Synaptic pathways that shape the excitatory drive in an OFF retinal ganglion cell

Abstract

Different types of retinal ganglion cells represent distinct spatiotemporal filters that respond selectively to specific features in the visual input. Much about the circuitry and synaptic mechanisms that underlie such specificity remains to be determined. This study examines how N-methyl-d-aspartate (NMDA) receptor signaling combines with other excitatory and inhibitory mechanisms to shape the output of small-field OFF brisk-sustained ganglion cells (OFF-BSGCs) in the rabbit retina. We used voltage clamp to separately resolve NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and inhibitory inputs elicited by stimulation of the receptive field center. Three converging circuits were identified. First is a direct glutamatergic input, arising from OFF cone bipolar cells (CBCs), which is mediated by synaptic NMDA and AMPA receptors. The NMDA input was saturated at 10% contrast, whereas the AMPA input increased monotonically up to 60% contrast. We propose that NMDA inputs selectively enhance sensitivity to low contrasts. The OFF bipolar cells, mediating this direct excitatory input, express dendritic kainate (KA) receptors, which are resistant to the nonselective AMPA/KA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX), but are suppressed by a GluK1- and GluK3-selective antagonist, (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-thiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione (UBP-310). The second circuit entails glycinergic crossover inhibition, arising from ON-CBCs and mediated by AII amacrine cells, which modulate glutamate release from the OFF-CBC terminals. The third circuit also comprises glycinergic crossover inhibition, which is driven by the ON pathway; however, this inhibition impinges directly on the OFF-BSGCs and is mediated by an unknown glycinergic amacrine cell that expresses AMPA but not KA receptors.

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

“…The AMPA receptor-mediated component of the DSGC's synaptic response only appeared at higher stimulus contrasts. In contrast, however, a number of other studies indicate that AMPA/NMDA receptor-mediated inputs to DSGCs scale together as a function of contrast, consistent with observations in other types of ganglion cells, suggesting that AMPA and NMDA receptors are driven by a common source of glutamate (Buldyrev et al, 2012; Diamond and Copenhagen, 1995; Manookin et al, 2010; Poleg-Polsky and Diamond, 2016b; Stafford et al, 2014). These diverging results have given rise to two distinct models that explain how the DS circuit coordinates inhibition/excitation over a range of stimulus contrasts (Figure 1A & D), which underlies the DSGC's robust ability to compute direction (Grzywacz and Amthor, 2007; Nowak et al, 2011; Poleg-Polsky and Diamond, 2016b).…”

Functional Circuitry of the Retina

“…In the retina, the distinct roles of these receptor types are less clear. Some ganglion cell types use NMDA receptors for the primary depolarizing response, whereas others have minimal NMDA receptor activity under physiological conditions (i.e., light-evoked responses with intact inhibition) (Manookin et al 2010, Venkataramani & Taylor 2010, Buldyrev et al 2012, Crook et al 2014). Both receptor types can respond to rapidly modulated presynaptic glutamate release (Stafford et al 2014).…”

Photoreceptor Cells With Profound Structural Deficits Can Support Useful Vision in Mice

“…The basis for this deficit and shift in response amplitudes is not clear, but retinal pathology or reduced photon capture may cause some circuits to fall below detection threshold while the response of others is increased. 38,39 Quality and Limitations of Vision in Rds P90 Mice…”