Introduction
Rod and cone photoreceptors transduce light, and they operate over different levels of illumination and chromatic ranges. In the vertebrate retina, there is a single type of rod and up to four types of cones. Light-evoked signals in rods and cones are transmitted to bipolar and horizontal cells at the first synapse in the visual system, and these signals subsequently diverge into multiple bipolar cell channels that terminate on amacrine and ganglion cells in the inner retina. Ganglion cells in turn project their axons via the optic nerve to terminate in numerous visual nuclei in the brain. The major retinal cell classes were recognized over 125 years ago (see Ramón y Cajal, 1894) and they have been defined in all vertebrates, from primitive fish to humans.
Photoreceptors are electrically coupled and the coupling influences both photoreceptor signaling and downstream bipolar cell pathways. Photoreceptors form excitatory, glutamate-mediated chemical synapses with both bipolar and horizontal cells. Glutamate release from photoreceptors is vesicular and graded in a smooth manner, and the rate of release of glutamate is high in the dark and low in the light. Bipolar cells are classified into two major subtypes, depolarizing (or ON-type) and hyperpolarizing (or OFF-type) based on their response to a centered light stimulus, respectively. Bipolar cells defined in mammalian retinas consist of a single rod type and 8 to 13 cone types based on their axonal and dendritic features, connectivity in the outer and inner retina, and transcriptomics. Bipolar cells provide excitatory glutamatergic output to amacrine and ganglion cells, and they have distinct functional properties, including center-surround antagonism and color opponency. Horizontal cells, consisting of one or two types in the mammalian retina, are electrically coupled, and their dendrites innervate cone synaptic terminals, called pedicles, whereas their axon terminals innervate rod synaptic terminals, called spherules. Horizontal cells mediate feedback to photoreceptors by modulation of photoreceptor voltage-gated calcium (Cav) channels, as well as feedforward signaling to bipolar cells. Horizontal cells regulate the synaptic gain of the photoreceptor output synapse and generate center-surround antagonistic receptive fields that underlie contrast enhancement and color opponency in visual image processing.
The networks formed by outer retinal neurons mediate early visual image processing that includes optimizing light sensitivity, chromatic discrimination, and spatiotemporal resolution of the visual image. These early visual signal components are conveyed by multiple bipolar cell channels to the inner retina, which further process the features of the visual scene before it is conveyed to the central nervous system.
Photoreceptors
Photoreceptors are coupled in networks
Electrical coupling and gap junctions between photoreceptors are well established in all vertebrate retinas. Coupling results in a mixing of photoreceptor signals, which average and reduce the variability of photoreceptor responses, increasing signal-to-noise ratios and the discrimination of objects.
In mammalian retina, photoreceptor coupling is predominantly rod-to-cone and cone-to-cone coupling. Electron microscopic studies showed cone and rod terminal gap junctions in multiple mammalian retinas. In monkey retina, there is coupling between cones with the same and different spectral sensitivities, and in ground squirrel retina, coupling occurs between cones of the same spectral type. Whereas extensive rod-to-rod coupling is present in nonmammalian retinas, it is not as well established in mammalian retinas, with few reports of rod-to-rod coupling conductances and small size gap junctions between rods in mouse, guinea pig, and monkey retinas.
Electrical coupling is mediated by gap junctional proteins called connexins (Cx), which span the extracellular space to form a channel between two adjacent plasma membranes. In mammals, including humans, photoreceptor gap junctions are formed by connexin 36 (Cx36), which is mainly localized to cone pedicle telodendria ( Fig. 22.1 ). Cx36 is present in mouse rods based on single-cell RNA sequencing and in situ hybridization analyses that show Cx36 mRNA, as well as Cx36 immunoreactivity at rod-to-cone junctions at the ultrastructural level. Failure to detect electrical coupling when Cx36 is genetically deleted from mouse rods or cones, or from both, is also evidence that Cx36 mediates electrical coupling between photoreceptors ( Fig. 22.1 ). Furthermore, deletion of cone Cx36 disrupts rod-to-rod electrical coupling, indicating that rods couple to cones and not rods. These findings indicate that rod-to-rod coupling is indirect in the mouse retina and support a rod-cone network model based on tracer spread from cones to rods of one cone coupled to approximately 30 rods, matching closely an electron microscopic study that reports approximately 30 rods converge onto a single cone.
