Retinal bipolar cells: elementary building blocks of vision

Journal name:
Nature Reviews Neuroscience
Volume:
15,
Pages:
507–519
Year published:
DOI:
doi:10.1038/nrn3783
Published online

Abstract

Retinal bipolar cells are the first 'projection neurons' of the vertebrate visual system — all of the information needed for vision is relayed by this intraretinal connection. Each of the at least 13 distinct types of bipolar cells systematically transforms the photoreceptor input in a different way, thereby generating specific channels that encode stimulus properties, such as polarity, contrast, temporal profile and chromatic composition. As a result, bipolar cell output signals represent elementary 'building blocks' from which the microcircuits of the inner retina derive a feature-oriented description of the visual world.

At a glance

Figures

  1. Organization of the bipolar cells in a mammalian retina.
    Figure 1: Organization of the bipolar cells in a mammalian retina.

    a | The retina is organized in three nuclear and two synaptic ('plexiform') layers. Light entering the eye passes the entire tissue to reach the light-sensitive outer segments of the rod and cone photoreceptors, where it is transduced into an electrical signal. At the first synaptic layer (the outer plexiform layer (OPL)), this signal is shaped by 1–3 types of horizontal cells and subsequently distributed onto ≥13 types of bipolar cells. Bipolar cells form parallel information pathways representing different transformations of the photoreceptor signal and provide the inner retina with highly pre-processed excitatory input. In the inner plexiform layer (IPL), bipolar cell axon terminals synapse onto amacrine cells and retinal ganglion cells (RGCs). Amacrine cells are the most diverse cell class in the retina (~42 distinct types exist) and provide bipolar cells and RGCs with mostly inhibitory or neuromodulatory input. Finally, ~20 types of RGCs integrate the input from distinct sets of bipolar cells and amacrine cells, and encode the result as trains of spikes to be sent to higher visual centres via their axons, which form the optic nerve. The detailed local interactions between bipolar cells, amacrine cells and RGCs in the inner retina fundamentally underpin the visual feature extraction capabilities of the retina. b | Morphologies of the 12 types of cone bipolar cells and the rod bipolar cell (RBC) in the mouse, which are arranged according to their IPL stratification level (top part of panel)6, 13, 22, 23. Some of the functional differences ('qualities' of the output signals) between bipolar cell types are indicated below this schematic. Depending on the polarity of their light response, bipolar cells can be grouped into ON and OFF cells. Moreover, some bipolar cells can be differentiated on the basis that they relay low-light signals from rods20, 48, 152 (denoted by purple bars). Mice possess short (S; blue) and medium (M; green) wavelength-sensitive cones, with many M-cones co-expressing S-opsin153, and depending on the cone type (or types) they contact, bipolar cells can be labelled as chromatic or achromatic13, 22, 78 (contacts denoted by blue and green bars; dimed bars indicate probable but not yet experimentally confirmed contacts). Bipolar cells with terminals in the IPL's central bulk respond more transiently (and often generate spikes) than those closer to the IPL borders (varying response denoted by graded purple bar). GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. The top panel of part b is adapted with permission from Ref. 13, Society for Neuroscience, is adapted with permission from Ref. 23 © (2004) Wiley, and is adapted from Ref. 6, Nature Publishing Group.

  2. Bipolar cell anatomy.
    Figure 2: Bipolar cell anatomy.

    Various factors can be used to determine bipolar cell types, notably the inner plexiform layer (IPL) strata (S1–S5) into which such cells send their axons. The images of mouse retinal slices (parts ac) show that type 3 bipolar cell axons stratify in S2 (strata shown in magenta) (part a), type 5 bipolar cell axons stratify in S3 (part b) and type 8 bipolar cell axons stratify in S4 and S5 (part c). Certain protein markers identify homologous bipolar cell types across species. Expression of CaBP5 labels rod bipolar cells (RBCs) in mouse (part d) and macaque (part e) retinae and the same types of ON and OFF cone bipolar cells (mouse: types 3 and 5; macaque: DB3 and DB4). Other markers reveal different bipolar cell types in different mammals. HCN4 is expressed in mouse type 3a OFF bipolar cells (part f) but in short wavelength (S)-cone-selective ON bipolar cells (BB) in ground squirrels (part g). Bipolar cells differ in the number and type of cones they contact, resulting in differences in chromatic tuning. Invaginating midget bipolar cells (IMBs; here revealed by Golgi staining) in the primate retina contact a single cone, inheriting its spectral sensitivity (part h). More commonly, bipolar cells seek or avoid contacts with specific cone types. Type 7 bipolar cells (here, from the GUS8.4 transgenic mouse) non-selectively contact all cones (circled) in their dendritic field (part i) and thus relay achromatic signals. By contrast, type 9 bipolar cells (here, from a CLM1 transgenic mouse retina immunostained for glutamate receptor 5 (magenta)) (part j) contact only S-cones and thus carry a S-cone (blue) signal. The dendritic trees (part k) and axon terminals (part l) of bipolar cells show territorial behaviour (territories are outlined in magenta), as shown here for mouse type 7 bipolar cells. Parts ad are adapted with permission from Ref. 23, © (2004) Wiley. Part e is adapted with permission from Ref. 30, Cambridge University Press. Part g is adapted with permission from Ref. 31, Wiley. Part h is adapted with permission from Ref. 154, © (2007) Wiley. Part j is republished with permission of Society for Neuroscience, from The primordial, blue-cone color system of the mouse retina. Haverkamp, S., Wässle, H., Duebel, J., Kuner, T., Augustine, G. J., Feng, G. & Euler, T. 25, 2005; permission conveyed through Copyright Clearance Center, Inc155. Parts k and l are adapted with permission from Ref. 13, Society for Neuroscience.

