The Neuronal Organization of the Retina
2012; Cell Press; Volume: 76; Issue: 2 Linguagem: Inglês
10.1016/j.neuron.2012.10.002
ISSN1097-4199
Autores Tópico(s)Neuroscience and Neuropharmacology Research
ResumoThe mammalian retina consists of neurons of >60 distinct types, each playing a specific role in processing visual images. They are arranged in three main stages. The first decomposes the outputs of the rod and cone photoreceptors into ∼12 parallel information streams. The second connects these streams to specific types of retinal ganglion cells. The third combines bipolar and amacrine cell activity to create the diverse encodings of the visual world—roughly 20 of them—that the retina transmits to the brain. New transformations of the visual input continue to be found: at least half of the encodings sent to the brain (ganglion cell response selectivities) remain to be discovered. This diversity of the retina’s outputs has yet to be incorporated into our understanding of higher visual function. The mammalian retina consists of neurons of >60 distinct types, each playing a specific role in processing visual images. They are arranged in three main stages. The first decomposes the outputs of the rod and cone photoreceptors into ∼12 parallel information streams. The second connects these streams to specific types of retinal ganglion cells. The third combines bipolar and amacrine cell activity to create the diverse encodings of the visual world—roughly 20 of them—that the retina transmits to the brain. New transformations of the visual input continue to be found: at least half of the encodings sent to the brain (ganglion cell response selectivities) remain to be discovered. This diversity of the retina’s outputs has yet to be incorporated into our understanding of higher visual function. Charles Darwin famously wrote that the eye caused him to doubt that random selection could create the intricacies of nature. Fortunately, Darwin did not know the structure of the retina: if he had, his slowly gestating treatise on evolution might never have been published at all. Among other wonders, the neurons of the retina are tiny (Figure 1). The ∼100 million rod photoreceptors appear to be the second most numerous neurons of the human body, after only the cerebellar granule cells. The retina’s projection neuron, the retinal ganglion cell, has less than 1% the soma-dendritic volume of a cortical or hippocampal pyramidal cell. Although the retina forms a sheet of tissue only ∼200 μm thick, its neural networks carry out feats of image processing that were unimagined even a few years ago (Gollisch and Meister, 2010Gollisch T. Meister M. Eye smarter than scientists believed: neural computations in circuits of the retina.Neuron. 2010; 65: 150-164Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). They require a rethinking not only of the retina’s function, but of the brain mechanisms that shape these signals into behaviorally useful visual perception. The retinal neurome—the census of its component cells—continues to be refined. An initial estimate of 55 cell types in the retina (Masland, 2001Masland R.H. The fundamental plan of the retina.Nat. Neurosci. 2001; 4: 877-886Crossref PubMed Scopus (496) Google Scholar) appears to have been something of an underestimate. Our understanding of the fundamental plan of the retina remains the same, but new image processing mechanisms are coming into view. My aims here are to see how close we have come to a complete census, to review the principles by which the diverse cell types are organized, to illustrate some of the ways in which they create the retina’s abilities, and to forecast the path by which we may progress. I will begin by outlining three large rules that govern relations among the retina’s neurons. The retina’s processing of information begins with the sampling of the mosaic of rod and cone photoreceptors by the bipolar and horizontal cells. The photoreceptors form a single sheet of regularly spaced cells. Rod photoreceptors, specialized for vision in dim light, outnumber cone photoreceptors by about 20-fold in all but a few mammalian retinas. All rods contain the same light-sensitive pigment, rhodopsin. With one known exception (so far), each cone contains one—and only one—of several cone opsins, each with a different spectral absorption; as will be discussed later, these are the basis of color vision. Both rods and cones respond to light by hyperpolarizing. Rods and the chromatic classes of cones can be easily identified in intact retinas by morphology and by their expression of the different opsins. This review will pass lightly over the rod system, which molecular dating shows to have been a late evolutionary addition to the retina’s tool kit. This is not to say that rods are unimportant, nor that they are uninteresting. Yet the retinal