scavenger. NO donors modulated horizontal cell activity by uncoupling the cells' lateral gap junctional interconnections and enhancing negative feedback to cones, again consistent with a light-adaptive role of NO. Direct evidence for light adaptation-induced release of NO has been obtained in fish (carp) and rabbit retinae. The results strongly suggest that control of retinal light adaptation is, under multiple neurochemical control, with NO and dopamine having an interactive role.     

Modeling of the vertebrate visual system. II. Application to the turtle cone retina

The model of the vertebrate cone retina was adapted to the turtle retina with its red cone- and L-channel-dominances. The model consists of an ordering of four spatial organizations of unit hexagons, weighted inputs for all cones in the receptive fields, and linear polarization factors based on data from literature on turtle retina. Data generated by the model for spatial and chromatic patterns of receptive fields, intensity-response curves, dynamic ranges for cones, horizontal and bipolar cells proved remarkably consistent with literature. The model also generates observed phenomena such as near-field enhancement of cones due to stray light effects and electrical coupling of like-cones and far-field decrease in responses due to negative feedback from L-type horizontal cells to cones. Annular stimuli were shown to be more effective than spot stimuli for horizontal cells. The formal approach of the model demonstrates factors which play roles in various observed phenomena and all aspects of model can be displayed and tested both qualitatively and quantitatively.     

Dynamics of skate horizontal cells

The all-rod retina of the skate (Raja erinacea or R. oscellata) is known to have the remarkable capability of responding to incremental flashes superimposed on background intensities that initially block all light-evoked responses and are well above the level at which rods saturate in mixed rod/cone retinas. To examine further the unusual properties of the skate visual system, we have analyzed responses of their horizontal cells to intensity-modulated step, sinusoidal, and white-noise stimuli. We found that during exposures to mean intensities bright enough to block responses to incremental stimuli, decremental stimuli were also initially blocked. Thereafter, the horizontal cells underwent a slow recovery phase during which there was marked nonlinearity in their response properties. The cell first (within 2-3 min) responded to decrements in intensity and later (after greater than 10 min) became responsive to incremental stimuli. After adaptation to a steady state, however, the responses to intensity modulation were nearly linear over a broad range of modulation depths even at the brightest mean levels of illumination. Indeed, examination of the steady-state responses over a 5-log-unit range of mean intensities revealed that the amplitude of the white noise-evoked responses depended solely on contrast, and was independent of the retinal irradiance as the latter was increased from 0.02 to 20 muW/cm2; i.e., contrast sensitivity remained unchanged over this 1,000-fold increase in mean irradiance. A decrement from the mean as brief as 2 s, however, disturbed the steady state. Another unexpected finding in this all-rod retina concerns surround-enhancement, a phenomenon observed previously for cone-mediated responses of horizontal cells in the retinas of turtle and catfish. While exposure to annular illumination induced response compression and a pronounced sensitivity loss in response to incremental light flashes delivered to the dark central region, the cell's sensitivity showed a significant increase when tested with a white noise or sinusoidally modulated central spot. Unlike horizontal cells in other retinas studied thus far, however, response dynamics remained unchanged. Responses evoked either by a small spot (0.25-mm diam) or by a large field light covering the entire retina were almost identical in time course. This is in contrast with past findings from cone-driven horizontal cells whose response waveform (dynamics) was dependent upon the size of the retinal area stimulated.     