  3. Shaping bipolar cell signals: dendrites and axon terminals.
    Figure 3: Shaping bipolar cell signals: dendrites and axon terminals.

    A | Bipolar cells receive glutamatergic inputs from photoreceptors and GABAergic inputs from horizontal cells (site 1) and, in turn, provide glutamatergic excitatory input to retinal ganglion cells (RGCs) and inhibitory amacrine cells (site 2). B | Light-driven calcium signals measured at the terminals of different mouse OFF bipolar cells illustrate clear differences in temporal tuning between such cells. ΔF/F indicates relative change in calcium indicator fluorescence. Ca | Cone terminals (corresponding to site 1 in panel A) make invaginating contacts with dendrites of ON cone bipolar cells (CBCs) that are sheathed by horizontal cell processes and have basal contacts with OFF CBC dendrites. Cb | Different types of bipolar cells (indicated by the different line colours) express different combinations of ionotropic glutamate receptors, which confer different temporal and adaptation properties53, 72. Da | The synaptic terminals of bipolar cells are key computational loci of the inner retina. For example, glutamate release through the ribbon complex underlies a range of adaptational properties at different time scales. Three synaptic vesicle pools are generally distinguished at the bipolar cell synaptic terminal. The rapidly releasable pool (RRP) consists of few vesicles that are primed for immediate, ultrafast neurotransmitter release (<10 ms). Next, the larger intermediate pool (IP) consists of vesicles that are tethered to the ribbon but not primed for release, and this pool typically becomes depleted over several hundreds of milliseconds. Finally, the reserve pool (RP) may contain many thousands of freely diffusible vesicles that slowly replenish adapted ribbons over time. Vesicle depletion at conventional synapses of amacrine cells may further contribute to generate complex adaptational effects. Db | The size and release rates of the three vesicle pools can be calculated from measurements of cumulative release during continuous stimulation156. Dc | Depletion of the RRP and the IP underlie short-term adaptational effects, such as paired-pulse depression. Dd | Depletion of the IP and the RP over longer timescales has been linked to contrast adaptation in the retinal circuit, whereas adaptation in amacrine cells may underlie contrast facilitation41, 42, 43, 91. EPSC, excitatory postsynaptic current. Part B is adapted with permission from Ref. 2, Cell Press/Elsevier.

  4. Building ganglion cell circuits from bipolar cell elementary operations.
    Figure 4: Building ganglion cell circuits from bipolar cell elementary operations.

    The bipolar cell response and the resulting retinal ganglion cell (RGC) output is depicted above and below each circuit, respectively (bars indicate light stimuli). Mammalian bipolar cell output is organized according to three main principles. First, bipolar cells carrying OFF and ON signals stratify in the distal inner plexiform layer (IPL) portions (layers 1 and 2) and proximal IPL portions (layers 3–5), respectively. Second, transient bipolar cell output is provided in the central bulk of the IPL (layers 2 and 3), whereas sustained output is found towards the IPL borders (layers 1 and 5). Third, achromatic (layers 2–4) and chromatic (layers 1 and 5) bipolar cell signals are segregated in a similar manner to transient and sustained outputs. Dendrites of individual RGCs stratify in one or more IPL layers, receiving synaptic input from a specific subset of bipolar cell types and inheriting a combination of their functional properties. a | In the mouse, transient OFF αRGCs stratify narrowly towards the IPL centre and thus receive input from only 1–2 transient OFF bipolar types157, whereas JAM-B OFF-RGCs158 stratify mainly in layer 1, where they receive input from a small subset of sustained bipolar cell types. Mouse W3 RGCs28, which are probably homologous to the 'local edge detectors' of other species159, stratify throughout the central bulk of the IPL, and receive input from a range of transient ON and OFF bipolar cell types6. Another 'use' of convergence is illustrated by primate ON parasol RGCs: their large dendritic arbors stratify narrowly in the IPL centre, where they receive input from spiking DB4-type bipolar cells7. By pooling the outputs of many spiking bipolar cells, parasol RGCs may preserve the timing of bipolar cell spikes while improving coding reliability94, 97. b | Single bipolar cells may also forward different signals to different postsynaptic partners ('multiplexing'). For instance, the involvement of an amacrine cell shapes the transfer function from a single bipolar cell to only one of two postsynaptic RGC types, thereby creating temporally distinct outputs130. c | Several RGC circuits process chromatic bipolar cell signals, usually yielding chromatically antagonistic responses (reviewed in Refs 74,75). Midget RGCs in the primate fovea receive input from single midget bipolar cells, which in turn randomly contact single cones. Thereby, a midget RGC inherits the chromatic tuning of a single cone137, with an antagonistic surround arising from lateral horizontal cell input (not shown). Alternatively, bipolar cells make cone type-selective contacts and RGCs become colour opponent by subtracting differently tuned bipolar cell pathways. Examples are primate 'small bistratified' RGCs with their blue-ON–yellow-OFF antagonistic responses, and blue-OFF RGCs in rabbits and ground squirrels, which inherit the blue-OFF signal from blue ON bipolar cells via a sign-inverting small-field amacrine cell82, 138. d | Spatially selective sampling of different OFF bipolar cell types may contribute to the computation of motion direction. Because starburst amacrine cell (SAC) dendrites are not perfectly planar145, OFF bipolar cells with presumably different kinetics systematically contact the dendrites as a function of distance from the SAC soma. As a result, the response amplitude in the SAC dendrite depends on the activation sequence of the bipolar cell types and thus, stimulus direction. DS, direction-selective.

