Michael A. Freed

The ON pathway rectifies the OFF pathway of the mammalian retina.

In the vertebrate visual system, ON cells respond to positive contrasts and OFF cells respond to negative contrasts, and thus both ON and OFF cells exhibit rectification. We investigated the retinal circuits by which the ON pathway rectifies the OFF pathway. White noise was projected onto an in vitro preparation of the mammalian retina and excitatory currents were recorded from retinal ganglion cells under whole-cell voltage clamp. Currents in OFF cells were more rectified than those in ON cells: thus, currents in ON cells were able to signal both positive and negative contrasts, but currents in OFF cells were virtually restricted to negative contrasts. Blocking signals in the ON pathway derectified currents in OFF ganglion cells, thus allowing them to be modulated by positive contrasts, indicating that the ON pathway normally rectifies currents in OFF ganglion cells. Such cross-rectification from ON to OFF pathways required intact glycinergic inhibition, indicating that a glycinergic amacrine cell, most likely the AII amacrine cell, allows the ON bipolar cell to hyperpolarize the OFF bipolar cell close to the threshold for transmitter release, thus rectifying excitatory currents in the OFF ganglion cell. Asymmetrical rectification of ON and OFF cells may be an adaptation to natural scenes that have more contrast levels below the mean than above. Thus, in order for ON and OFF pathways to encode an equal number of contrast levels, the ON cells must signal some negative contrasts.

ON-OFF amacrine cells in cat retina

We studied the morphology, photic responses, and synaptic connections of ON‐OFF amacrine cells in the cat retina by penetrating them with intracellular electrodes, staining them with horseradish peroxidase, and examining them with the electron microscope. In a sample of seven cells, we found two different morphological types: the A19, which ramifies narrowly in stratum 2 (sublamina a) of the inner plexiform layer, and the A22, which ramifies mostly in stratum 4 (sublamina b) but extends some dendrites to sublamina a. Both of these cell types have axon‐like processes that extend >800 μm from the conventional dendritic arbor.

Different Types of Ganglion Cell Share a Synaptic Pattern

Retinal ganglion cells comprise about 10 morphological types that also differ functionally. To determine whether functional differences might arise partially from differences in excitatory input, we quantified the distributions of ribbon contacts to four mammalian ganglion cell types [brisk‐transient (BT), brisk‐sustained (BS), local edge (LE), directionally selective (DS)], comparing small vs. large and “sluggish” vs. “brisk.” Cells in guinea pig retina were filled with fluorescent dye, immunostained for synaptic ribbons, and reconstructed with their ribbon contacts by confocal microscopy. False‐positive contacts were corrected by performing the same analysis on processes that lack synapses: glial stalks and rod bipolar axons. All types shared a domed distribution of membrane that was well fit by a Gaussian function (R2 = 0.96 ± 0.01); they also shared a constant density of contacts on the dendritic membrane, both across each arbor and across cell types (19 ± 1 contacts/100 μm2 membrane). However, the distributions of membrane across the retina differed markedly in width (BT > DS ≈ BS > LE) and peak density (BS > DS > LE > BT). Correspondingly, types differed in peak density of contacts (BS > DS ≈ LE > BT) and total number (BS ≈ BT > DS > LE). These differences between cell types in spatial extent and local concentration of membrane and synapses help to explain certain functional differences. J. Comp. Neurol. 507:1871–1878, 2008.

