NMDA Receptors Multiplicatively Scale Visual Signals and Enhance Directional Motion Discrimination in Retinal Ganglion Cells

Abstract

SUMMARY Postsynaptic responses in many CNS neurons are typically small and variable, often making it difficult to distinguish physiologically relevant signals from background noise. To extract salient information, neurons are thought to integrate multiple synaptic inputs and/or selectively amplify specific synaptic activation patterns. Here, we present evidence for a third strategy: directionally selective ganglion cells (DSGCs) in the mouse retina multiplicatively scale visual signals via a mechanism that requires both nonlinear NMDA receptor (NMDAR) conductances in DSGC dendrites and directionally tuned inhibition provided by the upstream retinal circuitry. Postsynaptic multiplication enables DSGCs to discriminate visual motion more accurately in noisy visual conditions without compromising directional tuning. These findings demonstrate a novel role for NMDARs in synaptic processing and provide new insights into how synaptic and network features interact to accomplish physiologically relevant neural computations.

“Silent” NMDA Synapses Enhance Motion Sensitivity in a Mature Retinal Circuit

“…However, as this increase in sensitivity was an effect of a disproportionate contrast-dependent scaling of the DSGC's spiking response amplitude (y–scaling), this operation can be considered ‘pseudo-additive’, to distinguish it from real x–scaling operations (Silver, 2010). Interestingly, even at low-contrasts (30%) where NMDA receptors strongly amplify responses, NMDA receptors scaled responses in a way that preserved DS tuning properties of the model DSGC (Figure 5G), similar to their effects observed at higher contrasts (Poleg-Polsky and Diamond, 2016a). Thus, a simple model that captures the multiplicative effects of NMDA receptors, predicts that the high-sensitivity NMDA pathway produces an additive scaling of the DSGCs output as a function of contrast.…”

“…In the matched model configuration, where synaptic inputs scale proportionately as a function of contrast, we found that NMDA-mediated inputs amplified responses in a multiplicative manner (Murphy and Miller, 2003; Poleg-Polsky and Diamond, 2016a). This is indicated by the stable fractional contribution of NMDA receptors across the entire contrast range (Figure 5A, right axis ).…”

“…First, the sensitivity of the residual synaptic responses measured in D-AP5 was similar to the non-NMDA and inhibitory inputs measured in control conditions (compare Figure 2C and 2E; Table S1). Second, the NMDA antagonist did not affect the sensitivity of the starbursts (Figure S3) (Poleg-Polsky and Diamond, 2016a). Taken together, these results suggest that multiple bipolar cells with different sensitivities drive starbursts and DSGCs in parallel, but do so using distinct complements of glutamate receptors.…”

“…Responses were driven by inhibitory and excitatory synaptic inputs that grew in contrast, similar to our experimental measurements. To simulate stimulus direction, excitation was set to be non-directional while GABA inhibition was highly directional (Poleg-Polsky and Diamond, 2016a). Interestingly, although the DSGCs spiking response was modulated by stimulus contrast and stimulus direction to a similar extent, NMDA receptors had a different effect in each context (Figures 5).…”

“…However, one potentially important difference could manifest in the way NMDA receptors scale the DSGC's contrast response function. In the matched model, NMDA receptors scale the DSGC's response in a multiplicative manner, simply because they scale togther with non-NMDA receptor-mediated inputs (Murphy and Miller, 2003; Poleg-Polsky and Diamond, 2016a, b). Multiplicative scaling increases the gain of the DSGC input-output function (increase in R max ; Figure 1C).…”