L and M cones, divided into two groups by absorption spectra, have not been distinguished by structure. Here, we report what may be such a difference. We reconstructed the synaptic terminals of 16 non-S cones and the dendritic arbors of their ON and OFF midget bipolar cells from high-magnification electron micrographs of serial thin sections of a small region of macaque fovea. Each cone terminal contacted a similar number (~16) of invaginating central elements provided by its ON midget bipolar cell. By contrast, the numbers of connections between a cone terminal and its OFF midget bipolar cell were grouped into two clusters: 30–37 versus 43–50 basal contacts in the triad-associated position and 41–47 versus 61–74 Outer Densities within those basal contacts. The coefficients of variation of these distributions were all in the range of 10% or lower, characteristic of single populations. If these two clusters correspond to M- and L-cone circuits, the results reveal structural differences between M and L cones and between their corresponding OFF midget bipolar cells.

As described in the companion paper, the synaptic terminal of a cone photoreceptor in macaque monkey makes an average of 35 or 46 basal contacts with the tips of the dendrites of its OFF midget bipolar cell. Each basal contact has one or more symmetrically thickened dense regions. These “Outer Densities,” averaging 48 or 67 in number, harbor clusters of ionotropic glutamate receptors and are ~0.8 μm (and ~1-ms diffusion time) from active zones associated with synaptic ribbons. Here, we show similarly appearing “Inner Densities,” averaging 53 or 74 in number, located more proximally on the dendrites of these OFF midget bipolar cells, ~0.4 μm inward from the tips of the dendrites and out of contact with the basal surface of the cone terminal. Compared to desmosome-like junctions, Inner Densities are closer to the terminal and are less dense and less thick. Each Inner Density is shared with another cell, the partners including diffuse bipolar cells, ON midget bipolar cells, and horizontal cells. Given the diversity of the partners, the OFF midget bipolar cells are unlikely to be in a synaptic relationship with the partners. Instead, Inner Densities are near enough to the active zones associated with synaptic ribbons to receive pulses of glutamate at concentrations effective for glutamate receptors. The role of Inner Densities is not known, but they might represent additional clusters of glutamate receptors.

Parallel processing of visual information begins at the first synapse in the retina between the photoreceptors and bipolar cells. Ten bipolar cell types have been previously described in the primate retina: one rod and nine cone bipolar types. In this paper, we describe an 11th type of bipolar cell identified in Golgi-stained macaque retinal whole mount and vertical section. Axonal stratification depth, in addition to dendritic and axonal morphology, distinguished the “giant” cell from all previously well-recognized bipolar cell types. The giant bipolar cell had a very large and sparsely branched dendritic tree and a relatively large axonal arbor that costratified with the DB4 bipolar cell near the center of the inner plexiform layer. The sparseness of the giant bipolar’s dendritic arbor indicates that, like the blue cone bipolar, it does not contact all the cones in its dendritic field. Giant cells contacting the same cones as midget bipolar cells, which are known to contact single long-wavelength (L) or medium-wavelength (M) cones, demonstrate that the giant cell does not exclusively contact short-wavelength (S) cones and, therefore, is not a variant of the previously described blue cone bipolar. This conclusion is further supported by measurement of the cone contact spacing for the giant bipolar. The giant cell contacts an average of about half the cones in its dendritic field (mean ± s.d. = 52 ± 17.6%; n = 6), with a range of 27–82%. The dendrites from single or neighboring giant cells that converge onto the same cones suggest that the giant cell may selectively target a subset of cones with a highly variable local density, such as the L or M cones.

Two morphological types of melanopsin-expressing ganglion cells have been described in primate retina. Both types show intrinsic light responses as well as rod- and cone-driven ON-type responses. Outer stratifying cells have their dendrites close to the inner nuclear layer (OFF sublamina); inner stratifying cells have their dendrites close to the ganglion cell layer (ON sublamina). Both inner and outer stratifying cells receive synaptic input via ribbon synapses, but the bipolar cell types providing this input have not been identified. Here, we addressed the question whether the diffuse (ON) cone bipolar type DB6 and/or rod bipolar cells contact melanopsin-expressing ganglion cells. Melanopsin containing ganglion cells in marmoset (Callithrix jacchus) and macaque (Macaca fascicularis) retinas were identified immunohistochemically; DB6 cells were labeled with antibodies against the carbohydrate epitope CD15, rod bipolar cells were labeled with antibodies against protein kinase C, and putative synapses between the two cells types were identified with antibodies against piccolo. For one inner cell, nearly all of the DB6 axon terminals that overlap with its dendrites in the two-dimensional space show areas of close contact. In vertical sections, the large majority of the areas of close contact also contain a synaptic punctum, suggesting that DB6 cells contact inner melanopsin cells. The output from DB6 cells accounts for about 30% of synapses onto inner melanopsin cells. Synaptic contacts between rod bipolar axons and inner dendrites were not observed. In the OFF sublamina, about 10% of the DB6 axons are closely associated with dendrites of outer cells, and in about a third of these areas, axonal en passant synapses are detected. This result suggests that DB6 cells may also provide input to outer melanopsin cells.

Color vision in mammals is based on the expression of at least two cone opsins that are sensitive to different wavelengths of light. Furthermore, retinal pathways conveying color-opponent signals are required for color discrimination. Most of the primates are trichromats, and “color-coded channels” of their retinas are unveiled to a large extent. In contrast, knowledge of cone-selective pathways in nonprimate dichromats is only slowly emerging, although retinas of dichromats like mice or rats are extensively studied as model systems for retinal information processing. Here, we review recent progress of research on color-coded pathways in nonprimate dichromats to identify differences or similarities between di- and trichromatic mammals. In addition, we applied immunohistochemical methods and confocal microscopy to retinas of different species and present data on their neuronal properties, which are expected to contribute to color vision. Basic neuronal features such as the “blue cone bipolar cell” exist in every species investigated so far. Moreover, there is increasing evidence for chromatic OFF channels in dichromats and retinal ganglion cells that relay color-opponent signals to the brain. In conclusion, di- and trichromats share similar retinal pathways for color transmission and processing.