Conductances evoked by light in the ON-β ganglion cell of cat retina

: When a bar of light (215 x 5000 microns) illuminates the receptive field of an ON-beta ganglion cell of cat retina, the cell depolarizes. Intracellular recording from the cat eyecup preparation shows that this depolarization is due to an increase in conductance (2.4 +/- 0.6 nS). Different phases of this depolarization have different reversal potentials, but all of these reversal potentials are more positive than the cells resting potential in the dark. When the light is turned on, there is an initial transient depolarization; the reversal potential measured for this transient is positive (23 +/- 11 mV). As the light is left on, the cell partially repolarizes to a sustained depolarization; the reversal potential measured for this sustained depolarization is close to zero (-1 +/- 5 mV). When the light is turned off, the cell repolarizes further; the reversal potential measured for this repolarization is negative (-18 +/- 7 mV), but still above the resting potential in the dark (-50 mV). To explain this variety of reversal potentials, at least two different synaptic conductances are required: one to ions which have a positive reversal potential and another to ions which have a negative reversal potential. Comparing the responses to broad and narrow bars suggests that these two conductances are associated with the center and surround, respectively. Finally, since an ON-beta cell in the area centralis receives about 200 synapses, these results indicate that a single synapse produces an average conductance increase of about 15 pS during a near-maximal depolarization.

Reliability and Frequency Response of Excitatory Signals Transmitted to Different Types of Retinal Ganglion Cell

The same visual stimulus evokes a different pattern of neural signals each time the stimulus is presented. Because this unreliability reduces visual performance, it is important to understand how it arises from neural circuitry. We asked whether different types of ganglion cell receive excitatory signals with different reliability and frequency content and, if so, how retinal circuitry contributes to these differences. If transmitter release is governed by Poisson statistics, the SNR of the postsynaptic currents (ratio of signal power to noise power) should grow linearly with quantal rate (qr), a prediction that we confirmed experimentally. Yet ganglion cells of the same type receive quanta at different rates. Thus to obtain a measure of reliability independent of quantal rate, we calculated the ratio SNR/qr, and found this measure to be type-specific. We also found type-specific differences in the frequency content of postsynaptic currents, although types whose dendrites branched at nearby levels of the inner plexiform layer (IPL) had similar frequency content. As a result, there was an orderly distribution of frequency response through the depth of the IPL, with alternating layers of broadband and high-pass signals. Different types of bipolar cell end at different depths of the IPL and provide excitatory synapses to ganglion cell dendrites there. Thus these findings indicate that a bipolar cell synapse conveys signals whose temporal message and reliability (SNR/qr) are determined by neuronal type. The final SNR of postsynaptic currents is set by the dendritic membrane area of a ganglion cell, which sets the numbers of bipolar cell synapses and thus the rate at which it receives quanta [SNR = qr x (SNR/qr)].

Voltage-Gated Sodium Channels Improve Contrast Sensitivity of a Retinal Ganglion Cell

Voltage-gated channels in a retinal ganglion cell are necessary for spike generation. However, they also add noise to the graded potential and spike train of the ganglion cell, which may degrade its contrast sensitivity, and they may also amplify the graded potential signal. We studied the effect of blocking Na+ channels in a ganglion cell on its signal and noise amplitudes and its contrast sensitivity. A spot was flashed at 1–4 Hz over the receptive field center of a brisk transient ganglion cell in an intact mammalian retina maintained in vitro. We measured signal and noise amplitudes from its intracellularly recorded graded potential light response and measured its contrast detection thresholds with an “ideal observer.” When Na+ channels in the ganglion cell were blocked with intracellular lidocaine N-ethyl bromide (QX-314), the signal-to-noise ratio (SNR) decreased (p < 0.05) at all tested contrasts (2–100%). Likewise, bath application of tetrodotoxin (TTX) reduced the SNR and contrast sensitivity but only at lower contrasts (≤50%), whereas at higher contrasts, it increased the SNR and sensitivity. The opposite effect of TTX at high contrasts suggested involvement of an inhibitory surround mechanism in the inner retina. To test this hypothesis, we blocked glycinergic and GABAergic inputs with strychnine and picrotoxin and found that TTX in this case had the same effect as QX-314: a reduction in the SNR at all contrasts. Noise analysis suggested that blocking Na+ channels with QX-314 or TTX attenuates the amplitude of quantal synaptic voltages. These results demonstrate that Na+ channels in a ganglion cell amplify the synaptic voltage, enhancing the SNR and contrast sensitivity.