References

  1. Dreosti, E., Odermatt, B., Dorostkar, M. M. & Lagnado, L. A genetically encoded reporter of synaptic activity in vivo. Nature Methods 6, 883889 (2009).
  2. Baden, T., Berens, P., Bethge, M. & Euler, T. Spikes in mammalian bipolar cells support temporal layering of the inner retina. Curr. Biol. 23, 4852 (2013).
    A study in mice showing direct measurements of light-evoked presynaptic calcium responses in axonal terminals of bipolar cells that stratify at different depths within the IPL.
  3. Yonehara, K. et al. The first stage of cardinal direction selectivity is localized to the dendrites of retinal ganglion cells. Neuron 79, 10781085 (2013).
    A mouse study demonstrating that direction selectivity is not a feature of bipolar cell output.
  4. Marvin, J. S. et al. An optimized fluorescent probe for visualizing glutamate neurotransmission. Nature Methods 10, 162170 (2013).
  5. Borghuis, B. G., Marvin, J. S., Looger, L. L. & Demb, J. B. Two-photon imaging of nonlinear glutamate release dynamics at bipolar cell synapses in the mouse retina. J. Neurosci. 33, 1097210985 (2013).
  6. Helmstaedter, M. et al. Connectomic reconstruction of the inner plexiform layer in the mouse retina. Nature 500, 168174 (2013).
    This paper provides a comprehensive, high-density electron microscopy-based reconstruction of a small patch of mouse retina.
  7. Puthussery, T., Venkataramani, S., Gayet-Primo, J., Smith, R. G. & Taylor, W. R. NaV1.1 channels in axon initial segments of bipolar cells augment input to magnocellular visual pathways in the primate retina. J. Neurosci. 33, 1604516059 (2013).
  8. Tartuferi, F. Sull'anatomia della retina. Int. Monatsschrift Anat.Physiol. 4, 421441 (in Italian) (1887).
  9. Lin, B. & Masland, R. H. Synaptic contacts between an identified type of ON cone bipolar cell and ganglion cells in the mouse retina. Eur. J. Neurosci. 21, 12571270 (2005).
  10. Morgan, J. L., Soto, F., Wong, R. O. & Kerschensteiner, D. Development of cell type-specific connectivity patterns of converging excitatory axons in the retina. Neuron 71, 10141021 (2011).
  11. Neumann, S. & Haverkamp, S. Characterization of small-field bistratified amacrine cells in macaque retina labeled by antibodies against synaptotagmin-2. J. Comp. Neurol. 521, 709724 (2013).
  12. Hartveit, E. Functional organization of cone bipolar cells in the rat retina. J. Neurophysiol. 77, 17161730 (1997).
  13. Wässle, H., Puller, C., Müller, F. & Haverkamp, S. Cone contacts, mosaics, and territories of bipolar cells in the mouse retina. J. Neurosci. 29, 106117 (2009).
    Key work on the anatomical identification of bipolar cell types and their organization in the mouse.
  14. Connaughton, V. P., Graham, D. & Nelson, R. Identification and morphological classification of horizontal, bipolar, and amacrine cells within the zebrafish retina. J. Comp. Neurol. 477, 371385 (2004).
  15. Li, Y. N., Tsujimura, T., Kawamura, S. & Dowling, J. E. Bipolar cell-photoreceptor connectivity in the zebrafish (Danio rerio) retina. J. Comp. Neurol. 520, 37863802 (2012).
  16. Cajal, S. R.Y. La rétine des vertébrés. La Cellule 9, 119257 (in French) (1893).
  17. Euler, T., Schneider, H. & Wässle, H. Glutamate responses of bipolar cells in a slice preparation of the rat retina. J. Neurosci. 16, 29342944 (1996).
  18. Euler, T. & Masland, R. H. Light-evoked responses of bipolar cells in a mammalian retina. J. Neurophysiol. 83, 18171829 (2000).
  19. Odermatt, B., Nikolaev, A. & Lagnado, L. Encoding of luminance and contrast by linear and nonlinear synapses in the retina. Neuron 73, 758773 (2012).
  20. Mataruga, A., Kremmer, E. & Muller, F. Type 3a and type 3b OFF cone bipolar cells provide for the alternative rod pathway in the mouse retina. J. Comp. Neurol. 502, 11231137 (2007).
  21. Puller, C., Ivanova, E., Euler, T., Haverkamp, S. & Schubert, T. OFF bipolar cells express distinct types of dendritic glutamate receptors in the mouse retina. Neuroscience 243, 136148 (2013).
  22. Breuninger, T., Puller, C., Haverkamp, S. & Euler, T. Chromatic bipolar cell pathways in the mouse retina. J. Neurosci. 31, 65046517 (2011).
  23. Ghosh, K. K., Bujan, S., Haverkamp, S., Feigenspan, A. & Wassle, H. Types of bipolar cells in the mouse retina. J. Comp. Neurol. 469, 7082 (2004).
  24. Joo, H. R., Peterson, B. B., Haun, T. J. & Dacey, D. M. Characterization of a novel large-field cone bipolar cell type in the primate retina: evidence for selective cone connections. Vis. Neurosci. 28, 2937 (2011).
  25. Light, A. C. et al. Organizational motifs for ground squirrel cone bipolar cells. J. Comp. Neurol. 520, 28642887 (2012).
  26. MacNeil, 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. 472, 7386 (2004).
  27. Baden, T. et al. A tale of two retinal domains: near-optimal sampling of achromatic contrasts in natural scenes through asymmetric photoreceptor distribution. Neuron 80, 12061217 (2013).
  28. Zhang, Y., Kim, I. J., Sanes, J. R. & Meister, M. The most numerous ganglion cell type of the mouse retina is a selective feature detector. Proc. Natl Acad. Sci. USA 109, E2391E2398 (2012).
  29. Bleckert, A., Schwartz, G. W., Turner, M. H., Rieke, F. & Wong, R. O. Visual space is represented by nonmatching topographies of distinct mouse retinal ganglion cell types. Curr. Biol. 24, 310315 (2014).
  30. Haverkamp, S., Haeseleer, F. & Hendrickson, A. A comparison of immunocytochemical markers to identify bipolar cell types in human and monkey retina. Vis. Neurosci. 20, 589600 (2003).