Evidence for D4 Receptor Regulation of Retinomotor Movement in Isolated Teleost Cone Inner-Outer Segments

Abstract: In the retinas of teleost fish, cone photoreceptors change shape in response to light and circadian signals. They elongate in the dark, contract in the light, and under conditions of constant darkness undergo appropriate movements at expected dusk and dawn. Dopamine induces cones to contract, thus mimicking the effect of light or expected dawn. To identify the receptor subtype responsible for mediating dopamine regulation of cone retinomotor movements, we have carried out pharmacological studies using isolated fragments of teleost cones consisting of cone inner segments-cone outer segments (CIS-COS). Isolated CIS-COS retain the ability to elongate in dark culture and contract when subsequently exposed to light or dopamine. We report that dark-induced elongation of CIS-COS was inhibited by dopamine and its agonists with an effectiveness ranking of dopamine = quinpirole > bromocriptine ⋙SKF-38393. After 60 min of elongation in dark culture, CIS-COS myoids contracted when subsequently cultured in the dark with dopamine or quinpirole. Quinpirole-induced inhibition of elongation and quinpirole-induced contraction were completely blocked by clozapine at 1 µ M or by sulpiride at 100 µ M . These effectiveness profiles for dopamine agonists and antagonists suggest that dopamine regulation of cone retinomotor movement is mediated by a D₄-like receptor.     

长时间暗适应和弱背景光对鲤鱼视网膜视锥水...

Using intact, immobilized carp preparations, changes in light responsiveness of cone horizontal cells and ultrastructures of their terminals in cone pedicles (HCTs) were correlatively examined in prolonged (greater than 2 h) darkness and after the presentation of a dim background light. Following background illumination cone horizontal cells exhibit high light responsiveness and HCTs give rise to a lot of long, fingerlike or ball-like extensions, called slender or round spinules. When the retina is left in the dark for more than 2 h, the light responsiveness of these cells is depressed, which is accompanied by a dramatic decrease of spinules. Thus light responsiveness of the cone horizontal cells seems to be well correlated with the number of spinules. The results suggest that spinules may play an important role in regulating light responsiveness of cone horizontal cells following background illumination by altering the efficacy of signal transfer across the synapses between cone photoreceptors and cone horizontal cells.     

长时间暗适应和弱背景光对鲤鱼视网膜视锥水平细胞的影响——形态和生理的相关研究

本工作利用电子显微镜及细胞内记录技术研究了在暗适应和弱背景光下鲤鱼视锥与水平细胞间突触部位超微结构及视锥水平细胞光反应的变化。在长时间暗适应(>2h)后,视锥水平细胞对光反应受到强烈压抑,其突起末端则外形光滑、圆钝。在施加弱背景光(15min)后,这些细胞的反应显著增大,其末端出现大量深陷于视锥小足内部的刺形结构,这种刺形结构增加了视锥与水平细胞间的突触传递效率,可能是视锥水平细胞光反应性增高的形态学基础。     

An interplexiform cell in the goldfish retina: light-evked response pattern and intracellular staining with horseradish peroxidase

Summary The light-evoked response pattern and morphology of one interplexiform cell were studied in the goldfish retina by intracellular recording and staining. The membrane potential of the cell spontaneously oscillated in the dark. In response to a brief light stimulus, the membrane potential initially gave a slow transient depolarization. During maintained light, the oscillations showed a tendency to be suppressed; the response of the cell to the offset of the stimulus was not so prominent. The perikaryon of the interplexiform cell was positioned at the proximal boundary of the inner nuclear layer. The cell had two broad layers of dendrites; one was diffuse in the inner plexiform layer, the other was more sparse in the outer plexiform layer. The morphological and electrophysiological characteristics of the cell are discussed in relation to dopaminergic interplexiform cells and the light-evoked release pattern of dopamine in the teleost retina.     

Circadian regulation of retinomotor movements. I. Interaction of melatonin and dopamine in the control of cone length

