Transience of the Retinal Output Is Determined by a Great Variety of Circuit Elements

Abstract

Retinal ganglion cells (RGCs) encrypt stimulus features of the visual scene in action potentials and convey them toward higher visual centers in the brain. Although there are many visual features to encode, our recent understanding is that the ~46 different functional subtypes of RGCs in the retina share this task. In this scheme, each RGC subtype establishes a separate, parallel signaling route for a specific visual feature (e.g., contrast, the direction of motion, luminosity), through which information is conveyed. The efficiency of encoding depends on several factors, including signal strength, adaptational levels, and the actual efficacy of the underlying retinal microcircuits. Upon collecting inputs across their respective receptive field, RGCs perform further analysis (e.g., summation, subtraction, weighting) before they generate the final output spike train, which itself is characterized by multiple different features, such as the number of spikes, the inter-spike intervals, response delay, and the rundown time (transience) of the response. These specific kinetic features are essential for target postsynaptic neurons in the brain in order to effectively decode and interpret signals, thereby forming visual perception. We review recent knowledge regarding circuit elements of the mammalian retina that participate in shaping RGC response transience for optimal visual signaling.

Keywords: amacrine cell; bipolar cell; ganglion cell; ganglion cell layer; inner plexiform layer; outer plexiform layer; parallel signaling; photoreceptor; retina.

Figure 1

Schematic drawing of the basic neuronal wiring of the mammalian retina. The vertical information stream encompasses the light-sensitive photoreceptors (PR), bipolar cells (BC), and retinal ganglion cells (RGC). These cells express glutamate (GLU), thus providing an excitatory (highlighted in blue) stream of signals (direction of information flow is indicated by yellow arrows). Horizontal cells (HC) and amacrine cells (AC) serve various forms of inhibition (red arrows) in the outer or the inner retina, respectively. HCs express GABA (highlighted in orange in the outer retina), whereas ACs release either glycine (GLY, highlighted in green) or GABA (highlighted in orange in the inner retina) as a neurotransmitter.

Figure 2

The diversity of response transience across the retinal ganglion cell population. Peri-event rasters of representative RGCs (a–d). Light-evoked spiking responses upon full-field illumination are rather similar across trials for each RGC, but they display a great variety in terms of their response length (or decay—expressed as the PSTHτ value in this work) for both the ON (cells 1 and 2) and OFF (cells 3 and 4) subpopulations. The white bar below the recordings represents the timing of the on- and off-set of the stimulus.

Figure 3

Excitatory signal processing in the outer retina. Photoreceptors (PR; dark grey, dark and light blue) release glutamate that binds to postsynaptic glutamate receptors located on dendrites of bipolar cells (BCs). OFF BCs (orange) express either AMPA or kainate ionotropic receptors that, upon glutamate binding, excite BCs. In contrast, ON BCs (magenta) have the metabotropic mGluR6 receptor on their dendrites and, unlike ionotropic receptors, hyperpolarize ON BCs when glutamate binding occurs (note that rods also form the same type of contact with the rod BCs). Horizontal cells (HC), amacrine cells (AC), and ganglion cells (GC, green) are also represented in the retinal circuitry.

Figure 4

Inhibitory mechanisms in the outer retina. Photoreceptors (PR; dark grey, dark and light blue) release glutamate that binds to ionotropic glutamate receptors located on the postsynaptic dendritic surfaces of horizontal cells (HC, green). HCs in turn release GABA as an inhibitory transmitter and provide feedback inhibition to PRs (left side of the scheme—note that HC to rod BC feedback inhibition is not shown in the diagram but exists as well) and feedforward inhibition to BCs (magenta—right half of the scheme). Amacrine cells (AC) and ganglion cells (GC) are also represented in the retinal circuitry.

Figure 5

Active membrane properties of bipolar cells. Most voltage-gated channels that determine active membrane properties of BCs and potentially shape the transience of light responses can be found in the axon terminal region (left panel). These include various Ca⁺⁺, K⁺, Na⁺, and Cl⁻ channels (middle panel), some of which increase, whereas others decrease the BC response transience (right panel). Color codes in the middle and right panels connect each channel type with a function they play in regulating BC response transience.