Rod gap junction coupling is regulated by ambient light levels with the highest conductance at night and the lowest during the day, consistent with light and circadian clock regulation of photoreceptor coupling. Additionally, electrical coupling conductance is eliminated by saturating light exposure during either subjective day or night. Light regulation of gap junction coupling is mediated by dopamine, which inhibits the gap junction conductance through dopamine D 2 -type receptors expressed by photoreceptors. Therefore in low light (scotopic/mesopic), when levels of dopamine are at their minimum, coupling between rods and cones is more prevalent, and in higher light conditions (photopic), with higher levels of dopamine, gap junction coupling is reduced, isolating rod and cone responses.
Photoreceptor electrical coupling is dynamic and improves the signal-to-noise ratio over the photoreceptor operating range. Under low illumination the spatial spread of rod signals and averaging of those signals within the rod network increases the signal-to-noise ratio and reduces rod response variability, which increases detectability of very dim images. Increased signal-to-noise ratio with cone-to-cone coupling is reported to improve discrimination of objects and increase the range of cone sensitivity by mixing light signals from different cone types. Rod-to-cone coupling also broadens the operating range and sensitivity of cones in mesopic light levels by transmitting the rod signal into the cones.
Rod-to-cone electrical coupling is the first step of a secondary rod signaling pathway to the inner retina that operates in mesopic levels. The rod signal is carried from rods to cones via gap junction coupling, and the photoreceptor signal is subsequently conveyed to the inner retina by cone bipolar cells. Rod signaling pathways to the inner retina are discussed in more detail in a later section of this chapter.
Photoreceptors send synaptic output to bipolar and horizontal cells
In all vertebrate retinas, the excitatory amino acid neurotransmitter, glutamate, is the photoreceptor neurotransmitter. Glutamate is released continuously at photoreceptor ribbon synapses in darkness and release is reduced in a graded fashion with increasing light levels. Glutamate release is mediated by the graded depolarization of photoreceptors and the activation of dihydropyridine-sensitive voltage-gated Cav1.4 channels at synaptic vesicle release sites near the synaptic ribbon. Mutations in Cav1.4 channels in humans are responsible for congenital stationary night blindness type 2 (CSNB2).
Photoreceptors form synaptic connections with rod and cone bipolar cells, and horizontal cells in the outer plexiform layer (OPL) at the first synapse in the visual system. Rod bipolar cells and ON-cone bipolar cells are characterized by an invaginating dendrite that ends within the photoreceptor terminal near the synaptic ribbon ( Fig. 22.2 ). Within the photoreceptor terminal, the invaginating bipolar cell dendrite and horizontal cell processes near the synaptic ribbon is commonly referred to as a synaptic triad. The OFF-cone bipolar cell dendritic tips are aligned along the base of the cone pedicle, and in general a cone pedicle is innervated by the dendrites of multiple cone bipolar subtypes. The complexity of the bipolar and horizontal cell contacts and the localization of the glutamate and γ-aminobutyric acid (GABA) transmitter receptors within the synaptic complex is illustrated for the monkey cone pedicle. Within the pedicle region, metabotropic glutamate receptors (mGluRs) are expressed by the invaginating ON-bipolar cell dendrite, and ionotropic glutamate receptors are expressed by the horizontal cell dendrites. Beneath the primate cone pedicle ( Fig. 22.2 ) is a layer of ionotropic glutamate receptor–expressing OFF-bipolar cell processes and two layers of ionotropic glutamate receptor–expressing horizontal cell processes, sandwiching bipolar cell dendrites bearing ionotropic GABAA receptors.