In lower vertebrates, cone retinomotor movements occur in response to changes in lighting conditions and to an endogenous circadian clock. In the light, cone myoids contract, while in the dark, they elongate. In order to test the hypothesis that melatonin and dopamine may be involved in the regulation of cone movement, we have used an in vitro eyecup preparation from Xenopus laevis that sustains light- and dark-adaptive cone retinomotor movement. Melatonin mimics darkness by causing cone elongation. Dark- and melatonin-induced cone elongation are blocked by dopamine. Dopamine also stimulates cone contraction in dark-adapted eyecups. The effect of dopamine appears to be mediated specifically by a dopamine receptor, possibly of the D2 type. The dopamine agonist apomorphine and the putative D2 agonist LY171555 induced cone contraction. In contrast, the putative D1 agonist SKF38393-A and specific alpha 1-, alpha 2-, and beta-adrenergic receptor agonists were without effect. Furthermore, the dopamine antagonist spiroperidol not only blocked light-induced cone contraction, but also stimulated cone elongation in the light. These results suggest that dopamine is part of the light signal for cone contraction, and that its suppression is part of the dark signal for cone elongation. Melatonin may affect cone movement indirectly through its influence on the dopaminergic system.     

Effect of melatonin agonists and antagonists on horizontal cell spinule formation and dopamine release in a fish retina

The crucian carp retina was used to study the effects of the melatonin antagonist p697 (N-pentanoyl 2-benzyltryptamine) and the melatonin agonists [+]- and [-]-AMMTC (N-acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazol e) on horizontal cell spinule formation, an indicator of the state of retinal adaptation. DH97 was capable of both counteracting dark-adaptive spinule degradation and inducing light-adaptive spinule formation at the beginning of the dark phase. Addition of dopamine receptor blockers opposed the action of DH97 on spinules, with SCH 23930, a D1 dopamine receptor antagonist, being more effective than the D2 receptor antagonist sulpiride. DH97 induced a twofold increase in dopamine release. We conclude that melatonin acts as a dark signal within the teleost retina by inhibiting the dopaminergic system. In accordance with this, both enantiomers of AMMTC prevented light-induced spinule formation, and reduced dopamine release to below dark-adaptive baseline levels. We suggest that the suppression of spinule formation by AMMTC may be due to either a direct inhibitory interaction between the melatonin agonist and horizontal cell dopamine D1 receptors, or an inhibitory effect on the activity of the dopamine-releasing interplexiform cells.     

Dopamine Induces Light-Adaptive Retinomotor Movements in Bullfrog Cones via D2 Receptors and in Retinal Pigment Epithelium via D1 Receptors

In the eyes of lower vertebrates, retinal photoreceptors and melanin pigment granules of the retinal pigment epithelium (RPE) exhibit characteristic retinomotor movements in response to changes in ambient illumination and to signals from an endogenous circadian clock. We previously reported that 3,4-dihydroxyphenylethylamine (dopamine) mimicked the effect of light on these movements in photo-receptors and RPE cells of green sunfish, Lepomis cyanellus, by interacting with D2 dopaminergic receptors. Here, we report that dopamine also mimics the effect of light on cone and RPE retinomotor movements in bullfrogs, Rana catesbeiana, i.e., dopamine induces cone contraction and RPE pigment dispersion. Dopamine induced cone contraction in isolated dark-adapted bullfrog retinas incubated in constant darkness in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). This effect of dopamine was inhibited by a D2 but not a D1 antagonist and mimicked by a D2 but not a D1 agonist. These results suggest that induction of cone contraction by dopamine is mediated by D2 dopaminergic receptors and that cone adenylate cyclase activity is inhibited. Thus, dopamine acts via the same type of receptor in both bullfrog and green sunfish retinas to induce cone contraction. In contrast, dopamine influences RPE retinomotor movement via different receptors in fish and bullfrog. Dopamine induced light-adaptive pigment dispersion in isolated dark-adapted bullfrog RPE-eyecups incubated in constant darkness in normal Ringer's solution. Because the retina was not present, these experiments demonstrate a direct effect of dopamine on bullfrog RPE. This effect of dopamine on bullfrog RPE was inhibited by a D1 but not a D2 antagonist and mimicked by a D1 but not a D2 agonist. Furthermore, agents that increase the concentration of intracellular cyclic AMP also induced pigment dispersion in dark-adapted bullfrog RPE-eyecups incubated in the dark. These results suggest that dopamine induces pigment dispersion in bullfrog RPE via D1 dopaminergic receptors. Thus, dopamine acts via different receptors on bullfrog (D1) versus green sunfish (D2) RPE to induce pigment dispersion. In addition, inhibitor studies indicate that pigment dispersion is actin dependent in teleost but not in bullfrog RPE. Dopamine-induced pigment dispersion was inhibited by cytochalasin D in isolated RPE sheets of green sunfish but not in RPE-eyecups of bullfrogs. Together, these observations indicate that dopamine mimics the effect of light on cone and RPE retinomotor movements in both fish and bullfrogs. However, in the RPE, different receptors mediate the effect of dopamine, and different cytoskeletal mechanisms are used to affect pigment transport.(ABSTRACT TRUNCATED AT 400 WORDS)     

