Presynaptic inhibition modulates spillover, creating distinct dynamic response ranges of sensory output

Sensory information is thought to be modulated by presynaptic inhibition. Although this form of inhibition is a well-studied phenomenon, it is still unclear what role it plays in shaping sensory signals in intact circuits. By visually stimulating the retinas of transgenic mice lacking GABAc receptor-mediated presynaptic inhibition, we found that this inhibition regulated the dynamic range of ganglion cell (GC) output to the brain. Presynaptic inhibition acted differentially upon two major retinal pathways; its elimination affected GC responses to increments, but not decrements, in light intensity across the visual scene. The GC dynamic response ranges were different because presynaptic inhibition limited glutamate release from ON, but not OFF, bipolar cells, which modulate the extent of glutamate spillover and activation of perisynaptic NMDA receptors at ON GCs. Our results establish a role for presynaptic inhibitory control of spillover in determining sensory output in the CNS.     

The temporal structure of transient ON/OFF ganglion cell responses and its relation to intra-retinal processing

A subpopulation of transient ON/OFF ganglion cells in the turtle retina transmits changes in stimulus intensity as series of distinct spike events. The temporal structure of these event sequences depends systematically on the stimulus and thus carries information about the preceding intensity change. To study the spike events' intra-retinal origins, we performed extracellular ganglion cell recordings and simultaneous intracellular recordings from horizontal and amacrine cells. Based on these data, we developed a computational retina model, reproducing spike event patterns with realistic intensity dependence under various experimental conditions. The model's main features are negative feedback from sustained amacrine onto bipolar cells, and a two-step cascade of ganglion cell suppression via a slow and a fast transient amacrine cell. Pharmacologically blocking glycinergic transmission results in disappearance of the spike event sequence, an effect predicted by the model if a single connection, namely suppression of the fast by the slow transient amacrine cell, is weakened. We suggest that the slow transient amacrine cell is glycinergic, whereas the other types release GABA. Thus, the interplay of amacrine cell mediated inhibition is likely to induce distinct temporal structure in ganglion cell responses, forming the basis for a temporal code. Action Editor: Jonathan D. Victor     

A model of anuran retina relating interneurons to ganglion cell responses

A model is presented which accounts for many characteristic response properties used to classify anuran ganglion cell types while being consistent with data concerning interneurons. In the model color is ignored and input stimuli are assumed to be only black and white at high contrast. We show that accurate ganglion cell responses are obtained even with simplified receptors and horizontal cells: Receptors are modeled as responding with a step change, while horizontal cells respond only to global changes in intensity brought about by full field illumination changes. A hyperpolarizing and depolarizing bipolar cell are generated y subtracting local receptor and horizontal potentials. Two transient amacrine cells (On and Off) are generated using a high-pass filter like mechanism with a thresholded output which responds to positive going changes in the corresponding bipolar cell potentials. The model shows how a selective combination of bipolar and amacrine channels can account for many of the response properties used to classify the anuran ganglion cell types (class-0 through 4) and makes several experimental predictions.     

Membrane currents and pharmacology of retinal bipolar cells: a comparative study on goldfish and mouse.

We obtained solitary bipolar cells using enzymatic (papain) dissociation of the goldfish and mouse (C57BL/6J, adult) retinae and measured the membrane currents of these cells by whole-cell patch clamp. Bipolar cells of these two species showed two main differences. A. Ca current 1. In the mouse, depolarization evoked a transient Ca current that had maximal amplitude at about -30 mV. 2. The Ca conductance was activated by voltage steps to potentials greater than -60 mV and inactivated fully at potentials greater than -20 mV. 3. The mouse Ca current was insensitive to Cd2+ or dihydropyridine. 4. Contrary to mouse, goldfish bipolar cells had a sustained Ca current, which was activated over a more positive potential range (greater than -30 mV), blocked by either 50 microM Cd2+ or 10 microM nifedipine, and markedly augmented by 10 microM Bay K8644. 5. The transient character of the Ca current in mouse bipolar cells may help to shape phasic responses of ganglion cells, while in goldfish the sustained nature of Ca current may contribute to shape tonic responses of ganglion cells. B. Pharmacology 1. We examined the effects of the inhibitory transmitters, glycine and GABA, on bipolar cells. 2. GABA produced strong inhibitory effects on bipolar cells of both goldfish and mouse. 3. The highest GABA sensitivity was found at the bipolar cell axon terminal, the site of reciprocal connection with amacrine cells. 4. GABA increased the Cl conductance. 5. Unlike GABA, glycine was effective only on the mouse bipolar cells. Axon terminals showed the highest glycine sensitivity. 6. Glycine-induced currents were also carried by Cl ions. 7. Since ECl in intact cells is assumed to be -55 mV, both GABA and glycine are thought to generate hyperpolarizing responses in cells maintained at their resting potential (ca. -45 mV). 8. The present study suggests that inhibition from amacrine cells to bipolar cells, found in both species, is mediated by different transmitters.     