Photoreceptor signaling to rod bipolar and ON-cone bipolar cells
Light reduces photoreceptor glutamate release onto rod bipolar and ON-cone bipolar cells, and these cells depolarize owing to a sign-inverting metabotropic glutamate receptor (mGluR) ( Fig. 22.3 ). The reduction in mGluR6 activation with light results in the opening of transient receptor potential, M1 isoform (TRPM1) ion channels to produce depolarization via the flux of nonselective cations. The rapid activation and high amplification of this signaling arises from a complex of mGluR6, G-proteins, GTPase-activating proteins, GPR179, and scaffolding proteins. Mutations in genes encoding nyctalopin (NYX), TRPM1, mGluR6 (GRM6), and other proteins in this signaling complex results in the “no b-wave” (nob) phenotype and underlies congenital stationary night blindness type 1 (CSNB1).
Photoreceptor signaling to OFF-cone bipolar cells
Light reduces photoreceptor glutamate release onto OFF-cone bipolar cells, and these cells hyperpolarize by the closure of the ionotropic glutamate receptors of kainate (KA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes. KA-evoked currents have slower kinetics and recover more slowly from desensitization, whereas AMPA-activated currents have fast kinetics and desensitize and recover quickly from desensitization. The response properties of OFF-cone bipolar cell subtypes are shaped by different, species-specific combinations of AMPA and KA receptors. For example, in mouse retina, one OFF-cone bipolar cell type expresses AMPA receptors, others express KA receptors, while still others express both AMPA and KA receptors. The differential expression and activation of KA receptors underlie differences in the OFF-cone bipolar cell temporal responses to light in mouse and monkey retina. In contrast, in ground squirrel retina, there is a segregation of AMPA and KA receptors to different OFF-cone bipolar types, which accounts for differences in their temporal response properties.
Photoreceptor signaling to horizontal cells
Horizontal cells are tonically depolarized in darkness by photoreceptor glutamate release and they hyperpolarize in response to light. For horizontal cells, this sign-conserving response occurs primarily through AMPA receptors and to a lesser degree via KA receptors. In primate retina, both H1 and H2 horizontal cell types express AMPA receptors on dendritic endings and at desmosome-like junctions with other horizontal cells, but H2s, that preferentially synapse with S-cones, lack KA receptors at these synapses. The preponderance of A-type horizontal cell dendrites express AMPA receptors and a smaller fraction have KA receptors; in contrast, B-type horizontal cell dendrites show a complementary distribution with a greater fraction of KA receptors than AMPA receptors. Additionally, horizontal cell axons exhibit AMPA receptors on their terminals. The differential expression of the AMPA and KA receptors suggests that the two horizontal cell types process signals with different temporal response properties.
Interplexiform cells
Interplexiform cells modulate retinal neurons
Interplexiform cells, which form a sparsely occurring amacrine cell population in all vertebrate retinas, synthesize and release dopamine with increasing light levels. Interplexiform cell bodies are in the inner nuclear layer (INL) and they give rise to a widespread network of processes in the inner plexiform layer (IPL) and in most vertebrates, sparsely occurring processes that ramify in the OPL. Dopamine is released from dopaminergic processes extrasynaptically, and dopamine diffuses throughout the retina to act in a paracrine manner on all retinal cell classes. Dopamine acts via two families of G-protein–coupled receptors, D 1 and D 2, which are selectively expressed by multiple retinal cell types. For example, dopamine regulates photoreceptor coupling by activation of D 2 receptors, and bipolar and horizontal cell coupling by activation of D 1 receptors.
Dopamine exerts modulatory effects on a large number of ion channel types. Among these actions in mammals, dopamine acts at horizontal cell D 1 receptors to modulate Cav channels and at ON-cone bipolar cells to modulate voltage-gated Na channels. Acting at D 2 /D 4 receptors, dopamine modulates mouse photoreceptor Cav and hyperpolarization-activated cyclic nucleotide-gated channels. The influence of dopamine on outer retinal neuronal signaling pathways is indicative of the importance that dopamine and other neuroactive peptides and molecules such as nitric oxide have on the modulation of outer retina cell networks and early visual image processing.