Reciprocal changes in center and surrounding S potentials of fish retina in response to dopamine

Effects of dopamine (DA) were examined on the intracellularly recorded potential from horizontal cells in the fish (Eugerres plumieri) retina. DA (100 M in the perfusate) augmented the center S potential in a response to a spot illumination and attenuated the surrounding S potential to an annular light by approximately 40%. These reciprocal changes in the S potentials were associated with a slight depolarization (2.5 mV) of the horizontal cell, and were reversible in 10–15 min. The results indicate that DA at this concentration does not affect directly the synaptic transmission from photoreceptors to horizontal cells, while it appears to interfere selectively with the lateral propagation of an S potential. The effects of DA observed may represent an aspect of function of DA-containing interplexiform cells in the retina.     

Dopamine D1 Receptors Regulate the Light Dependent Development of Retinal Synaptic Responses

Retinal synaptic connections and function are developmentally regulated. Retinal synaptic activity plays critical roles in the development of retinal synaptic circuitry. Dopamine receptors have been thought to play important roles in the activity-dependent synaptic plasticity in central nervous system. The primary goal of this study is to determine whether dopamine D1 receptor regulates the activity-dependent development of retinal light responsiveness. Accordingly, we recorded electroretinogram from wild type mice and mice with genetic deletion of D1 dopamine receptor (D1−/− mice) raised under cyclic light conditions and constant darkness. Our results demonstrated that D1−/− mice have reduced amplitudes of all three major components of electroretinogram in adulthood. When the relative strength of the responses is considered, the D1−/− mice have selective reduction of the amplitudes of a-wave and oscillatory potentials evoked by low-intermediate intensities of lights. During postnatal development, D1−/− mice have increased amplitude of b-wave at the time of eye-opening but reduced developmental increase of the amplitude of b-wave after eye opening. Light deprivation from birth significantly reduced the amplitudes of b-wave and oscillatory potentials, increased the outer retinal light response gain and altered the light response kinetics of both a- and b-waves of wild type mice. In D1−/− mice, the effect of dark rearing on the amplitude of oscillatory potentials was diminished and dark rearing induced effects on the response gain of outer retina and the kinetics of a-wave were reversed. These results demonstrated roles of dopamine D1 receptor in the activity-dependent functional development of mouse retina.     

Inositol incorporation into phosphoinositides in retinal horizontal cells of Xenopus laevis: enhancement by acetylcholine, inhibition by glycine

The absorption of light by photoreceptor cells leads to an increased incorporation of [2-3H]inositol into phosphoinositides of horizontal cells in the retina of Xenopus laevis in vitro. We have identified several retinal neurotransmitters that are involved in regulating this response. Incubation with glycine, the neurotransmitter of an interplexiform cell that has direct synaptic input onto horizontal cells, abolishes the light effect. This inhibition is reversed by preincubation with strychnine. Acetylcholine added to the culture medium enhances the incorporation of [2-3H]inositol into phosphoinositides in horizontal cells when retinas are incubated in the dark. This effect is inhibited by preincubation with atropine. However, atropine alone does not inhibit the light-enhanced incorporation of [2-3H]inositol into phosphoinositides in the retina. gamma-Aminobutyric acid, the neurotransmitter of retinal horizontal cells in X. laevis, as well as dopamine and norepinephrine, have no effect on the incorporation of [2-3H]inositol into phosphoinositides. These studies demonstrate that the light-enhanced incorporation of [2-3H]inositol into phosphoinositides of retinal horizontal cells is regulated by specific neurotransmitters, and that there are probably several synaptic inputs into horizontal cells which control this process.     