  31. Puller, C., Ondreka, K. & Haverkamp, S. Bipolar cells of the ground squirrel retina. J. Comp. Neurol. 519, 759774 (2011).
  32. Li, W. & DeVries, S. H. Bipolar cell pathways for color and luminance vision in a dichromatic mammalian retina. Nature Neurosci. 9, 669675 (2006).
  33. Schubert, T. et al. Development of presynaptic inhibition onto retinal bipolar cell axon terminals is subclass-specific. J. Neurophysiol. 100, 304316 (2008).
  34. Wassle, H., Grunert, U., Martin, P. R. & Boycott, B. B. Immunocytochemical characterization and spatial distribution of midget bipolar cells in the macaque monkey retina. Vision Res. 34, 561579 (1994).
  35. Cuenca, N. et al. The neurons of the ground squirrel retina as revealed by immunostains for calcium binding proteins and neurotransmitters. J. Neurocytol. 31, 649666 (2002).
  36. Puthussery, T., Gayet-Primo, J., Taylor, W. R. & Haverkamp, S. Immunohistochemical identification and synaptic inputs to the diffuse bipolar cell type DB1 in macaque retina. J. Comp. Neurol. 519, 36403656 (2011).
  37. Connaughton, V. P. Bipolar cells in the zebrafish retina. Vis. Neurosci. 28, 7793 (2011).
  38. Pang, J. J., Gao, F. & Wu, S. M. Stratum-by-stratum projection of light response attributes by retinal bipolar cells of Ambystoma. J. Physiol. 558, 249262 (2004).
  39. Haverkamp, S., Mockel, W. & Ammermüller, J. Different types of synapses with different spectral types of cones underlie color opponency in a bipolar cell of the turtle retina. Vis. Neurosci. 16, 801809 (1999).
  40. Masland, R. H. The neuronal organization of the retina. Neuron 76, 266280 (2012).
  41. Ozuysal, Y. & Baccus, S. A. Linking the computational structure of variance adaptation to biophysical mechanisms. Neuron 73, 10021015 (2012).
  42. Nikolaev, A., Leung, K. M., Odermatt, B. & Lagnado, L. Synaptic mechanisms of adaptation and sensitization in the retina. Nature Neurosci. 16, 934941 (2013).
  43. Manookin, M. B. & Demb, J. B. Presynaptic mechanism for slow contrast adaptation in mammalian retinal ganglion cells. Neuron 50, 453464 (2006).
  44. Baden, T., Euler, T., Weckstrom, M. & Lagnado, L. Spikes and ribbon synapses in early vision. Trends Neurosci. 36, 480488 (2013).
  45. Taylor, W. R. & Smith, R. G. Trigger features and excitation in the retina. Curr. Opin. Neurobiol. 21, 672678 (2011).
  46. Hack, I., Peichl, L. & Brandstätter, J. H. An alternative pathway for rod signals in the rodent retina: rod photoreceptors, cone bipolar cells, and the localization of glutamate receptors. Proc. Natl Acad. Sci. USA 96, 1413014135 (1999).
  47. Fyk-Kolodziej, B., Qin, P. & Pourcho, R. G. Identification of a cone bipolar cell in cat retina which has input from both rod and cone photoreceptors. J. Comp. Neurol. 464, 104113 (2003).
  48. Haverkamp, S. et al. Type 4 OFF cone bipolar cells of the mouse retina express calsenilin and contact cones as well as rods. J. Comp. Neurol. 507, 10871101 (2008).
  49. Li, W., Chen, S. & DeVries, S. H. A fast rod photoreceptor signaling pathway in the mammalian retina. Nature Neurosci. 13, 414416 (2010).
  50. Koike, C., Numata, T., Ueda, H., Mori, Y. & Furukawa, T. TRPM1: a vertebrate TRP channel responsible for retinal ON bipolar function. Cell Calcium 48, 95101 (2010).
  51. Regus-Leidig, H. & Brandstatter, J. H. Structure and function of a complex sensory synapse. Acta Physiol. 204, 479486 (2012).
  52. DeVries, S. H. Bipolar cells use kainate and AMPA receptors to filter visual information into separate channels. Neuron 28, 847856 (2000).
  53. Lindstrom, S. H., Ryan, D. G., Shi, J. & Devries, S. H. Kainate receptor subunit diversity underlying response diversity in retinal Off bipolar cells. J. Physiol. 592, 14571477 (2014).
    A detailed dissection of how OFF bipolar cell types (in the ground squirrel) inherit different kinetic properties based on differential expression of glutamate receptor types on their dendrites.
  54. Borghuis, B. G., Looger, L. L., Tomita, S. & Demb, J. B. Kainate receptors mediate signaling in both transient and sustained off bipolar cell pathways in mouse retina. J. Neurosci. 34, 61286139 (2014).
  55. Masu, M. et al. Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell 80, 757765 (1995).
  56. Cao, Y. et al. Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. Proc. Natl Acad. Sci. USA 109, 79057910 (2012).
  57. Pearring, J. N. et al. A role for nyctalopin, a small leucine-rich repeat protein, in localizing the TRP melastatin 1 channel to retinal depolarizing bipolar cell dendrites. J. Neurosci. 31, 1006010066 (2011).
  58. Cao, Y. et al. Targeting of RGS7/Gβ5 to the dendritic tips of ON-bipolar cells is independent of its association with membrane anchor R7BP. J. Neurosci. 28, 1044310449 (2008).
  59. Cao, Y. et al. Retina-specific GTPase accelerator RGS11/G β 5S/R9AP is a constitutive heterotrimer selectively targeted to mGluR6 in ON-bipolar neurons. J. Neurosci. 29, 93019313 (2009).
  60. Jeffrey, B. G. et al. R9AP stabilizes RGS11-G β5 and accelerates the early light response of ON-bipolar cells. Vis. Neurosci. 27, 917 (2010).
  61. Ray, T. A. et al. GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells. J. Neurosci. 34, 63346343 (2014).
  62. Sulaiman, P., Fina, M., Feddersen, R. & Vardi, N. Ret-PCP2 colocalizes with protein kinase C in a subset of primate ON cone bipolar cells. J. Comp. Neurol. 518, 10981112 (2010).
  63. Xu, Y. et al. Retinal ON bipolar cells express a new PCP2 splice variant that accelerates the light response. J. Neurosci. 28, 88738884 (2008).