In the retina, rod bipolar (RBP) cells synapse with many rods, and suppression of rod outer segment and synaptic noise is necessary for their detection of rod single-photon responses (SPRs). Depending on the rods’ signal-to-noise ratio (SNR), the suppression mechanism will likely eliminate some SPRs as well, resulting in decreased quantum efficiency. We examined this synapse in rabbit, where 100 rods converge onto each RBP. Suction electrode recordings showed that rabbit rod SPRs were difficult to distinguish from noise (independent SNR estimates were 2.3 and 2.8). Nonlinear transmission from rods to RBPs improved response detection (SNR = 8.7), but a large portion of the rod SPRs was discarded. For the dimmest flashes, the loss approached 90%. Despite the high rejection ratio, noise of two distinct types was apparent in the RBP traces: low-amplitude rumblings and discrete events that resembled the SPR. The SPR-like event frequency suggests that they result from thermal isomerizations of rhodopsin, which occurred at the rate 0.033/s/rod. The presence of low-amplitude noise is explained by a sigmoidal input–output relationship at the rod—RBP synapse and the input of noisy rods. The rabbit rod SNR and RBP quantum efficiency are the lowest yet reported, suggesting that the quantum efficiency of the rod—RBP synapse may depend on the SNR in rods. These results point to the possibility that fewer photoisomerizations are discarded for species such as primate, which has a higher rod SNR.

Much of what is currently known about the visual response of retinal bipolar cells is based on studies of rod-dominant responses to flashes in the dark in the isolated retina. This minireview summarizes quantitative findings on contrast processing in the intact light-adapted retina based on intracellular recording from more than 400 cone-driven bipolar cells in the tiger salamander: 1) In the main, the contrast responses of ON and OFF cells are surprisingly similar, suggesting a need to refine the view that ON and OFF cells provide the selective substrates for processing of positive and negative contrasts, respectively. 2) Overall, the response is quite nonlinear, showing very high gain for small contrasts, some 10–15 times greater than that of cones, but then quickly approaches saturation for higher contrasts. 3) Under optimal conditions of light adaptation, both classes of bipolar cells show evidence for efficient coding with respect to the contrasts in natural images. 4) There is a marked diversity within both the ON and OFF bipolar cell populations and an absence of discrete subtypes. The dynamic ranges bracket the range of contrasts in nature. 5) For both ON and OFF cells, the receptive field organization shows a striking symmetry between center and surround for responses of the same polarity and thus opposite contrast polarities. 6) The latency difference between ON and OFF cells is about 30 ms, which seems qualitatively consistent with a delay due to the G-protein cascade in ON bipolar cells. 7) In sum, we report quantitative evidence for at least 11 transformations in signal processing that occur between the voltage response of cones and the voltage response of bipolar cells.

Zebrafish are an existing model for genetic and developmental studies due to their rapid external development and transparent embryos, which allow easy manipulation and observation of early developmental stages. The application of the zebrafish model to vision research has allowed for examination of retinal development and the characteristics of different retinal cell types, including bipolar cells. In particular, bipolar cell development, including differentiation, maturation, and gene expression, has been documented, as has physiological properties, such as voltage- and ligand-gated currents, and neurotransmitter receptor and ion channel expression. Mutant strains and transgenic lines have been used to document how bipolar cell connections and/or development may be altered, and toxicological studies examining how environmental factors may impact bipolar cell activity have been performed. The purpose of this paper was to review the existing literature on zebrafish bipolar cells, to provide a comprehensive overview of current information pertaining to this retinal cell type.

Bipolar cells (BCs) are critical relay neurons in the retina that are organized into parallel signaling pathways. The three main signaling pathways in the mammalian retina are the rod, ON cone, and OFF cone BCs. Rod BCs mediate incrementing dim light signals from rods, and ON cone and OFF cone BCs mediate incrementing and decrementing brighter light signals from cones, respectively. The outputs of BCs are shaped by inhibitory inputs from GABAergic and glycinergic amacrine cells in the inner plexiform layer, mediated by three distinct types of inhibitory receptors: GABAA, GABAC, and glycine receptors. The three main BC pathways receive distinct forms of inhibition from these three receptors that shape their light-evoked inhibitory signals. Rod BC inhibition is dominated by slow GABAC receptor inhibition, while OFF cone BCs are dominated by glycinergic inhibition. The inhibitory inputs to BCs are also shaped by serial inhibitory connections between GABAergic amacrine cells that limit the spatial profile of BC inhibition. We discuss our recent studies on how inhibitory inputs to BCs are shaped by receptor expression, receptor properties, and neurotransmitter release properties and how these affect the output of BCs.

Bipolar cells play a vital role in the transfer of visual information across the vertebrate retina. The synaptic output of these neurons is regulated by factors that are extrinsic and intrinsic. Relatively little is known about the intrinsic factors that regulate neurotransmitter exocytosis. Much of what we know about intrinsic presynaptic mechanisms that regulate glutamate release has come from the study of the unusually large and accessible synaptic terminal of the goldfish rod-dominant bipolar cell, the Mb1 bipolar cell. However, over the past several years, examination of presynaptic mechanisms governing neurotransmitter release has been extended to the mammalian rod bipolar cell. In this review, we discuss the recent advances in our understanding of synaptic vesicle dynamics and neurotransmitter release in rodent rod bipolar cells and consider how these properties help to shape the synaptic output of the mammalian retina.