Circadian regulation of teleost retinal cone movements in vitro

In the retinas of many species of lower vertebrates, retinal photoreceptors and pigment epithelium pigment granules undergo daily movements in response to both diurnal, and in the case of teleost cone photoreceptors, endogenous circadian signals. Typically, these cone movements take place at dawn and at dusk when teleosts are maintained on a cyclic light (LD) regime, and at expected dawn and expected dusk when animals are maintained in continuous darkness (DD). Because these movements are so strictly controlled, they provide an overt indicator of the stage of the underlying clock mechanism. In this study we report that both light-induced and circadian-driven cone myoid movements in the Midas cichlid (Cichlasoma citrinellum), occur normally in vitro. Many of the features of retinomotor movements found in vivo also occur in our culture conditions, including responses to light and circadian stimuli and dopamine. Circadian induced predawn contraction and maintenance of expected day position in response to circadian modulation, are also normal. Our studies suggest that circadian regulation of cone myoid movement in vitro is mediated locally by dopamine, acting via a D2 receptor. Cone myoid contraction can be induced at midnight and expected mid-day by dark culture with dopamine or the D2 receptor agonist LY171555. Further, circadian induced predawn contraction can be increased with either dopamine or LY171555, or may be reversed with the dopamine D2 antagonist, sulpiride. Sulpiride will also induce cone myoid elongation in retinal cultures at expected mid- day, but will not induce cone myoid elongation at dusk. In contrast, circadian cone myoid movements in vitro were unaffected by the D1 receptor agonist SCH23390, or the D1 receptor antagonist SKF38393. Our short-term culture experiments indicate that circadian regulation of immediate cone myoid movement does not require humoral control but is regulated locally within the retina. The inclusion of dopamine, or dopamine receptor agonists and antagonists in our cultures, has indicated that retinal circadian regulation may be mediated by endogenously produced dopamine, which acts via a D2 mechanism.     

Intrinsic cone adaptation modulates feedback efficiency from horizontal cells to cones.

Processing of visual stimuli by the retina changes strongly during light/dark adaptation. These changes are due to both local photoreceptor-based processes and to changes in the retinal network. The feedback pathway from horizontal cells to cones is known to be one of the pathways that is modulated strongly during adaptation. Although this phenomenon is well described, the mechanism for this change is poorly characterized. The aim of this paper is to describe the mechanism for the increase in efficiency of the feedback synapse from horizontal cells to cones. We show that a train of flashes can increase the feedback response from the horizontal cells, as measured in the cones, up to threefold. This process has a time constant of approximately 3 s and can be attributed to processes intrinsic to the cones. It does not require dopamine, is not the result of changes in the kinetics of the cone light response and is not due to changes in horizontal cells themselves. During a flash train, cones adapt to the mean light intensity, resulting in a slight (4 mV) depolarization of the cones. The time constant of this depolarization is approximately 3 s. We will show that at this depolarized membrane potential, a light-induced change of the cone membrane potential induces a larger change in the calcium current than in the unadapted condition. Furthermore, we will show that negative feedback from horizontal cells to cones can modulate the calcium current more efficiently at this depolarized cone membrane potential. The change in horizontal cell response properties during the train of flashes can be fully attributed to these changes in the synaptic efficiency. Since feedback has major consequences for the dynamic, spatial, and spectral processing, the described mechanism might be very important to optimize the retina for ambient light conditions.