  64. De Sevilla Müller, L. P., Liu, J., Solomon, A., Rodriguez, A. & Brecha, N. C. Expression of voltage-gated calcium channel α2δ4 subunits in the mouse and rat retina. J. Comp. Neurol. 521, 24862501 (2013).
  65. Sulaiman, P. et al. Kir2.4 surface expression and basal current are affected by heterotrimeric G-proteins. J. Biol. Chem. 288, 74207429 (2013).
  66. Rampino, M. A. & Nawy, S. A. Relief of Mg2+-dependent inhibition of TRPM1 by PKCα at the rod bipolar cell synapse. J. Neurosci. 31, 1359613603 (2011).
  67. Morgans, C. W. et al. TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells. Proc. Natl Acad. Sci. USA 106, 1917419178 (2009).
  68. Koike, C. et al. TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. Proc. Natl Acad. Sci. USA 107, 332337 (2010).
    References 67 and 68 first showed that TRPM1 is the cation channel that lies downstream of the mGluR6 signalling cascade in mouse ON bipolar cells.
  69. Gilliam, J. C. & Wensel, T. G. TRP channel gene expression in the mouse retina. Vision Res. 51, 24402452 (2011).
  70. Haverkamp, S., Grünert, U. & Wässle, H. Localization of kainate receptors at the cone pedicles of the primate retina. J. Comp. Neurol. 436, 471486 (2001).
  71. Haverkamp, S., Grünert, U. & Wässle, H. The cone pedicle, a complex synapse in the retina. Neuron 27, 8595 (2000).
    This study in the macaque provides a demonstration of the complexity of photoreceptor-to-bipolar cell connections.
  72. DeVries, S. H., Li, W. & Saszik, S. Parallel processing in two transmitter microenvironments at the cone photoreceptor synapse. Neuron 50, 735748 (2006).
    A study in ground squirrels that provides evidence for the notion that functional differences in bipolar cell types may in part result from different contact morphologies with cones.
  73. Vardi, N., Duvoisin, R., Wu, G. & Sterling, P. Localization of mGluR6 to dendrites of ON bipolar cells in primate retina. J. Comp. Neurol. 423, 402412 (2000).
  74. Neitz, J. & Neitz, M. The genetics of normal and defective color vision. Vision Res. 51, 633651 (2011).
  75. Dacey, D. M., Crook, J. D. & Packer, O. S. Distinct synaptic mechanisms create parallel S-ON & S-OFF color opponent pathways in the primate retina. Vis. Neurosci. 31, 113 (2013).
  76. Nathans, J. The evolution and physiology of human color vision: insights from molecular genetic studies of visual pigments. Neuron 24, 299312 (1999).
  77. Wong, K. Y. & Dowling, J. E. Retinal bipolar cell input mechanisms in giant danio. III. ON-OFF bipolar cells and their color-opponent mechanisms. J. Neurophysiol. 94, 265272 (2005).
  78. Dunn, F. A. & Wong, R. O. Diverse strategies engaged in establishing stereotypic wiring patterns among neurons sharing a common input at the visual system's first synapse. J. Neurosci. 32, 1030610317 (2012).
  79. Lee, S. C. & Grünert, U. Connections of diffuse bipolar cells in primate retina are biased against S-cones. J. Comp. Neurol. 502, 126140 (2007).
  80. Mariani, A. P. Bipolar cells in monkey retina selective for the cones likely to be blue-sensitive. Nature 308, 184186 (1984).
  81. Puller, C. & Haverkamp, S. Bipolar cell pathways for color vision in non-primate dichromats. Vis. Neurosci. 28, 5160 (2011).
  82. Mills, S. L., Tian, L. M., Hoshi, H., Whitaker, C. M. & Massey, S. C. Three distinct blue-green color pathways in a mammalian retina. J. Neurosci. 34, 17601768 (2014).
  83. Polyak, S. L. The Retina (University of Chicago Press, 1941).
  84. Kryger, Z., Galli-Resta, L., Jacobs, G. H. & Reese, B. E. The topography of rod and cone photoreceptors in the retina of the ground squirrel. Vis. Neurosci. 15, 685691 (1998).
  85. Thoreson, W. B. & Mangel, S. C. Lateral interactions in the outer retina. Prog. Retin. Eye Res. 31, 407441 (2012).
  86. Vardi, N., Zhang, L. L., Payne, J. A. & Sterling, P. Evidence that different cation chloride cotransporters in retinal neurons allow opposite responses to GABA. J. Neurosci. 20, 76577663 (2000).
  87. Duebel, J. et al. Two-photon imaging reveals somatodendritic chloride gradient in retinal ON-type bipolar cells expressing the biosensor Clomeleon. Neuron 49, 8194 (2006).
  88. Miller, R. F. & Dacheux, R. F. Intracellular chloride in retinal neurons: measurement and meaning. Vision Res. 23, 399411 (1983).
  89. Gollisch, T. & Meister, M. Eye smarter than scientists believed: neural computations in circuits of the retina. Neuron 65, 150164 (2010).
    A key review that discusses how retinal feature extraction relies heavily on non-linearities in bipolar cell processing.
  90. Schwartz, G. W. et al. The spatial structure of a nonlinear receptive field. Nature Neurosci. 15, 15721580 (2012).
    A demonstration of how comparatively simple cascade models may account for a substantial fraction of mouse RGC response variance under complex stimulation.
  91. Baccus, S. A. & Meister, M. Fast and slow contrast adaptation in retinal circuitry. Neuron 36, 909919 (2002).
  92. Spruston, N., Jaffe, D. B. & Johnston, D. Dendritic attenuation of synaptic potentials and currents: the role of passive membrane properties. Trends Neurosci. 17, 161166 (1994).
  93. Sherry, D. M. & Yazulla, S. Goldfish bipolar cells and axon terminal patterns: a Golgi study. J. Comp. Neurol. 329, 188200 (1993).
  94. Baden, T. & Euler, T. Early vision: where (some of) the magic happens. Curr. Biol. 23, R1096R1098 (2013).
