Fig. 5. The major types of amacrine cells in mammalian retina are shown. Amacrine cells comprise the most diverse class of retinal neurons. This illustrates amacrine cells that were morphologically identified in rabbit retina. Narrow-field amacrine cells are shown in the top row, and wide-field amacrine cells are shown in the lower two rows. (Reprinted from [73], with permission from Elsevier.)

PRESYNAPTIC INHIBITION

Presynaptic inhibition of bipolar cell terminals by amacrine cells exists in two general forms and contributes to the temporal and spatial properties of visual processing. Local presynaptic inhibition, also called feedback inhibition, mediated by reciprocal synapses between bipolar and amacrine cells shapes the time course [20] and extent of glutamate release [22]. Lateral inhibition, mediated by long-distance presynaptic inhibitory signaling from amacrine cells, contributes to the antagonistic receptive field surround of ganglion cells [44–46].

Asymmetric Presynaptic Inhibition

Both ON and OFF bipolar cells receive presynaptic input from amacrine cells, suggesting that signaling to ON and OFF ganglion cells is shaped by presynaptic inhibition. However, presynaptic inhibition differentially shapes ON and OFF pathway signaling in the IPL [22]. This was demonstrated by eliminating the main type of presynaptic inhibition to bipolar cells. When GABAC receptor-mediated presynaptic inhibition was eliminated, Sagdullaev and colleagues showed that ON but not OFF ganglion cell responses were greatly enhanced, suggesting that presynaptic inhibition was asymmetric (Fig. 6). Electrophysiological measurements of lightand electrically evoked excitation to ganglion cells showed that presynaptic inhibition affected the dynamic response ranges in ON ganglion cells by limiting glutamate release from ON but not OFF bipolar cells. Presynaptic inhibition of ON bipolar cells modulates the dynamic response range by limiting the extent of glutamate spillover and activation of perisynaptic NMDA receptors (Fig. 6).

Spillover transmission occurs at some synapses, including ON ganglion cells, when glutamate diffuses from the release sites and activates perisynaptic receptors. Recent evidence suggests that spillover activation of NMDA receptors occurs only at ON ganglion cells (Fig. 7) [22]. When glutamate release is increased or glutamate uptake is blocked, glutamate concentrations are increased, and spillover is enhanced. Sagdullaev and colleagues found that manipulations that increased spillover enhanced the activation of NMDA receptors in ON but not OFF ganglion cells. These findings suggest another

asymmetry is present in the IPL; NMDA receptors are located perisynaptically in ON and synaptically in OFF ganglion cell synapses (Fig. 6).

Presynaptic Inhibition Is Filtered by GABA Receptor Properties

GABAergic inhibition occurs at the terminals of all classes of bipolar cell. Pharmacological studies indicated that two types of ionotropic GABA receptors, GABAA and GABAC receptors, are present on bipolar terminals [47, 48]. Pharmacologically isolated GABAA and GABAC receptors mediate distinct inhibitory responses to applied GABA [48]. GABAA receptor-mediated responses rise and decay rapidly, while GABAC receptor-mediated responses rise and decay slowly (Fig. 7A). Do these distinct GABA receptor properties shape light-evoked inhibitory responses? We found that these distinct GABA receptors temporally filter synaptic input to bipolar cells [41]. Recordings of light-evoked inhibitory postsynaptic currents (L-IPSCs) from rod bipolar cells demonstrate that slowly responding GABAC receptors prolong the response decay (Fig. 7B). By contrast, the rapidly activating and decaying GABAA receptors (Fig. 7B) determine the rise time and peak amplitude of the response [49].

GABA application experiments indicated that diverse classes of bipolar cells have different proportions of GABAA and GABAC receptors [47, 48], suggesting that light-evoked inhibition is differentially filtered at different classes of bipolar cells. Eggers and colleagues [50] showed that the L-IPSC time course varied in different bipolar cell classes, depending on the relative contributions of GABAA and GABAC receptors. These findings suggest that GABAergic L-IPSCs are temporally filtered by distinct receptors; GABAC receptor-mediated L-IPSCs are prolonged, and GABAA receptor-mediated L-IPSCs are brief. GABAergic L-IPSCs recorded in rod bipolar cells decay slowly because they are dominated by GABAC receptors, while OFF cone bipolar cell L-IPSCs decayed rapidly, reflecting a larger GABAA receptor contribution. These observations demonstrate that different GABA receptor complements differentially tune inhibition for specific bipolar cell types. These two forms of presynaptic inhibition limit bipolar cell outputs in distinct ways. Slow GABAC receptors limit the extent of glutamate release and the duration excitatory responses in amacrine and ganglion cells. Fast GABAA receptors, by contrast, limit the initial glutamate release and the initial postsynaptic excitatory responses. Different complements of GABAA and GABAC receptors also appear to match the time course of inhibition with the time course of photoreceptor input to different bipolar cells. Rod bipolar cells receive prolonged excitatory input from rod photoreceptors and prolonged presynaptic inhibition mediated by GABAC receptors. OFF cone bipolar cells receive brisk excitatory input from cone photoreceptors and fast presynaptic inhibition mediated by GABAA receptors.

Presynaptic Inhibition May Be Shaped by Transmitter Release Differences

It is not known whether GABAA and GABAC receptors receive input from similar or distinct presynaptic amacrine cell inputs. To address this issue, Eggers and colleagues [49] used deconvolution analysis [51] to estimate the GABA release time courses associated with GABAA and GABAC receptor-mediated light-evoked currents. They found that the apparent release time courses for inputs to GABAA and GABAC receptor-containing synapses were distinct. Although this finding is consistent with

Fig. 6. Asymmetric presynaptic inhibition differentially affects ON and OFF pathway signaling. Raster plots (upper traces) and peristimulus time histograms (PSTHs; middle) illustrating spontaneous and light-evoked firing in WT (Ai) and GABACR null (Null) (Aii) ON-center ganglion cells (GCs); and WT (Bi) and Null (Bii) OFF GCs. The lower traces in (A) and (B) indicate the duration of the stimuli, a bright, centered spot for ON GCs and a dark, centered spot for OFF GCs, presented on an adapting background. Spontaneous and light-evoked firing rates were significantly increased only in ON GCs in Null mice compared to WT mice. C The asymmetric presynaptic inhibition of glutamate release from bipolar cells (BCs) and spillover activation of postsynaptic NMDA (N-methyl-D-aspartate) receptors (NMDARs)on GCs. Ci GABAergic feedback from amacrine cells (ACs) limits glutamate release from ON bipolar cells and limits spillover activation of perisynaptic (NMDARs) on ON GCs dendrites. GABACR-mediated negative feedback confines synaptic transmission and extends the dynamic response range of ON GCs. Cii When GABACR-mediated inhibition is eliminated, the modulation of the excitatory transmission is disrupted and glutamate release is enhanced. D In the OFF pathway, the activation of synaptically localized AMPARs and NMDARs on OFF GC dendrites is not limited by GABACR-mediated feedback to OFF BCs. The output gain of OFF GCs is high because their excitatory inputs are not appreciably modulated by presynaptic inhibition. For simplicity, only the inhibitory feedback component of a reciprocal synapse between a BC and an AC is shown. GABA γ-aminobutyric acid RGC retinal ganglion cell (Reprinted from [22], with permission from Elsevier.)