Figure 6

Self-regulation of bipolar cell responses. There are two identified mechanisms by which retinal bipolar cells (BCs) likely self-regulate their light responses. One of them takes place via glutamate transporters that sequester glutamate from the synaptic cleft, and thereby the effects of the transmitter and the light response become more transient (left panel). A second mechanism occurs through mGluR7 receptors that bind some of the released molecules and exert their effect on the dynamics of release and the light response itself (right panel). The net effect of the activation of mGluR7 receptors in the BC axon terminals makes BC responses more sustained (also see the text).

Figure 7

Inhibitory mechanisms in the inner retina. (a) Upon glutamate release from rod bipolar cells (BCs, magenta), A17 amacrine cells (ACs, orange) provide a relative sluggish GABAergic inhibitory feedback to rod BCs and make BC and postsynaptic AII AC (green) responses more transient. (b) ACs also provide feedforward inhibition to retinal ganglion cells (RGCs) in the inner retina. Both glycinergic and GABAergic interactions result in more sustained RGC responses in certain circuits (two middle panels), whereas the activation of some GABAergic contacts results in more transient RGC responses (rightmost panel). (c) Certain ACs in the retina, upon activation, provide opposite polarity inhibition to inner retinal neurons. In the presented circuit, AII ACs (green) receive glutamatergic excitation from rod BCs (magenta) that have ON polarity, and in turn, the AII cell forms inhibitory glycinergic synapses with opposite polarity OFF cone BCs (blue). This type of interaction is called crossover inhibition. (d) ACs (red) often make inhibitory synapses with other ACs (orange). Via such disinhibitory mechanisms, the transience of the final output RGCs (green) can be finely tuned to suit certain visual functions.

Figure 8

Signal interference through parallel retinal pathways. (a) Representative ON retinal ganglion cell (RGC) light-evoked rasters (left column) and peristimulus time histogram (PSTH) cohorts (right column) were obtained to light stimuli of various strength (intensity is reflected in the right top corner). RGC PSTHτ values (for more information, see [146]) changed non-monotonously during this experiment while the stimulus intensity was gradually increased (see also panel (c)). PSTHs clearly show a very sensitive, relatively delayed response component (red arrow) and a less sensitive but fast response component (light blue arrow). These two components differ in their delays but appear similar in response decay, and therefore PSTHτ values are shifted towards the sustained range when the two signals are summated (mesopic conditions—2nd, 3rd, and 4th panels), whereas they appear transient when only one signal is present (scotopic condition—1st panel) or dominates over the other component (photopic conditions—5th, 6th, and 7th panels; see also panel (c)). (b) A similar experiment was performed for this representative OFF RGC. PSTHτ values of this RGC clearly changed during this experiment when the stimulus intensity was gradually increased. This OFF RGC also showed a very sensitive and delayed response (red arrow) as well as a faster but less sensitive (light blue arrow) response component. The two signal components differed in their delays and sensitivities and a slight alteration in PSTHτ values occurred as a result of the summation of components (mostly in mesopic conditions—middle panels). While the distinction of response components can clearly be differentiated for the ON RGC in (a), this OFF cell (and most examined RGCs) showed a less obvious and less separable summation of incoming signals. (c,d) Diagrams show that similar to cells shown in panels (a,b) (values of these cells appear in blue and red in the diagrams), most recorded RGCs displayed stimulus strength-driven changes of PSTHτ values (grey curves). (e) The diagram shows minimum/maximum PSTHτ value pairs for the recorded ON (blue) and OFF (red) cells during the course of the stimulus intensity recording paradigm. The examined RGCs showed ~18–73% PSTHτ changes during the course of this experiment.

Figure 9

Summary of potential signal summation mechanisms affecting RGC response transience. (a) Two bipolar cells (BCs) of different subtypes provide transient inputs to the same retinal ganglion cell (RGC; light blue EPSC curves). These two inputs have dissimilar delays (due to differential BC signaling and/or a different location of synapses over the RGC dendritic arbor), and therefore the summation of the responses results in an intermediate or sustained RGC spiking response. (b) This RGC receives excitatory inputs from two sources: from a transient BC (light blue EPSC) and from a gap junction-coupled amacrine cell (AC; purple depolarization). If the dynamics of these two inputs differ, their summation will induce intermediate and/or sustained RGC spiking. (c) This RGC receives excitation from a BC (light blue EPSC) and delayed inhibition (red IPSC) from an AC, resulting in a transient RGC response. (d) An RGC that receives excitation from a BC (light blue EPSC) and inhibition (red IPSC) from an AC. In this scenario, the two inputs have about the same delays, and therefore the excitation will be truncated and the RGC output is an intermediate/sustained spiking.