Horizontal cells
Horizontal cells are inhibitory interneurons
Horizontal cells are the only population of inhibitory interneurons in the outer retina. They have large receptive fields owing to their expansive lateral processes in the OPL that collect inputs from numerous photoreceptors, and to their extensive electrical coupling with neighboring horizontal cells. Given these properties, horizontal cells have a global role in outer retinal signal processing, including generating antagonistic center-surround receptive fields and providing synaptic gain control of photoreceptor output at the local level.
In nonmammalian vertebrates, there are from two to as many as five horizontal cell subtypes, and they are characterized by their selective innervation of rods and different spectral cone types. In most mammals there are two horizontal cell types, characterized by dendritic processes and a large axon terminal system that innervate photoreceptors, and dendritic or axonal processes that form connections with bipolar cell dendrites. Different nomenclatures are used for mammalian horizontal cells. Most common are A-type and B-type, which correspond to H2 and H1, respectively, in primates. Mice and rats have only a B-type horizontal cell.
A-type horizontal cell dendrites innervate cone pedicles and are without axons. B-type horizontal cell dendrites innervate cone pedicles, and they have an extensive axon terminal system that innervates rod spherules ( Fig. 22.4 ). The axon terminal system is generally considered to be electrically isolated from the B-type cell body, although axons may carry signals between the cell body and the axon terminal, allowing blending of rod and cone signals, albeit in an unusual unidirectional manner.
Horizontal cells form coupled networks
Extensive electrical coupling between horizontal cells is well established with coupling of homologous horizontal cell types to form separate networks. In addition, the axon terminal system of B-type horizontal cells couple independently, forming a third network. The electrical spread of horizontal cell signals across the horizontal cell network and the degree of coupling is dynamically modulated by dopamine, retinoic acid, and light. There is reduced coupling in long-term, complete dark-adapted (scotopic), and full light-adapted (photopic) conditions; in contrast, low to intermediate light (mesopic) levels when rod signaling is dominant produce the greatest degree of horizontal cell coupling. In monkey retina, receptive field sizes and the extent of coupling are also largest in dark-adapted conditions with reduced sizes in mesopic and photopic conditions. Tracer coupling and receptive field mapping confirm the relationship between tracer spread and receptive field size as a function of background light intensity in both horizontal cell types in the rabbit retina. This means that antagonistic surrounds formed by horizontal cells are broad under dim light conditions and narrow in bright light, properties that would differentially influence the bipolar cell receptive field properties and contrast sensitivity conveyed to the inner retina.
Mammalian horizontal cell gap junctions are formed by connexins that are distinct from photoreceptor connexins. In rabbit retina, A-type and B-type horizontal cell dendrites are coupled by Cx50, and the B-type axon terminal system is coupled by Cx57. In mouse retina, which only has B-type horizontal cells, both the dendrites and axonal terminals are coupled by Cx57 ; in addition, Cx50 is found in axons, and infrequently at the same location as Cx57, indicating the likely presence of two molecularly different gap junctions. The deletion of Cx57 in mouse eliminated cell coupling and reduced horizontal cell receptive field sizes, which is consistent with gap junctions contributing to the size of horizontal cell receptive fields.
Horizontal cell synaptic output is mediated by GABA
Horizontal cells are a primary source of GABA in the vertebrate outer retina based on GABA immunostaining, and in some vertebrates, the localization of the GABA synthetic enzymes (GAD65 and GAD67) and the vesicular GABA transporter (VGAT), which concentrates GABA into synaptic vesicles. Horizontal cells express GABAA receptors, including ρ-subunit–containing GABAA receptors at the dendritic tips and axonal terminals. Horizontal cell feedforward targets bipolar cells, which show GABAA receptors on their dendrites within the OPL. Differential chloride gradients are found in ON- and OFF-bipolar cell dendrites due to the action of Na-K-Cl cotransporter 1 (NKCC1) or K-Cl cotransporter 2 (KCC2) and this would underlie the polarity of their antagonistic surrounds via feedforward inhibition. The prominent expression of extrasynaptic GABAA receptor subunits, such as ɑ6 in horizontal cells and bipolar cell dendrites, indicate that tonically active GABA-induced currents play a role in signaling in the OPL.