circuitry truly dedicated to rod function includes only four cell types: the rod itself, a bipolar cell that receives input only from rods (“rod bipolar cell”), an amacrine cell that modulates the bipolar cell’s output, and an amacrine cell that feeds the output of the rod system into the circuitry that processes information derived from cones. A second pathway from rods to ganglion cells exists in some animals (it involves gap junctions with cones), but in either case the strategy is the same: the late-evolving rods inject their signals into circuitry that had already developed to service the cones (Famiglietti and Kolb, 1975Famiglietti Jr., E.V. Kolb H. A bistratified amacrine cell and synaptic cirucitry in the inner plexiform layer of the retina.Brain Res. 1975; 84: 293-300Crossref PubMed Scopus (220) Google Scholar; Nelson, 1982Nelson R. AII amacrine cells quicken time course of rod signals in the cat retina.J. 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Synaptic connections of the narrow-field, bistratified rod amacrine cell (AII) in the rabbit retina.J. Comp. Neurol. 1992; 325: 152-168Crossref PubMed Scopus (213) Google Scholar). The types of cones are structurally and, as far as is known, functionally similar. (This review pertains primarily to mammalian retinas.) Their functional types are defined by the opsin that each type expresses. A generic mammal expresses one short wavelength-sensitive cone and one long wavelength. Comparison of the two outputs forms the basis of most color vision. The numbers of rods and cones are known with great precision. They have been counted and their topography mapped for dozens of mammalian and nonmammalian species. These have been collected at http://www.retinalmaps.com.au (Collin, 2008Collin S.P. A web-based archive for topographic maps of retinal cell distribution in vertebrates.Clin. Exp. Optom. 2008; 91: 85-95Crossref PubMed Scopus (26) Google Scholar). For humans and the common laboratory animals, the accounting of photoreceptor cells is complete. As neural populations, horizontal cells are equally simple. The large majority of mammals have two types of horizontal cells. Both of them feed back onto the rod or cone photoreceptors. Some rodents have only one type, and there have occasionally been proposals of a third type in some animals. Despite some variation in morphological detail, though, horizontal cells appear to follow a fairly simple plan (Müller and Peichl, 1993Müller B. Peichl L. Horizontal cells in the cone-dominated tree shrew retina: morphology, photoreceptor contacts, and topographical distribution.J. Neurosci. 1993; 13: 3628-3646PubMed Google Scholar; Peichl et al., 1998Peichl, L., Sandmann, D., Boycott, B.B., Chalupa, L.M., and Finlay, B.L. (1998). Comparative anatomy and function of mammalian horizontal cells. Paper presented at: Development and Organization of the Retina: From Molecules to Function (New York: Plenum Press).Google Scholar). Horizontal cells provide inhibitory feedback to rods and cones and possibly to the dendrites of bipolar cells, though this remains controversial (Herrmann et al., 2011Herrmann R. Heflin S.J. Hammond T. Lee B. Wang J. Gainetdinov R.R. Caron M.G. Eggers E.D. Frishman L.J. McCall M.A. Arshavsky V.Y. Rod vision is controlled by dopamine-dependent sensitization of rod bipolar cells by GABA.Neuron. 2011; 72: 101-110Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). The leading interpretation of this function is that it provides a mechanism of local gain control to the retina. The horizontal cell, which has a moderately wide lateral spread and is coupled to its neighbors by gap junctions, measures the average level of illumination falling upon a region of the retinal surface. It then subtracts a proportionate value from the output of the photoreceptors. This serves to hold the signal input to the inner retinal circuitry within its operating range, an extremely useful function in a natural world where any scene may contain individual objects with brightness that varies across several orders of magnitude. The signal representing the brightest objects would otherwise dazzle the retina at those locations, just as a bright object in a dim room saturates a camera’s film or chip, making it impossible to photograph the bright object at the same time as the dimmer ones. Because the horizontal cells are widely spreading cells, their feedback signal spatially overshoots the edges of a bright object. This means that objects neighboring a bright object have their signal reduced as well; in the extreme, the area just outside a white object on a black field is made to be blacker than black. This creates edge enhancement and is part of the famous “center-surround” organization described in classic visual physiology (Hartline, 1938Hartline H.K. The response of single optic nerve fibers of the vertebrate eye to illumination of the retina.Am. J. Physiol. 