Synaptic organization and ionic basis of on and off channels in mudpuppy retina. I. Intracellular analysis of chloride-sensitive electrogenic properties of receptors, horizontal cells, bipolar cells, and amacrine cells

Intracellular recordings from receptors, horizontal cells, bipolars, and amacrines have been carried out in the perfused mudpuppy eyecup. The introduction of a chloride-free (c-f) medium results in initial transient potential changes in many cells followed by a slow loss of light-evoked activity of the depolarizing bipolar, the horizontal cell, and the on depolarization of amacrine cells. The hyperpolarizing bipolar remains responsive to light stimulation in a c-f medium, but the antagonistic surround mechanism is abolished. These effects are reversible after returning to a normal ionic medium. The results of this study provide insight into the retinal connections which underlie ganglion cell receptive field organization. It is concluded that the depolarizing bipolar is excitatory to on ganglion cells and is also the pathway for on-excitation of on-off cells. The hyperpolarizing bipolar mediates the off discharge of off and on-off cells. Amacrine cells receive input from both depolarizing and hyperpolarizing bipolar cells. These findings raise the possibility that transmembrane movements of chloride ions are critical for the light responsiveness of horizontal and depolarizing bipolar cell activity.     

Synaptic inputs to the ganglion cells in the tiger salamander retina

The postsynaptic potentials (PSPs) that form the ganglion cell light response were isolated by polarizing the cell membrane with extrinsic currents while stimulating at either the center or surround of the cell's receptive field. The time-course and receptive field properties of the PSPs were correlated with those of the bipolar and amacrine cells. The tiger salamander retina contains four main types of ganglion cell: "on" center, "off" center, "on-off", and a "hybrid" cell that responds transiently to center, but sustainedly, to surround illumination. The results lead to these inferences. The on-ganglion cell receives excitatory synpatic input from the on bipolars and that synapse is "silent" in the dark. The off-ganglion cell receives excitatory synaptic input from the off bipolars with this synapse tonically active in the dark. The on-off and hybrid ganglion cells receive a transient excitatory input with narrow receptive field, not simply correlated with the activity of any presynaptic cell. All cell types receive a broad field transient inhibitory input, which apparently originates in the transient amacrine cells. Thus, most, but not all, ganglion cell responses can be explained in terms of synaptic inputs from bipolar and amacrine cells, integrated at the ganglion cell membrane.     

Inhibitory mechanisms within the receptive fields of X-and Y-type retinal ganglion cells of the cat (author's transl)]

Two-stages of the inhibitory mechanisms were assumed within the on-center receptive field (RF) of the cat's retinal ganglion cell on the basis of the following two experiments: 1) Effect of background intensity upon the magnitude of the response to the RF-centered spot of stimulus, and 2) the time course of the inhibitory effect when the additional spot of light is presented in the same RF center region. The first stage is an inhibitory feed-back from horizontal cell to the photoreceptor. Both X-and Y-fields have this feed-back route. By this gain control machanisms, the ganglion cell will respond to the intensity ratio of the spot to the backgound. The second stage of inhibitory mechanism in X-field is the feed-back from sustained amacrine cell to the bipolar cell. Above two stages of feed-back mechanism in X-field explain the strong maintained suppressive effect produced by the additional spot of light. On the other hand, the Y-type ganglion cell will recive the inhibitory input via feed-forward path from trannsient amacrine cell. This explains the transient on- and of f-suppressive effects     

Melanopsin mediates retrograde visual signaling in the retina

The canonical flow of visual signals proceeds from outer to inner retina (photoreceptors→bipolar cells→ganglion cells). However, melanopsin-expressing ganglion cells are photosensitive and functional sustained light signaling to retinal dopaminergic interneurons persists in the absence of rods and cones. Here we show that the sustained-type light response of retinal dopamine neurons requires melanopsin and that the response is mediated by AMPA-type glutamate receptors, defining a retrograde retinal visual signaling pathway that fully reverses the usual flow of light signals in retinal circuits.     

