A retinal circuit that vetoes optokinetic responses to fast visual motion

Abstract

Optokinetic nystagmus (OKN) is a visuomotor reflex that works in tandem with the vestibulo-ocular reflex (VOR) to stabilize the retinal image during self-motion. OKN requires information about both the direction and speed of retinal image motion. Both components are computed within the retina because they are already encoded in the spike trains of the specific class of retinal output neurons that drives OKN ─ the ON direction-selective ganglion cells (ON DSGCs). The synaptic circuits that shape the directional tuning of ON DSGCs, anchored by starburst amacrine cells, are largely established. By contrast, little is known about the cells and circuits that account for the slow speed preference of ON DSGCs and, thus, of OKN that they drive. A recent study in rabbit retina implicates feedforward glycinergic inhibition as the key suppressor of ON DSGC responses to fast motion. Here, we used serial-section electron microscopy, patch recording, pharmacology, and optogenetic and chemogenetic manipulations to probe this circuit in mouse retina. We confirm a central role for feedforward glycinergic inhibition onto ON DSGCs and identify a surprising primary source for this inhibition ─ the VGluT3 amacrine cell (VG3 cell). VG3 cells are retinal interneurons that release both glycine and glutamate, exciting some neurons and inhibiting others. Their role in suppressing the response of ON DSGCs to rapid global motion is surprising. VG3 cells had been thought to provide glutamatergic excitation to ON-DSGCs, not glycinergic inhibition, and because they have strong receptive fields surrounds which might have been expected to render them unresponsive to global motion. In fact, VG3 cells are robustly activated by the sorts of fast global motion that suppress ON DSGCs and weaken optokinetic responses as revealed by dendritic Ca+2 imaging, since surround suppression is less prominent when probed with moving gratings than with spots. VG3 cells excite many ganglion cell types through their release of glutatmate. We confirmed that for one such type, the ON-OFF DSGCs, VG3 cells enhance the response to fast motion in these cells, just as they suppress it in ON DSGCs. Together, our results assign a novel function to VGluT3 cells in shaping the velocity range over which retinal slip drives compensatory image stabilizing eye movements. In addition, fast speed motion signal from VGluT3 cells is used by ON-OFF DSGCs to extend the speed range over which they respond, and might be used to shape the speed tuning or temporal bandwidth of the responses of other RGCs.

Asymmetric retinal direction tuning predicts optokinetic eye movements across stimulus conditions

“…Further insight into how oDSGCs encode motion can be gained by comparing their tuning properties to those of the more comprehensively studied ooDSGCs. While prior work has focused on speed tuning as the primary difference between oDSGCs and ooDSGCs 14,26,49,57,79 , our results reveal an additional difference between these two classes of DSGCs that has been previously overlooked: oDSGCs are contrast-sensitive ( Fig 7 ), whereas ooDSGCs are not 62 . In ooDSGCs, preservation of E/I across contrasts is apparently critical for retaining contrast-invariant direction tuning 61,63 .…”

“…The asymmetric spike tuning of Superior and Inferior oDSGCs is associated with differences in the magnitude of excitatory synaptic input to each cell type (Fig 3). Three synaptic partners are primary candidates for the source of this asymmetry: (1) glutamatergic input from bipolar cells (types 5 and 7), (2) cholinergic input from SACs, and (3) glutamatergic input from VGluT3 amacrine cells [44][45][46]49,50,58,77,78 . Glutamatergic conductances in oDSGCs rely on AMPARs and NMDARs, whereas cholinergic conductances rely on nicotinic AChRs 79 .…”

“…Differences in the postsynaptic currents of Superior and Inferior oDSGCs could result from asymmetries in presynaptic wiring and/or the postsynaptic properties of each oDSGC type. Serial block-face electron microscopy 40,49,50 and analysis of dendritic stratification 21 have not yet provided evidence of presynaptic wiring differences between oDSGCs with different preferred directions. Thus, we investigated possible postsynaptic asymmetries that might account for the differences in how Superior and Inferior oDSGCs encode motion.…”

Rejection of inappropriate synaptic partners mediated by transcellular FLRT2-UNC5 signaling

“…We next investigated the consequences of removing the FLRT2-UNC5C signaling system for DS circuit synaptic specificity. Normally, starburst amacrine cells provide virtually all of the inhibitory synapses onto ooDSGC dendrites (Bleckert et al, 2018; Mani et al, 2022; Sivyer et al, 2019; Yoshida et al, 2001). However, mutant ooDSGCs send dendrites into IPL regions lacking starburst arbors (Fig.…”

“…However, it is highly unlikely that these synapses are derived from a cell type that normally connects to ooDSGCs. Aside from starburst cells, ooDSGCs can also receive synapses from several other amacrine types, but these synapses are either glutamatergic (Mani et al, 2022) or are targeted to the cell body rather than the dendritic arbor (Bleckert et al, 2018). Thus, the presence of non-starburst inhibitory inputs onto ooDSGC dendrites represents a striking loss of specificity.…”