1938; 121: 400-415Google Scholar; Kuffler, 1953Kuffler S.W. Discharge patterns and functional organization of mammalian retina.J. Neurophysiol. 1953; 16: 37-68PubMed Google Scholar). But the inner retina contains many more lateral pathways than the outer, and creates both simple and sophisticated contextual effects. Indeed, Peichl and González-Soriano, 1994Peichl L. González-Soriano J. Morphological types of horizontal cell in rodent retinae: a comparison of rat, mouse, gerbil, and guinea pig.Vis. Neurosci. 1994; 11: 501-517Crossref PubMed Google Scholar pointed out that the ganglion cells of mice and rats have a quite ordinary center-surround organization, but these retinas lack one type of horizontal cell altogether. Perhaps the horizontal cells are best imagined as carrying out a step of signal conditioning, which globally adjusts the signal for reception by the inner retina, rather than being tasked primarily with the detection of edges. The synapses by which horizontal cells provide their feedback signals appear to use both conventional and unconventional mechanisms; they remain a matter of active investigation (Hirano et al., 2005Hirano A.A. Brandstätter J.H. Brecha N.C. Cellular distribution and subcellular localization of molecular components of vesicular transmitter release in horizontal cells of rabbit retina.J. Comp. Neurol. 2005; 488: 70-81Crossref PubMed Scopus (29) Google Scholar; Jackman et al., 2011Jackman S.L. Babai N. Chambers J.J. Thoreson W.B. Kramer R.H. A positive feedback synapse from retinal horizontal cells to cone photoreceptors.PLoS Biol. 2011; 9: e1001057Crossref PubMed Scopus (16) Google Scholar; Klaassen et al., 2011Klaassen L.J. Sun Z. Steijaert M.N. Bolte P. Fahrenfort I. Sjoerdsma T. Klooster J. Claassen Y. Shields C.R. Ten Eikelder H.M. et al.Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels.PLoS Biol. 2011; 9: e1001107Crossref PubMed Scopus (25) Google Scholar). Taken as morphological populations, however, the horizontal cells are relatively simple. They can be stained for a variety of marker proteins in different animals. They, too, have been quantitatively mapped across the retinal surface in many species (Collin, 2008Collin S.P. A web-based archive for topographic maps of retinal cell distribution in vertebrates.Clin. Exp. Optom. 2008; 91: 85-95Crossref PubMed Scopus (26) Google Scholar). Early physiological recordings suggested that there were four types of bipolar cells: ON, OFF, sustained, and transient (Kaneko, 1970Kaneko A. Physiological and morphological identification of horizontal, bipolar and amacrine cells in goldfish retina.J. Physiol. 1970; 207: 623-633Crossref PubMed Google Scholar; Werblin and Dowling, 1969Werblin F.S. Dowling J.E. Organization of the retina of the mudpuppy, Necturus maculosus. II. Intracellular recording.J. Neurophysiol. 1969; 32: 339-355PubMed Google Scholar). Modern anatomical work and subsequent physiological evidence indicate that the true number of bipolar cell types is about 12. This has been a gradual realization. Initial studies used synapse densities (Cohen and Sterling, 1990Cohen E. Sterling P. Demonstration of cell types among cone bipolar neurons of cat retina.Philos. Trans. R. Soc. Lond. B Biol. Sci. 1990; 330: 305-321Crossref PubMed Google Scholar) to distinguish the types. As marker proteins of increasing specificity were discovered, the number of putative bipolar cell types gradually increased. Recent studies seem to have brought this to its conclusion. A set of intersecting methods was used to classify the bipolar cells of the rabbit (MacNeil et al., 2004MacNeil M.A. Heussy J.K. Dacheux R.F. Raviola E. Masland R.H. The population of bipolar cells in the rabbit retina.J. Comp. Neurol. 2004; 472: 73-86Crossref PubMed Scopus (53) Google Scholar). The strategy was to seek a complete survey of bipolar cell types by using several methods with different sampling biases. For purposes of classification, the purely anatomical samples were complemented by a set of cells injected with Lucifer yellow after physiological recording, so that their responses to light could be used as part of the classification. The bipolar cells of the rabbit were divided into a rod bipolar cell and 12 types of cone bipolar cells. In near-perfect agreement, Wässle et al., 2009Wässle H. Puller C. Müller F. Haverkamp S. Cone contacts, mosaics, and territories of bipolar cells in the mouse retina.J. Neurosci. 