Synaptic inhibition tunes contrast computation in the retina

Abstract

Inhibition shapes activity and signal processing in neural networks through numerous mechanisms mediated by many different cell types. Here, we examined how one type of GABAergic interneuron in the retina, the A17 amacrine cell, influences visual information processing. Our results suggest that A17s, which make reciprocal feedback inhibitory synapses onto rod bipolar cell (RBC) synaptic terminals, extend the luminance range over which RBC synapses compute temporal contrast and enhance the reliability of contrast signals over this range. Inhibition from other amacrine cells does not influence these computational features. Although A17-mediated feedback is mediated by both GABAA and GABAC receptors, the latter plays the primary role in extending the range of contrast computation. These results identify specific functions for an inhibitory interneuron subtype, as well as specific synaptic receptors, in a behaviorally relevant neural computation.

Keywords: Amacrine cell; Feedback inhibition; Ribbon synapse; Weber contrast.

Figure 1 |. Logistic functions determine response gain

A, Theoretical intensity response functions plotted over the working range of luminance signaling in RBCs. The change in response level from ϕ₁ to ϕ₂ is shown on the y-axis for a perfectly linear-log function ( y = (m − log (ϕ)) + b; black) and for a nonlinear-log Hill function (gray). B, Plot of contrast gain over the range of ϕ₁ values predicted from the difference in response levels determined by the two curves shown in panel A.

Figure 2 |. Inhibition alters the relationship between φ₁ and RRP size

A, Top, intensity of the light stimulus over time for a family of light stimuli to measure RRP depletion. Bottom, average responses across 10 cells for control conditions (black traces) and in the presences of 0.5 µM TTX, 3 µM Strychnine, 5 µM SR95531, and 50 µM TPMPA (gray traces) to block all inhibition. Traces are presented in order of increasing ϕ₁ intensity from the top down. Dashed box denotes time window for calculating charge transfer. B, Average charge transfer of the transient peak in response to ϕ₁ (red) and ϕ₂ (blue), plotted against ϕ₁ and normalized to the ϕ₁ step to 72 r*/rod/sec, for control responses. Dashed lines are the Hill equation fits to the data. Black circles show the sum of the responses to ϕ₁ and ϕ₂ at each ϕ₁. Error bars indicate standard deviation. C, Average charge transfer of the transient peak in response to ϕ₁ (red) and ϕ₂ (blue), normalized to the ϕ₁ step to 72 r*/rod/sec, during inhibitory block. Solid lines show Hill equation fits to the data. Error bars indicate standard deviation. D, Average (solid lines) and standard error (shading), for Hill fits to each cell in control conditions (black) and during inhibitory block (gray; n=10).

Figure 3 |. Inhibition alters contrast gain across a range of φ₁

A, Top, intensity of the light stimulus over time for a family of light stimuli to measure contrast gain. Bottom, average responses across 11 cells for control conditions (black traces) and in the presences of 0.5 µM TTX, 3 µM strychnine, 5 µM SR95531, and 50 µM TPMPA (gray traces) to block all inhibition. B, Average charge transfer of the transient peak in response ϕ₂ in control (black symbols) and during inhibitory blockade (gray symbols) plotted against the ϕ₁ and normalized to the maximal response in control. Solid lines show sigmoid fits for qualitative comparisons between the two distributions. Dashed line plots the actual Weber contrast between ϕ₁ and ϕ₂ for each pair, plotted against ϕ₁ and scaled for comparison to transient EPSCs. Error bars indicate standard deviation. Asterisks indicate p values that reached significance following Bonferroni correction (i.e., α=0.01; **: p<0.01, ***: p<0.001).

Figure 4 |. Lateral inhibition does not influence ϕ₁-RRP relationship or contrast gain

A, Top, intensity of the light stimulus over time for a family of light stimuli to measure RRP depletion. Bottom, average responses across 6 cells for control conditions (black traces) and in the presence of 0.5 µM TTX and 3 µM strychnine (gray traces) to block lateral inhibition. Traces are presented in order of increasing ϕ₁ intensity from the top down. B, Average charge transfer of the transient peak in response to ϕ₂, for control responses (black symbols), and during block of lateral inhibition with 0.5 µM TTX and 3 µM strychnine (gray symbols) plotted against ϕ₁ and normalized to the ϕ₁ step to 72 r*/rod/sec in control. Error bars indicate standard deviation. Solid lines are Hill fits to the data. (n=6). C, Top, intensity of the light stimulus over time for a family of light stimuli to measure contrast gain. Bottom, average responses across 5 cells for control conditions (black traces) and in the presence of 0.5 µM TTX and 3 µM strychnine (gray traces) to block all inhibition. D, Average charge transfer of the transient peak in response to ϕ₁, for control responses (black symbols), and during block of lateral inhibition with 0.5 µM TTX and 3 µM strychnine (gray symbols) plotted against ϕ₁ and normalized to the maximal response. Error bars indicate standard deviation (n=5). Solid lines show sigmoid fits for qualitative comparisons between the two distributions.

Figure 5 |. GABA_C receptors are responsible for shaping contrast gain

A, Top, intensity of the light stimulus over time for a family of light stimuli to measure RRP depletion. Bottom, average responses across 12 cells for control conditions (0.5 µM TTX, 3 µM strychnine; black traces) and following addition of 50 µM TPMPA (gray traces) to block GABA_C receptors. B, Average charge transfer of the transient peak in response ϕ₂ in control (black symbols) and during GABA_C blockade (gray symbols), plotted against the ϕ₁ and normalized to the maximal response in control. Error bars indicate standard deviation (n=12). C, Top, intensity of the light stimulus over time for a family of light stimuli to measure contrast gain. Bottom, average responses across 12 cells for control conditions (0.5 µM TTX, 3 µM strychnine; black traces) with the addition of 50 µM TPMPA (gray traces) to block GABA_C receptors. D, Average charge transfer of the transient peak in response ϕ₂ in control (black symbols) and during GABA_C blockade (gray symbols), plotted against the ϕ₁ and normalized to the maximal response in control. Error bars indicate standard deviation (n=12). Asterisks indicate p values that reached significance following Bonferroni correction (i.e., α=0.01; **: p<0.01). Solid lines show sigmoid fits for qualitative comparisons between the two distributions.