Horizontal cell responses initiate center-surround antagonistic receptive fields
The most comprehensively characterized synaptic pathway from horizontal cells mediates inhibitory feedback to photoreceptors. In the dark, horizontal cells have a relatively positive resting membrane potential (–40 mV to –30 mV) and respond to white light with graded hyperpolarization, concurrent with the reduction of glutamate release from photoreceptors. Consistent across all vertebrate retinas are the large receptive fields of horizontal cells, providing feedback signals that subtract from those originating from the narrow receptive fields of photoreceptors ( Fig. 22.5 ). The horizontal cell–modulated photoreceptor responses transmitted to bipolar cells contribute, together with inhibitory signals from amacrine cells, to the center-surround antagonistic receptive fields of both ON- and OFF-bipolar cells. The molecular, cellular, and synaptic mechanisms mediating this interaction remain under investigation.
Horizontal cell feedback is mediated within the photoreceptor synaptic triad between horizontal cell dendrites and the photoreceptor terminal. Surround-induced horizontal cell hyperpolarization increases Cav1.4 currents in cones ( Fig. 22.5 ), and this produces a higher rate of glutamate release, depolarizing the OFF-bipolar cells and hyperpolarizing the ON-bipolar cells. Several mechanisms that produce this inhibitory feedback are supported by evidence obtained in fish and amphibian retinas, including (1) horizontal cell release of GABA directly onto photoreceptors, (2) ephaptic coupling, wherein the current entering horizontal cell glutamate receptor channels and hemichannels alters the potential in the synaptic cleft, and (3) elevation of the pH in the synaptic cleft when horizontal cells hyperpolarize, all cellular mechanisms that could mediate increasing Cav1.4 channel current in photoreceptors when horizontal cells hyperpolarize. These different mechanisms of feedback may be dominant in different species, under different conditions, and over separate temporal ranges.
In mammalian retina, horizontal cell to photoreceptor feedback signaling favors the third mechanism. Although most models of mammalian horizontal cells do not include photoreceptor feedback responses due directly to GABA receptors, there is a report of this in mouse retina. Cx hemichannels that mediate ephaptic coupling in fish are not present in the mammalian synaptic cleft. Whereas pannexin hemichannels participate in horizontal feedback in zebrafish, in mouse retina there is very sparse pannexin immunostaining on some horizontal cell invaginating tips, where it would have to be localized to support an ephaptic mechanism.
However, there is a twist. Horizontal cells do release GABA, but they respond autaptically to their own release of GABA, and the presence of GABA is sustained, likely owing in part to the lack of GABA uptake transporters in mammalian horizontal cells. Owing to the high permeability of bicarbonate in GABAA receptors. the horizontal cell membrane potential can change the pH in the synaptic cleft via the voltage-induced driving force on bicarbonate efflux ( Fig. 22.6 ). Hyperpolarization that accompanies a large spot or annular light stimulus causes an increase in cleft pH that increases cone Cav channel activation followed by increased glutamate release. Sodium-proton exchangers (NHEs) also have a role in acidifying the synaptic cleft, an effect typically induced by neuronal depolarization. This inhibitory feedback mechanism in the photoreceptor synaptic cleft acts rapidly to regulate glutamate release in a manner that maintains optimal synaptic gain at each local synaptic site, in addition to when more global actions, such as surround illumination, broadly alter horizontal cell membrane potential.
As noted previously, mammalian horizontal cells are GABAergic: they immunostain for GABA and show immunostaining for the vesicular and SNARE proteins required for GABA release. Horizontal cells also express several GABAA receptor subunits that mediate an autaptic response to GABA. In mouse and rat retina, horizontal cells strongly express ρ-subunit–containing GABAA receptors at the tips of their processes in the photoreceptor synaptic clefts, such that when the GABA release is eliminated by genetically mediated VGAT deletion in mouse horizontal cells, and the autaptic reception of their own GABA release is halted, feedback inhibition of cones is eliminated ( Fig. 22.7 ).