Retinal ganglion cells – spatial organization of the receptive field reduces temporal redundancy

According to the ‘redundancy reduction’ hypothesis, a visual neuron removes correlations from an image to reduce redundancy in the spike train, thus increasing the efficiency of information coding. However, all elaborations of this general hypothesis have treated spatial and temporal correlations separately. To investigate how a retinal ganglion cell responds to combined spatial and temporal correlations, we selected those cells with center–surround receptive field and presented a stimulus with strong spatiotemporal correlations: we presented a random sequence of intensities (of white noise) to the receptive field center and then activated the surround with the same sequence. We found that, for most cells, activating the surround reduced temporal redundancy in the spike train. Although the surround often reduced the information rate of the spike train it always increased the amount of information per spike. However, when the surround was modulated by a different white‐noise sequence than the center, eliminating spatial–temporal correlations, the surround no longer reduced redundancy or increased information per spike. The proposed mechanism for redundancy reduction is based on the temporal properties of the center and surround: the surround signal is delayed behind the center signal and subtracted from it; this implements a differentiator which removes low frequencies from the stimulus, thus reducing redundancy in the spike train. These results extend the redundancy reduction hypothesis by indicating that the spatial organization of the receptive field into center and surround can reduce temporal redundancy within the spike train of a ganglion cell.

A Mammalian Retinal Ganglion Cell Implements a Neuronal Computation That Maximizes the SNR of Its Postsynaptic Currents

Neurons perform computations by integrating excitatory and inhibitory synaptic inputs. Yet, it is rarely understood what computation is being performed, or how much excitation or inhibition this computation requires. Here we present evidence for a neuronal computation that maximizes the signal-to-noise power ratio (SNR). We recorded from OFF delta retinal ganglion cells in the guinea pig retina and monitored synaptic currents that were evoked by visual stimulation (flashing dark spots). These synaptic currents were mediated by a decrease in an outward current from inhibitory synapses (disinhibition) combined with an increase in an inward current from excitatory synapses. We found that the SNR of combined excitatory and disinhibitory currents was voltage sensitive, peaking at membrane potentials near resting potential. At the membrane potential for maximal SNR, the amplitude of each current, either excitatory or disinhibitory, was proportional to its SNR. Such proportionate scaling is the theoretically best strategy for combining excitatory and disinhibitory currents to maximize the SNR of their combined current. Moreover, as spot size or contrast changed, the amplitudes of excitatory and disinhibitory currents also changed but remained in proportion to their SNRs, indicating a dynamic rebalancing of excitatory and inhibitory currents to maximize SNR. SIGNIFICANCE STATEMENT We present evidence that the balance of excitatory and disinhibitory inputs to a type of retinal ganglion cell maximizes the signal-to-noise ratio power ratio (SNR) of its postsynaptic currents. This is significant because chemical synapses on a retinal ganglion cell require the probabilistic release of transmitter. Consequently, when the same visual stimulus is presented repeatedly, postsynaptic currents vary in amplitude. Thus, maximizing SNR may be a strategy for producing the most reliable signal possible given the inherent unreliability of synaptic transmission.

Synaptic noise is an information bottleneck in the inner retina during dynamic visual stimulation.

At chemical synapses, vesicles fuse with the presynaptic membrane at random, generating noise in postsynaptic currents. To determine how much noise synapses generate, we recorded excitatory postsynaptic currents from ganglion cells in an in vitro preparation of the mammalian retina during flickering visual stimulation. Postsynaptic currents received noise from three sources: substantial noise from bipolar cell synapses, somewhat more from the presynaptic retinal circuitry, but little from sources intrinsic to the ganglion cell. Presynaptic circuit elements but not bipolar cell synapses were significant sources of noise shared by pairs of ganglion cells. Signal‐to‐noise ratio was substantially reduced from the presynaptic bipolar cell array to the postsynaptic ganglion cell, indicating that synaptic noise can reduce the amount of information transmitted to a neuron.