2009; 29: 106-117Crossref PubMed Scopus (133) Google Scholar classified the bipolar cells of the mouse using immunostaining for recently discovered type-specific markers and transgenic strains in which one or a few types of bipolar cells express a fluorescent marker. These were supplemented by microinjection, to reveal the cells’ finest processes and their contacts. They found one type of rod driven bipolar cell and 11 types that receive inputs primarily from cones (Figure 2). Because they are population stains, these methods allowed an estimate of the total number of bipolar cells of each type, which could then be added up for comparison with the total number of bipolar cells known by independent methods to exist in the mouse (Jeon et al., 1998Jeon C.J. Strettoi E. Masland R.H. The major cell populations of the mouse retina.J. Neurosci. 1998; 18: 8936-8946Crossref PubMed Google Scholar). The identified individual cell types correctly added up to the known total number of bipolar cells. Thus, “…the catalog of 11 cone bipolar cells and one rod bipolar cell is complete, and all major bipolar cell types of the mouse retina appear to have been discovered” (Wässle et al., 2009Wässle H. Puller C. Müller F. Haverkamp S. Cone contacts, mosaics, and territories of bipolar cells in the mouse retina.J. Neurosci. 2009; 29: 106-117Crossref PubMed Scopus (133) Google Scholar). This concept is simple, but it is topologically fairly subtle (Figure 3). From partial evidence, it was suspected a decade ago that each cone makes output to each of the types of bipolar cells—a critical principle for the signal processing of the retina. Wässle et al., 2009Wässle H. Puller C. Müller F. Haverkamp S. Cone contacts, mosaics, and territories of bipolar cells in the mouse retina.J. Neurosci. 2009; 29: 106-117Crossref PubMed Scopus (133) Google Scholar could confirm that this occurs for each of the 11 types of bipolar cells that they identified in the mouse. The exception is a specialized “blue cone bipolar,” which selectively contacts the short wavelength sensitive cones, as is necessary if the chromatic information is not to be degraded. Symmetrically, some bipolar cells avoid the terminals—they are numerically infrequent—of blue cones. And there is some crosstalk with the rods. But the central principle, which dominates the structural and functional organization of the retina, is that each bipolar cell contacts all of the cone terminals within the spread of its dendritic arbor. This is a geographically simple rule. Functionally, however, this arrangement allows something more sophisticated. By tuning the characteristics of the cone-to-bipolar synapses, each type of bipolar cell can transmit a different parsing of the cone’s output. Bipolar cells express distinctive sets of receptors, ion channels, and intracellular signaling systems. This right away suggests that each of the cells has a unique physiology, and so far that has consistently turned out to be the case. As a consequence, it is believed that each of the ∼12 anatomical types of bipolar cell that contacts a given cone transmits to the inner retina a different component extracted from the output of that cone. What types of information are segregated into the dozen parallel channels? A simple case is the blue cone bipolar. In the inner retina, this type of bipolar cell contacts a ganglion cell that compares short and long wavelengths; the ganglion cell then becomes a blue-ON, green-OFF ganglion cell. In the ground squirrel (a favorite because it contains a large number of cones), the bipolar cells that contact both classes of cones have been shown to have the expected broad spectral sensitivity, and presumably transmit the simple brightness of a stimulus, independent of its color (Breuninger et al., 2011Breuninger T. Puller C. Haverkamp S. Euler T. Chromatic bipolar cell pathways in the mouse retina.J. Neurosci. 2011; 31: 6504-6517Crossref PubMed Scopus (35) Google Scholar; Li and DeVries, 2006Li W. DeVries S.H. Bipolar cell pathways for color and luminance vision in a dichromatic mammalian retina.Nat. Neurosci. 2006; 9: 669-675Crossref PubMed Scopus (57) Google Scholar). Among the non-chromatic bipolar cells, a classic example is the segregation of responses into ON and OFF channels, the ON channels having their axon terminals in the inner half of the inner plexiform layer (IPL) and the OFF bipolars having their terminals in the outer half (Famiglietti et al., 1977Famiglietti Jr., E.V. Kaneko A. Tachibana M. Neuronal architecture of on and off pathways to ganglion cells in carp retina.Science. 1977; 198: 1267-1269Crossref PubMed Google Scholar; Nelson et al., 1978Nelson R. Famiglietti Jr., E.V. Kolb H. Intracellular staining reveals different levels of stratification for on- and off-center ganglion cells in cat retina.J. Neurophysiol. 