Synaptic connections of calbindin-immunoreactive cone bipolar cells in the inner plexiform layer of rabbit retina

In the mammalian retina, information concerning various aspects of an image is transferred in parallel, and cone bipolar cells are thought to play a major role in this parallel processing. We have examined the synaptic connections of calbindin-immunoreactive (IR) ON cone bipolar cells in the inner plexiform layer (IPL) of rabbit retina and have compared these synaptic connections with those that we have previously described for neurokinin 1 (NK1) receptor-IR cone bipolar cells. A total of 325 synapses made by calbindin-IR bipolar axon terminals have been identified in sublamina b of the IPL. The axons of calbindin-IR bipolar cells receive synaptic inputs from amacrine cells through conventional synapses and are coupled to putative AII amacrine cells via gap junctions. The major output from calbindin-IR bipolar cells is to amacrine cell processes. These data resemble our findings for NK1 receptor-IR bipolar cells. However, the incidences of output synapses to ganglion cell dendrites of calbindin-IR bipolar cells are higher compared with the NK1-receptor-IR bipolar cells. On the basis of stratification level and synaptic connections, calbindin-IR ON cone bipolar cells might thus play an important role in the processing of various visual aspects, such as contrast, orientation, and approach sensing, and in transferring rod signals to the ON cone pathway.     

Fast and slow contrast adaptation in retinal circuitry

The visual system adapts to the magnitude of intensity fluctuations, and this process begins in the retina. Following the switch from a low-contrast environment to one of high contrast, ganglion cell sensitivity declines in two distinct phases: a fast change occurs in <0.1 s, and a slow decrease over approximately 10 s. To examine where these modulations arise, we recorded intracellularly from every major cell type in the salamander retina. Certain bipolar and amacrine cells, and all ganglion cells, adapted to contrast. Generally, these neurons showed both fast and slow adaptation. Fast effects of a contrast increase included accelerated kinetics, decreased sensitivity, and a depolarization of the baseline membrane potential. Slow adaptation did not affect kinetics, but produced a gradual hyperpolarization. This hyperpolarization can account for slow adaptation in the spiking output of ganglion cells.     

Adaptation to Changes in Higher-Order Stimulus Statistics in the Salamander Retina

Adaptation in the retina is thought to optimize the encoding of natural light signals into sequences of spikes sent to the brain. While adaptive changes in retinal processing to the variations of the mean luminance level and second-order stimulus statistics have been documented before, no such measurements have been performed when higher-order moments of the light distribution change. We therefore measured the ganglion cell responses in the tiger salamander retina to controlled changes in the second (contrast), third (skew) and fourth (kurtosis) moments of the light intensity distribution of spatially uniform temporally independent stimuli. The skew and kurtosis of the stimuli were chosen to cover the range observed in natural scenes. We quantified adaptation in ganglion cells by studying linear-nonlinear models that capture well the retinal encoding properties across all stimuli. We found that the encoding properties of retinal ganglion cells change only marginally when higher-order statistics change, compared to the changes observed in response to the variation in contrast. By analyzing optimal coding in LN-type models, we showed that neurons can maintain a high information rate without large dynamic adaptation to changes in skew or kurtosis. This is because, for uncorrelated stimuli, spatio-temporal summation within the receptive field averages away non-gaussian aspects of the light intensity distribution.     