Horizontal cells also feed inhibition forward to bipolar cells
Horizontal cell feedforward was implied by the presence of horizontal cell synaptic contacts on bipolar cell dendrites, suggesting another pathway by which horizontal cells provide antagonistic surround inhibition to bipolar cells. Horizontal synaptic contacts are common in mudpuppy retina and have been described in rabbit and human retina. In cat and mouse OPL, horizontal cell processes and bipolar cell dendrites form junctions and, although lacking synaptic vesicles, are a possible site of synaptic transmission. In mammals, GABAA receptors are localized to bipolar cell dendrites. In mouse retina, horizontal cell dendritic varicosities are located about 1 µm under the base of the cone pedicles in apposition with bipolar cell dendrites expressing GABAA receptor subunits and other horizontal cell processes, suggesting possible postsynaptic sites that mediate GABA’s action ( Fig. 22.8 ). In contrast to the local signal at the horizontal cell dendritic tips, which provides the synaptic gain signal that optimizes individual photoreceptor release of glutamate onto bipolar cells, the GABAergic signals from horizontal cells at these dendritic varicosities are hypothesized to carry global signals from the horizontal cell and contribute to the antagonistic surrounds in bipolar cells.
Feedforward signaling contributes to bipolar cell surround inhibition in salamander based on electrophysiological recordings and chloride imaging of mouse ON-bipolar cell dendrites. Electrophysiological evidence supporting horizontal cell feedforward signaling has not been observed frequently in mammals. One difficulty involves the extensive GABAA receptor inputs to bipolar cells at their axon terminals from amacrine cells, and this strong inhibitory input tends to make detection of smaller, more slowly changing horizontal cell GABAergic inputs at the dendrites of bipolar cells complicated to isolate for study.
Horizontal cells play key roles in chromatic visual processing
The first stage of color processing in vertebrate retinas, following the transduction of light stimuli by cones having chromatically distinct sensitivities, first reported in goldfish, is mediated by horizontal cell feedback to cones that generates color-opponent pathways. Mammalian and nonmammalian vertebrates show many similarities in this processing, but there are important differences. In nonmammalian retinas, there is a rich variety of photoreceptor types, including retinas with double cones and cones with oil droplets that mediate chromatic sensitivity. In turtles and fish, the chromatic spectrum is sampled by cones with peak chromatic absorption wavelengths ranging from around 350 nm (UV range) to nearly 700 nm (far red range), twice the range found in mammals. Their color tuning occurs through a cascaded system of color-opponent pathways using horizontal cell antagonistic feedback signaling to cones of different chromatic sensitivity. Red cones signal to one class of horizontal cells, accounting for a monochromatic luminosity (L) signal in L-type cone horizontal cells, and this is fed back to green cones, which in turn synapse with horizontal cells that show red-green color opponency, generating the first type of spectrally sensitive, or chromaticity signal, in C-type cone horizontal cells. This signal is fed back to blue cones, the output of which goes to a further horizontal cell type that shows blue-green antagonism. In zebrafish another cone type with UV sensitivity also contributes to sequential analysis, with additional feedback pathways being implemented to generate chromatic antagonism.
Mammals have a single rod with sensitivity in the medium-wavelength (M, green) range of the chromatic spectrum, and two or three cone types with different chromatic sensitivities in the long-wavelength region (L, red), medium-wavelength region (M, green) range, and short-wavelength regions (S, blue or UV). Circuitry for chromatic antagonism in dichromat mammalian retinas uses green M-cones and UV or blue S-cones that signal in varying ratios to a single horizontal cell type, which feed back to both cone types. This results in a spectrum of variably tuned M- and S-cone signals, dependent on the density of cone horizontal cell inputs, providing varying degrees of chromatic tuning. In ventral M-cone–poor regions of mouse retina, rod input, which has a peak sensitivity near that of M-cones, appears to be used to generate color opponency.