1978; 41: 472-483PubMed Google Scholar). The difference between ON and OFF responses is due to the expression of two classes of glutamate receptor. OFF bipolar cells express AMPA and kainate type receptors, which are cation channels opened by glutamate; since photoreceptor cells hyperpolarize in response to light, these bipolar cells hyperpolarize in response to light as well, because less glutamate arrives from the cone synapse. ON bipolar cells express mGluR6, a metabotropic receptor, which, when glutamate binds to the receptor, leads to closing of the cation channel TRPM1. The receptor is thus sign inverting. When light causes less glutamate to be received from the photoreceptor terminal, cation channels open and the cell depolarizes (Morgans et al., 2009Morgans C.W. Zhang J. Jeffrey B.G. Nelson S.M. Burke N.S. Duvoisin R.M. Brown R.L. TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells.Proc. Natl. Acad. Sci. USA. 2009; 106: 19174-19178Crossref PubMed Scopus (107) Google Scholar; Shen et al., 2009Shen Y. Heimel J.A. Kamermans M. Peachey N.S. Gregg R.G. Nawy S. A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells.J. Neurosci. 2009; 29: 6088-6093Crossref PubMed Scopus (92) Google Scholar). Similarly, the distinction between sustained and transient bipolar cells is caused by the expression of rapidly or slowly inactivating glutamate receptors (Awatramani and Slaughter, 2000Awatramani G.B. Slaughter M.M. Origin of transient and sustained responses in ganglion cells of the retina.J. Neurosci. 2000; 20: 7087-7095PubMed Google Scholar; DeVries, 2000DeVries S.H. Bipolar cells use kainate and AMPA receptors to filter visual information into separate channels.Neuron. 2000; 28: 847-856Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). This creates four classes of bipolar cells: ON-sustained, ON-transient, OFF-sustained, and OFF-transient. In detail, the different structural/molecular types of bipolar cells show a wide diversity of response waveforms in response to light; aside from the simple tonic versus phasic dimension, these responses display complex mixtures of the two (Wu et al., 2001Wu S.M. Gao F. Maple B.R. Integration and segregation of visual signals by bipolar cells in the tiger salamander retina.Prog. Brain Res. 2001; 131: 125-143Crossref PubMed Google Scholar). The functional meanings of these are only beginning to be understood (Freed, 2000Freed M.A. Parallel cone bipolar pathways to a ganglion cell use different rates and amplitudes of quantal excitation.J. Neurosci. 2000; 20: 3956-3963PubMed Google Scholar). A case in point is the expression of differing sets of regulation of G protein signaling (RGS) proteins, which control the kinetics of the response to synaptic input in ON bipolar cells (Cao et al., 2012Cao Y. Pahlberg J. Sarria I. Kamasawa N. Sampath A.P. Martemyanov K.A. Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons.Proc. Natl. Acad. Sci. USA. 2012; 109: 7905-7910Crossref PubMed Scopus (17) Google Scholar). Another is a type of bipolar cell that generates Na+ action potentials. Na+ currents have been known to occur from studies of many retinas, but their functions are unclear (Ichinose and Lukasiewicz, 2007Ichinose T. Lukasiewicz P.D. Ambient light regulates sodium channel activity to dynamically control retinal signaling.J. Neurosci. 2007; 27: 4756-4764Crossref PubMed Scopus (24) Google Scholar; Ichinose et al., 2005Ichinose T. Shields C.R. Lukasiewicz P.D. Sodium channels in transient retinal bipolar cells enhance visual responses in ganglion cells.J. Neurosci. 2005; 25: 1856-1865Crossref PubMed Scopus (39) Google Scholar; Ma et al., 2005Ma Y.P. Cui J. Pan Z.H. Heterogeneous expression of voltage-dependent Na+ and K+ channels in mammalian retinal bipolar cells.Vis. Neurosci. 2005; 22: 119-133Crossref PubMed Scopus (20) Google Scholar; Zenisek et al., 2001Zenisek D. Henry D. Studholme K. Yazulla S. Matthews G. Voltage-dependent sodium channels are expressed in nonspiking retinal bipolar neurons.J. Neurosci. 2001; 21: 4543-4550PubMed Google Scholar). In the ground squirrel, the structurally defined bipolar cell termed cb5b has a large tetrodotoxin (TTX)-sensitive Na+ current. These cells signal the onset of a light step with a few all-or-nothing action potentials (Figure 4). In response to a continually graded noise stimulus (more closely representing a natural scene), they generate both graded and spiking responses, the spikes occurring with millisecond precision. The cells select for stimulus sequences in which transitions to light are preceded by a period of darkness. Their axon terminals costratify with the dendrites of a specific group of ganglion cells, and these ganglion cells encode light onset with a short latency burst of spikes. It thus appears that this bipolar cell trades the bandwidth inherent in graded signaling for spikes that can elicit a rapid and reliable response in transient-type ganglion cells (Saszik and DeVries, 2012Saszik S. DeVries S.H. A mammalian retinal bipolar cell uses both graded changes in membrane voltage and all-or-nothing Na+ spikes to encode light.J. Neurosci. 