  95. Burrone, J. & Lagnado, L. Electrical resonance and Ca2+ influx in the synaptic terminal of depolarizing bipolar cells from the goldfish retina. J. Physiol. 505, 571584 (1997).
  96. Protti, D. A., Flores-Herr, N. & von Gersdorff, H. Light evokes Ca2+ spikes in the axon terminal of a retinal bipolar cell. Neuron 25, 215227 (2000).
    The first study to demonstrate that light can drive spikes in retinal bipolar cells (the study was conducted in goldfish).
  97. Baden, T., Esposti, F., Nikolaev, A. & Lagnado, L. Spikes in retinal bipolar cells phase-lock to visual stimuli with millisecond precision. Curr. Biol. 21, 18591869 (2011).
  98. Cui, J. & Pan, Z. H. Two types of cone bipolar cells express voltage-gated Na+ channels in the rat retina. Vis. Neurosci. 25, 635645 (2008).
  99. Saszik, 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. 32, 297307 (2012).
  100. Hu, H. J. & Pan, Z. H. Differential expression of K+ currents in mammalian retinal bipolar cells. Vis. Neurosci. 19, 163173 (2002).
  101. Okada, T., Horiguchi, H. & Tachibana, M. Ca2+-dependent Cl current at the presynaptic terminals of goldfish retinal bipolar cells. Neurosci. Res. 23, 297303 (1995).
  102. Connaughton, V. P. & Maguire, G. Differential expression of voltage-gated K+ and Ca2+ currents in bipolar cells in the zebrafish retinal slice. Eur. J. Neurosci. 10, 13501362 (1998).
  103. Müller, F. et al. HCN channels are expressed differentially in retinal bipolar cells and concentrated at synaptic terminals. Eur. J. Neurosci. 17, 20842096 (2003).
  104. Euler, T. & Wässle, H. Different contributions of GABAA and GABAC receptors to rod and cone bipolar cells in a rat retinal slice preparation. J. Neurophysiol. 79, 13841395 (1998).
  105. Eggers, E. D., McCall, M. A. & Lukasiewicz, P. D. Presynaptic inhibition differentially shapes transmission in distinct circuits in the mouse retina. J. Physiol. 582, 569582 (2007).
  106. Ivanova, E., Müller, U. & Wässle, H. Characterization of the glycinergic input to bipolar cells of the mouse retina. Eur. J. Neurosci. 23, 350364 (2006).
  107. Vigh, J., Vickers, E. & von Gersdorff, H. Light-evoked lateral GABAergic inhibition at single bipolar cell synaptic terminals is driven by distinct retinal microcircuits. J. Neurosci. 31, 1588415893 (2011).
  108. Masland, R. H. The tasks of amacrine cells. Vis. Neurosci. 29, 39 (2012).
  109. Esposti, F., Johnston, J., Rosa, J. M., Leung, K. M. & Lagnado, L. Olfactory stimulation selectively modulates the OFF pathway in the retina of zebrafish. Neuron 79, 97110 (2013).
  110. Yang, J., Pahng, J. & Wang, G. Y. Dopamine modulates the off pathway in light-adapted mouse retina. J. Neurosci. Res. 91, 138150 (2013).
  111. Tooker, R. E. et al. Nitric oxide mediates activity-dependent plasticity of retinal bipolar cell output via S-nitrosylation. J. Neurosci. 33, 1917619193 (2013).
  112. Ayoub, G. S. & Matthews, G. Substance P modulates calcium current in retinal bipolar neurons. Vis. Neurosci. 8, 539544 (1992).
  113. Casini, G. et al. Expression of the neurokinin 1 receptor in the rabbit retina. Neuroscience 115, 13091321 (2002).
  114. Zenisek, D., Davila, V., Wan, L. & Almers, W. Imaging calcium entry sites and ribbon structures in two presynaptic cells. J. Neurosci. 23, 25382548 (2003).
  115. Llobet, A., Cooke, A. & Lagnado, L. Exocytosis at the ribbon synapse of retinal bipolar cells studied in patches of presynaptic membrane. J. Neurosci. 23, 27062714 (2003).
  116. Singer, J. H., Lassova, L., Vardi, N. & Diamond, J. S. Coordinated multivesicular release at a mammalian ribbon synapse. Nature Neurosci. 7, 826833 (2004).
  117. Midorikawa, M., Tsukamoto, Y., Berglund, K., Ishii, M. & Tachibana, M. Different roles of ribbon-associated and ribbon-free active zones in retinal bipolar cells. Nature Neurosci. 10, 12681276 (2007).
  118. tom Dieck, S. & Brandstätter, J. H. Ribbon synapses of the retina. Cell Tissue Res. 326, 339346 (2006).
  119. LoGiudice, L. & Matthews, G. The role of ribbons at sensory synapses. Neuroscientist 15, 380391 (2009).
  120. Beaumont, V., Llobet, A. & Lagnado, L. Expansion of calcium microdomains regulates fast exocytosis at a ribbon synapse. Proc. Natl Acad. Sci. USA 102, 1070010705 (2005).
  121. Jackman, S. L. et al. Role of the synaptic ribbon in transmitting the cone light response. Nature Neurosci. 12, 303310 (2009).
    Seminal work on how calcium drives release at a ribbon synapse (in lizards).
  122. Sikora, M. A., Gottesman, J. & Miller, R. F. A computational model of the ribbon synapse. J. Neurosci. Methods 145, 4761 (2005).
  123. Palmer, M. J. Modulation of Ca2+-activated K+ currents and Ca2+-dependent action potentials by exocytosis in goldfish bipolar cell terminals. J. Physiol. 572, 747762 (2006).
  124. Awatramani, G. B. & Slaughter, M. M. Intensity-dependent, rapid activation of presynaptic metabotropic glutamate receptors at a central synapse. J. Neurosci. 21, 741749 (2001).
  125. Veruki, M. L., Morkve, S. H. & Hartveit, E. Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nature Neurosci. 9, 13881396 (2006).
  126. Guerrero, G. et al. Heterogeneity in synaptic transmission along a Drosophila larval motor axon. Nature Neurosci. 8, 11881196 (2005).
  127. Euler, T. & Denk, W. Dendritic processing. Curr. Opin. Neurobiol. 11, 415422 (2001).
  128. Baden, T. & Hedwig, B. Primary afferent depolarization and frequency processing in auditory afferents. J. Neurosci. 30, 1486214869 (2010).