Weber and noise adaptation in the retina of the toad Bufo marinus

Responses to flashes and steps of light were recorded intracellularly from rods and horizontal cells, and extracellularly from ganglion cells, in toad eyecups which were either dark adapted or exposed to various levels of background light. The average background intensities needed to depress the dark-adapted flash sensitivity by half in the three cell types, determined under identical conditions, were 0.9 Rh*s-1 (rods), 0.8 Rh*s-1 (horizontal cells), and 0.17 Rh*s-1 (ganglion cells), where Rh* denotes one isomerization per rod. Thus, there is a range (approximately 0.7 log units) of weak backgrounds where the sensitivity (response amplitude/Rh*) of rods is not significantly affected, but where that of ganglion cells (1/threshold) is substantially reduced, which implies that the gain of the transmission from rods to the ganglion cell output is decreased. In this range, the ganglion cell threshold rises approximately as the square root of background intensity (i.e. in proportion to the quantal noise from the background), while the maintained rate of discharge stays constant. The threshold response of the cell will then signal light deviations (from a mean level) of constant statistical significance. We propose that this type of ganglion cell desensitization under dim backgrounds is due to a post-receptoral gain control driven by quantal fluctuations, and term it noise adaptation in contrast to the Weber adaptation (desensitization proportional to the mean background intensity) of rods, horizontal cells, and ganglion cells at higher background intensities.     

Retinal ganglion cells can rapidly change polarity from Off to On

Retinal ganglion cells are commonly classified as On-center or Off-center depending on whether they are excited predominantly by brightening or dimming within the receptive field. Here we report that many ganglion cells in the salamander retina can switch from one response type to the other, depending on stimulus events far from the receptive field. Specifically, a shift of the peripheral image--as produced by a rapid eye movement--causes a brief transition in visual sensitivity from Off-type to On-type for approximately 100 ms. We show that these ganglion cells receive inputs from both On and Off bipolar cells, and the Off inputs are normally dominant. The peripheral shift strongly modulates the strength of these two inputs in opposite directions, facilitating the On pathway and suppressing the Off pathway. Furthermore, we identify certain wide-field amacrine cells that contribute to this modulation. Depolarizing such an amacrine cell affects nearby ganglion cells in the same way as the peripheral image shift, facilitating the On inputs and suppressing the Off inputs. This study illustrates how inhibitory interneurons can rapidly gate the flow of information within a circuit, dramatically altering the behavior of the principal neurons in the course of a computation.     

Crossover inhibition in the retina: circuitry that compensates for nonlinear rectifying synaptic transmission

In the mammalian retina, complementary ON and OFF visual streams are formed at the bipolar cell dendrites, then carried to amacrine and ganglion cells via nonlinear excitatory synapses from bipolar cells. Bipolar, amacrine and ganglion cells also receive a nonlinear inhibitory input from amacrine cells. The most common form of such inhibition crosses over from the opposite visual stream: Amacrine cells carry ON inhibition to the OFF cells and carry OFF inhibition to the ON cells (”crossover inhibition”). Although these synapses are predominantly nonlinear, linear signal processing is required for computing many properties of the visual world such as average intensity across a receptive field. Linear signaling is also necessary for maintaining the distinction between brightness and contrast. It has long been known that a subset of retinal outputs provide exactly this sort of linear representation of the world; we show here that rectifying (nonlinear) synaptic currents, when combined thorough crossover inhibition can generate this linear signaling. Using simple mathematical models we show that for a large set of cases, repeated rounds of synaptic rectification without crossover inhibition can destroy information carried by those synapses. A similar circuit motif is employed in the electronics industry to compensate for transistor nonlinearities in analog circuits.     

Morphological and functional organization of ON and OFF pathways in the adult newt retina

Morphological and functional organization of ON and OFF pathways in the adult newt retina were examined by intracellular recording and staining techniques and immunohistochemistry. Synaptotagmin immunoreactivity discriminated three broad bands within the IPL: the distal band (sublamina I), the middle band (sublamina II) consisting of two dense punctate bands (sublaminae II(a) and II(b)), and proximal band (sublamina III). The Lucifer-yellow labeled OFF amacrine and ganglion cells send their processes mainly in sublamina I and/or II(a) where OFF bipolar cells extend their axon terminals, while ON amacrine and ganglion cells send their processes in sublamina III and/or II(b) where ON bipolar cells extend their axon terminals. Processes of ON-OFF amacrine and ganglion cells ramify broadly in the whole thickness of the IPL. Many bipolar cells responded to light spot with a transient hyperpolarization at both light onset and offset. They are probably subtypes of ON bipolar cells, because their axon terminals branch mainly in sublaminae III and/or II(b), although a few cells ramified the axon at both sublaminae II(a) and III. Two immunohistochemical markers for bipolar cells, PKC and RB-1, identified axon terminals in sublaminae III and/or II(b). From the ramification pattern of axon terminal, they are probably subtypes of ON bipolar cells. ChAT-ir amacrine cells ramified their dendrites in either sublamina I or II(b). Altogether, present studies support the general idea of segregation of ON and OFF pathways in sublaminae a and b of the IPL.     