2012; 32: 297-307Crossref PubMed Scopus (22) Google Scholar). The central structural characteristic that defines the ∼12 types of bipolar cells is the level of the inner plexiform layer at which their axons terminate. In other words, the bipolar cells receive input from all of the cones within their reach, as just described, but they terminate on very restricted sets of postsynaptic partners. Distinction of functional types on this basis is confirmed by molecular differences that correlate with types that have been defined in this way. The specificity is again confirmed by the fact that different sets of ganglion cells (as well as amacrine cells) costratify with them. These, too, represent distinct types: they have different central projections, different physiologies, and different molecular signatures. Although there is amacrine cell crosstalk between the layers (see below) the bulk of the inner retina’s connectivity occurs within the layers. The stalks of bipolar cell axons, and the proximal dendrites of ganglion cells, often pass through several laminae to reach their final level of stratification, but few synapses are made with these connecting processes en passant: the main work of synaptic connectivity is done within the layers. Indeed, the lamination of the inner plexiform layer is a fundamental guide to the retina’s wiring diagram. All bipolar cells and all ganglion cells are stratified—some in narrow layers, some in broader ones, some in multiple ones, but always stratified. One may imagine the array of bipolar cell axon terminals as transmitting a cafeteria of stimulus properties, among which the ganglion cell chooses depending on the type of information that particular ganglion cell will finally transmit to central visual structures. This connectivity builds the initial foundation of the response selectivity that distinguishes functional types of ganglion cell: if the different retinal ganglion cells get selective inputs from differently responding bipolar cells, they are right away imbued with differing types of response to light themselves. Note that these connections are not limited to the one-to-one case—ganglion cells that stratify in several layers can take some of their properties from one type of bipolar cell, and other properties from a different one. A slightly tricky conceptual issue should be clarified here. There are two main influences upon the responses to light of bipolar cells. As just described, the first is their synaptic drive from the rod or cone photoreceptors, as expressed through the bipolar cells' differing glutamate receptors and modified by their signaling proteins and ion channels. These features are intrinsic to the bipolar cells, controlled by the set of proteins that each type of bipolar cell expresses. But the bipolar cells are also influenced by inputs from amacrine cells (Figure 5), and those effects are included in the bipolar cell’s “response to light” as well. Bipolar cells are short, fat neurons (Figure 1) and are electrotonically compact. Thus, a recording from the soma of the bipolar cell does not simply monitor a signal transmitted from dendrite to soma to axon of the bipolar cell, like watching a railway train pass a vantage point alongside its tracks. Instead, a soma recording monitors the effects of all of the bipolar cell's inputs, including the signals that impinge on its axon terminals from amacrine cells (Bieda and Copenhagen, 2000Bieda M.C. Copenhagen D.R. Inhibition is not required for the production of transient spiking responses from retinal ganglion cells.Vis. Neurosci. 2000; 17: 243-254Crossref PubMed Scopus (11) Google Scholar; DeVries and Schwartz, 1999DeVries S.H. Schwartz E.A. Kainate receptors mediate synaptic transmission between cones and ‘Off’ bipolar cells in a mammalian retina.Nature. 1999; 397: 157-160Crossref PubMed Scopus (161) Google Scholar; Euler and Masland, 2000Euler T. Masland R.H. Light-evoked responses of bipolar cells in a mammalian retina.J. Neurophysiol. 2000; 83: 1817-1829PubMed Google Scholar; Matsui et al., 1998Matsui K. Hosoi N. Tachibana M. Excitatory synaptic transmission in the inner retina: paired recordings of bipolar cells and neurons of the ganglion cell layer.J. Neurosci. 1998; 18: 4500-4510Crossref PubMed Google Scholar; Saszik and DeVries, 2012Saszik S. DeVries S.H. A mammalian retinal bipolar cell uses both graded changes in membrane voltage and all-or-nothing Na+ spikes to encode light.J. Neurosci. 2012; 32: 297-307Crossref PubMed Scopus (22) Google Scholar). Thus, the output of the bipolar cell onto the ganglion cell includes both the intrinsic response properties of the bipolar cell and the actions of amacrine cells upon the bipolar cell. The bipolar cell is as much an integrating center as it is a conduit from outer retina to inner. The second controller of the ganglion cell response is direct inpu
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