In some mammals, including trichromat primates, L-cones and M-cones signal to the same horizontal cell type, which similarly feeds back to both cone types, leading to bipolar cells with variably tuned L- and M-cone opponent signals forwarded to bipolar cells. In this scheme, the relative weighting of L- and M-cone inputs to the receptive field center and the mixed (L + M or yellow) antagonistic surround of the bipolar cell recipients is determined variably by how many L- and M-cones make input to the particular horizontal cell that is the source of negative feedback ( Fig. 22.9 ).
In trichromat primates, L- and M-cones, and some S-cones, synapse with H1 horizontal cell dendrites, but S-cones preferentially contact H2 horizontal cells, which also receive minor input from L- and M-cones. The S-cone signal, following mixed chromatic feedback from horizontal cells, is then passed on directly via dedicated cone bipolar cells to the ON sublamina of the IPL, contacting the dendrites of small bistratified ganglion cells. In monkey retina, another bipolar cell type carrying mixed L- and M-cone (or yellow) signals, terminates on the dendrites of the same bistratified ganglion cell in the OFF sublamina ( Fig. 22.10 ). Together the blue ON-bipolar cell and the yellow OFF-bipolar cell contacting the dendrites of their ganglion cell target form an effective antagonistic interaction producing antagonistic blue-yellow chromatic sensitivity interaction without a major role for horizontal cells, as the surrounds cancel out. There are additional color-opponent pathways in nonprimate and primate retinas.
Horizontal cells influence ganglion cell responses
Contributions of horizontal cells to ganglion cell antagonistic surrounds have been established with simultaneous recordings of horizontal cells and ganglion cells in fish and rabbit. More recently, the impact of horizontal cell activity on ganglion cell response properties and receptive field structure has been demonstrated by experimentally silencing horizontal cell responsivity in mouse retina. Selective ablation of horizontal cells with targeted diphtheria toxin, as well as genetic deletion of AMPA receptors in horizontal cells that eliminate their responses to light, leads to pronounced changes to some ganglion cell receptive field structures, reducing surround inhibition and altering spatial frequency tuning. A silencing approach using expression of pharmacologically selective actuator module-glycine receptors (PSAM-GlyR), which shunts the horizontal cell membrane potential with chloride conductance, produces a reduction of transient ganglion cell excitatory inputs and enhanced ON- but suppressed OFF-ganglion cell responses, Compared with a simple concept of center-surround antagonism, these experimental models reveal detailed and specific components of the role horizontal cells play in forming responses of different types of ganglion cells. Remaining features of surround antagonism in ganglion cells are mediated by other lateral inhibitory systems, such as those operating in the inner retina through amacrine cell inhibition.
Bipolar cells
Bipolar cells carry separate information streams from the outer to the inner retina
Bipolar cells carry the light signals in parallel visual pathways to the inner retina and convey numerous visual image features, including ON- and OFF-center responsiveness, transient and sustained light responses, spatial and temporal resolution, chromatic discrimination, and local motion origin. The functional diversity of bipolar cell responses arises from both excitatory and inhibitory inputs from photoreceptors and horizontal cells in the outer retina, and the inhibitory inputs from amacrine cells in the inner retina.
Rod and cone bipolar cell subtypes have distinct morphologic features ( Fig. 22.11 ) and light response properties. In the best characterized mammalian retinas, including the mouse and monkey, there is one morphologic rod bipolar cell type and 8 to 13 cone bipolar cell types. A general functional feature found across all vertebrates is the segregation of the ON- and OFF-bipolar cell light responses in the OPL. As described earlier, ON-bipolar cell dendrites invaginate rod and cone terminals and OFF-bipolar cell dendrites predominantly make basal or flat contacts at the base of cone pedicles. There is mixing of the rod and cone input to bipolar cells in the vertebrate retina. In nonmammalian retinas, there is little segregation of bipolar cell contacts with rods and cones, with mixed rod and cone bipolar cell types, and in mouse and rabbit retina the majority of rod bipolar cells receive some cone photoreceptor input, and conversely, some OFF-cone bipolar cell types receive rod photoreceptor input ( Fig. 22.11 ).
