Retinal bipolar cells: elementary building blocks of vision

Journal name:
Nature Reviews Neuroscience
Year published:
Published online


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


  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.


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Author information


  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' (, 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