  129. Gaudry, Q., Hong, E. J., Kain, J., de Bivort, B. L. & Wilson, R. I. Asymmetric neurotransmitter release enables rapid odour lateralization in Drosophila. Nature 493, 424428 (2013).
  130. Asari, H. & Meister, M. Divergence of visual channels in the inner retina. Nature Neurosci. 15, 15811589 (2012).
    A study in salamanders that provides the first evidence that individual bipolar cells may have different synaptic transfer functions according to the different postsynaptic partners.
  131. Asari, H. & Meister, M. The projective field of retinal bipolar cells and its modulation by visual context. Neuron 81, 641652 (2014).
    This study presents evidence that individual salamander bipolar cells functionally feed into an unexpectedly large number and variety of postsynaptic circuits.
  132. Sumbul, U. et al. A genetic and computational approach to structurally classify neuronal types. Nature Commun. 5, 3512 (2014).
  133. Sun, W., Li, N. & He, S. Large-scale morphological survey of mouse retinal ganglion cells. J. Comp. Neurol. 451, 115126 (2002).
  134. Volgyi, B., Chheda, S. & Bloomfield, S. A. Tracer coupling patterns of the ganglion cell subtypes in the mouse retina. J. Comp. Neurol. 512, 664687 (2009).
  135. Roska, B. & Werblin, F. Vertical interactions across ten parallel, stacked representations in the mammalian retina. Nature 410, 583587 (2001).
    Key work in rabbits on the functional stratification rules of the IPL.
  136. Awatramani, G. B. & Slaughter, M. M. Origin of transient and sustained responses in ganglion cells of the retina. J. Neurosci. 20, 70877095 (2000).
  137. Field, G. D. et al. Functional connectivity in the retina at the resolution of photoreceptors. Nature 467, 673677 (2010).
  138. Chen, S. & Li, W. A color-coding amacrine cell may provide a blue-off signal in a mammalian retina. Nature Neurosci. 15, 954956 (2012).
  139. Borst, A. & Euler, T. Seeing things in motion: models, circuits, and mechanisms. Neuron 71, 974994 (2011).
  140. Briggman, K. L., Helmstaedter, M. & Denk, W. Wiring specificity in the direction-selectivity circuit of the retina. Nature 471, 183188 (2011).
  141. Hausselt, S. E., Euler, T., Detwiler, P. B. & Denk, W. A dendrite-autonomous mechanism for direction selectivity in retinal starburst amacrine cells. PLoS Biol. 5, e185 (2007).
  142. Oesch, N., Euler, T. & Taylor, W. R. Direction-selective dendritic action potentials in rabbit retina. Neuron 47, 739750 (2005).
  143. Schachter, M. J., Oesch, N., Smith, R. G. & Taylor, W. R. Dendritic spikes amplify the synaptic signal to enhance detection of motion in a simulation of the direction-selective ganglion cell. PLoS Comput. Biol. 6, e1000899 (2010).
  144. Sivyer, B. & Williams, S. R. Direction selectivity is computed by active dendritic integration in retinal ganglion cells. Nature Neurosci. 16, 18481856 (2013).
  145. Kim, J. S. et al. Space–time wiring specificity supports direction selectivity in the retina. Nature 509, 331336 (2014).
    A demonstration in mice that OFF starburst amacrine cells tend to receive inputs from different types of bipolar cells depending on dendritic eccentricity.
  146. Garvert, M. M. & Gollisch, T. Local and global contrast adaptation in retinal ganglion cells. Neuron 77, 915928 (2013).
  147. Bolinger, D. & Gollisch, T. Closed-loop measurements of iso-response stimuli reveal dynamic nonlinear stimulus integration in the retina. Neuron 73, 333346 (2012).
  148. Volgyi, B., Deans, M. R., Paul, D. L. & Bloomfield, S. A. Convergence and segregation of the multiple rod pathways in mammalian retina. J. Neurosci. 24, 1118211192 (2004).
  149. Bloomfield, S. A. & Dacheux, R. F. Rod vision: pathways and processing in the mammalian retina. Prog. Retin. Eye Res. 20, 351384 (2001).
  150. Dunn, F. A. & Rieke, F. The impact of photoreceptor noise on retinal gain controls. Curr. Opin. Neurobiol. 16, 363370 (2006).
  151. Tsukamoto, Y., Morigiwa, K., Ueda, M. & Sterling, P. Microcircuits for night vision in mouse retina. J. Neurosci. 21, 86168623 (2001).
  152. Tsukamoto, Y. & Omi, N. Functional allocation of synaptic contacts in microcircuits from rods via rod bipolar to AII amacrine cells in the mouse retina. J. Comp. Neurol. 521, 35413555 (2013).
  153. Roehlich, P., Van Veen, T. & Szél, A. Two different visual pigments in one retinal cone cell. Neuron 13, 11591166 (1994).
  154. Puller, C., Haverkamp, S. & Grünert, U. OFF midget bipolar cells in the retina of the marmoset, Callithrix jacchus, express AMPA receptors. J. Comp. Neurol. 502, 442454 (2007).
  155. Haverkamp, S. et al. The primordial, blue-cone color system of the mouse retina. J. Neurosci. 25, 54385445 (2005).
  156. Neves, G. & Lagnado, L. The kinetics of exocytosis and endocytosis in the synaptic terminal of goldfish retinal bipolar cells. J. Physiol. 515, 181202 (1999).
  157. Pang, J. J., Gao, F. & Wu, S. M. Light-evoked excitatory and inhibitory synaptic inputs to ON and OFF α ganglion cells in the mouse retina. J. Neurosci. 23, 60636073 (2003).
  158. Kim, I. J., Zhang, Y., Yamagata, M., Meister, M. & Sanes, J. R. Molecular identification of a retinal cell type that responds to upward motion. Nature 452, 478482 (2008).
  159. van Wyk, M., Taylor, W. R. & Vaney, D. I. Local edge detectors: a substrate for fine spatial vision at low temporal frequencies in rabbit retina. J. Neurosci. 26, 1325013263 (2006).
  160. Ichinose, T., Fyk-Kolodziej, B. & Cohn, J. Roles of on cone bipolar cell subtypes in temporal coding in the mouse retina. J. Neurosci. 34, 87618771 (2014).