Electrophysiological evidence for push-pull interactions in the inner retina of turtle

The responses of the inner retinal neurons of turtle to light spots of sizes were studied in an attempt to reveal characteristics that may reflect possible interactions of the neural circuits underlying the center and surround responses. For the ON-OFF cells, the responses were also analyzed to observe whether interference or augmentation of these responses occur. The intracellular recordings revealed several such interactions, observed either in the form of altered spike activity or as changes in the transiency of the light responses. The ON-responding amacrine cell presented in this study became more sustained, while for the ON-OFF amacrine cells larger light spots tended to make the responses more transient and both the ON and OFF components became more pronounced. The spiking activity of the OFF-type ganglion cell shifted in relation to the light stimulus and the number of spikes observed upon presentation of larger spots increased. We suggest that the surround circuits activated by increasing light spots may substantially influence and reorganize not only the overall center-surround balance, but also the center response of the cells. Although it cannot be excluded that intrinsic membrane properties also influence these processes to some extent, it is more likely that lateral inhibition and disinhibitory mechanisms play the leading role in this process.     

Trigger features and excitation in the retina

This review focuses on recent advances in our understanding of how neural divergence and convergence give rise to complex encoding properties of retinal ganglion cells. We describe the apparent mismatch between the number of cone bipolar cell types, and the diversity of excitatory input to retinal ganglion cells, and outline two possible solutions. One proposal is for diversity in the excitatory pathways to be generated within axon terminals of cone bipolar cells, and the second invokes narrow-field glycinergic amacrine cells that can apparently act like bipolar cells by providing excitatory drive to ganglion cells. Finally we highlight two advances in technique that promise to provide future insights; automation of electron microscope data collection and analysis, and the use of the ideal observer to quantitatively compare neural performance at all levels.     

Mouse Ganglion-Cell Photoreceptors Are Driven by the Most Sensitive Rod Pathway and by Both Types of Cones

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are depolarized by light by two mechanisms: directly, through activation of their photopigment melanopsin; and indirectly through synaptic circuits driven by rods and cones. To learn more about the rod and cone circuits driving ipRGCs, we made multielectrode array (MEA) and patch-clamp recordings in wildtype and genetically modified mice. Rod-driven ON inputs to ipRGCs proved to be as sensitive as any reaching the conventional ganglion cells. These signals presumably pass in part through the primary rod pathway, involving rod bipolar cells and AII amacrine cells coupled to ON cone bipolar cells through gap junctions. Consistent with this interpretation, the sensitive rod ON input to ipRGCs was eliminated by pharmacological or genetic disruption of gap junctions, as previously reported for conventional ganglion cells. A presumptive cone input was also detectable as a brisk, synaptically mediated ON response that persisted after disruption of rod ON pathways. This was roughly three log units less sensitive than the rod input. Spectral analysis revealed that both types of cones, the M- and S-cones, contribute to this response and that both cone types drive ON responses. This contrasts with the blue-OFF, yellow-ON chromatic opponency reported in primate ipRGCs. The cone-mediated response was surprisingly persistent during steady illumination, echoing the tonic nature of both the rod input to ipRGCs and their intrinsic, melanopsin-based phototransduction. These synaptic inputs greatly expand the dynamic range and spectral bandpass of the non-image-forming visual functions for which ipRGCs provide the principal retinal input.     

Rod vision is controlled by dopamine-dependent sensitization of rod bipolar cells by GABA

Dark and light adaptation of retinal neurons allow our vision to operate over an enormous light intensity range. Here we report a mechanism that controls the light sensitivity and operational range of rod-driven bipolar cells that mediate dim-light vision. Our data indicate that the light responses of these cells are enhanced by sustained chloride currents via GABA(C) receptor channels. This sensitizing GABAergic input is controlled by dopamine D1 receptors, with horizontal cells serving as a plausible source of GABA release. Our findings expand the role of dopamine in vision from its well-established function of suppressing rod-driven signals in bright light to enhancing the same signals under dim illumination. They further reveal a role for GABA in sensitizing the circuitry for dim-light vision, thereby complementing GABA's traditional role in providing dynamic feedforward and feedback inhibition in the retina.