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Affiliations

  1. Werner Reichardt Centre for Integrative Neuroscience (CIN), University of Tübingen, 72076 Tübingen, Germany.

    • Thomas Euler,
    • Timm Schubert &
    • Tom Baden
  2. Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany.

    • Thomas Euler,
    • Timm Schubert &
    • Tom Baden
  3. Bernstein Centre for Computational Neuroscience Tübingen, University of Tübingen, 72076 Tübingen, Germany.

    • Thomas Euler &
    • Tom Baden
  4. Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany.

    • Silke Haverkamp

Competing interests statement

The authors declare no competing interests.

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Author details

  • Thomas Euler

    Thomas Euler studied biology at the University in Mainz, Germany, and completed his Ph.D. in 1996 at the Max Planck Institute for Brain Research in Frankfurt, Germany. He worked at the Harvard Medical School, Boston, Massachusetts, USA, and Massachusetts General Hospital, Boston, USA, until he returned to Germany in 2000 and joined the Max Planck Institute for Medical Research in Heidelberg. Since 2009, he is a professor for Ophthalmic Research at the Werner Reichardt Centre for Integrative Neuroscience of the University of Tübingen, Germany. His focus is retinal signal processing.

  • Silke Haverkamp

    Silke Haverkamp received her Ph.D. from the University of Oldenburg, Germany, and did her postdoctoral research at Boston University, Massachusetts, USA, and then at the Moran Eye Center in Salt Lake City, Utah, USA. She returned to Germany and joined the Max Planck Institute for Brain Research in Frankfurt, where her research group now focuses on the structure and function of neurons and synaptic circuits within the mammalian retina.

  • Timm Schubert

    Timm Schubert received his Ph.D. in neuroscience from the University of Oldenburg, Germany. He was a postdoctoral researcher at Washington University in St. Louis, Missouri, USA, and University of Washington, Seattle, USA, before he joined Thomas Euler's laboratory at the Centre for Integrative Neuroscience of the University of Tübingen, Germany. Currently, his research is focused on synaptic interactions in the outer retina.

  • Tom Baden

    Tom Baden studied natural sciences at the University of Cambridge, UK, and completed his Ph.D. at the Department of Zoology, Cambridge, in 2008. He then worked as a postdoctoral researcher at the MRC Laboratory for Molecular Biology until 2010 when he joined the laboratory of Thomas Euler as a postdoctoral researcher. He is also co-founder of 'TReND in Africa' (www.TReNDinAfrica.org), aiming to foster science education and research on the African continent.

Supplementary information

PDF files

  1. Supplementary information S1 (figure) (452 KB)

    Organization of the bipolar cell types in the mouse retina.

  2. Supplementary information S2 (table) (112 KB)

    Immunomarkers and transgenic lines for mouse bipolar cells

Additional data