Animals can use their eyes to detect moving objects, which helps them to avoid predators and other threats, and to spot potential prey or allies. Visual information from the eyes is sent to the brain, which processes the information to form a coherent picture of how the objects are moving. This processing has to be able to account for movements of the head, eyes, and body—which can cause the image of an object on the retina within the eye to move even if the object itself remains stationary.

Within the retina, light is converted into electrical signals by cells called rods and cones. A layer of cells called bipolar cells relay these signals to the ‘ganglion’ cells, which in turn pass them on to the brain. In mice, a type of ganglion cell called the W3 ganglion cell has been shown to respond selectively to small moving objects, but exactly how these cells acquire their motion sensitivity remained unclear.

Kim et al. now reveal that cells called amacrine cells, which regulate the transfer of signals from the bipolar cells to ganglion cells, supply the information needed for motion detection. The mouse eye contains up to 50 different types of amacrine cells. One of these—called the VG3-amacrine cell—increases its activity whenever an object moves relative to its background, but decreases its activity whenever the object and background move together. The overall effect is that the cells respond selectively to the presence of small moving objects.

Most amacrine cells regulate the transfer of signals within the retina by inhibiting the activity of ganglion cells. But, Kim et al. show that VG3-amacrine cells release a molecule called glutamate to activate W3 ganglion cells when a moving object is detected. These unusual and specialized cells are, thus, an essential component of a circuit in the nervous system that supports motion detection. It is possible that some other types of amacrine cells may also play specialized roles in the detection of other features in the visual world.

A diverse array of circuits in the retina processes signals from photoreceptors and parses information into spike trains of 20–30 types of retinal ganglion cells (RGCs), each encoding distinct aspects of the visual scene (Masland, 2012). The most abundant RGC type in the mouse retina (W3-RGC) was recently shown to respond selectively to movements of small—in terms of size on the retina—objects (Zhang et al., 2012). Detecting object motion is a challenging task as head, body, and eye movements frequently shift the retinal image (Martinez-Conde et al., 2004; Sakatani and Isa, 2007). To distinguish movements of objects and the background, object motion sensitive (OMS) RGCs respond to differences in the timing of texture movements in their receptive field center and surround (Olveczky et al., 2003; Zhang et al., 2012). W3-RGCs share key properties with OMS RGCs in rabbit and salamander, but, due to stronger surround suppression, do not respond at the border of larger objects (Zhang et al., 2012). This feature is reminiscent of local-edge-detector RGCs described in several species (Levick, 1967; Zeck et al., 2005; Roska et al., 2006). W3-RGCs, thus, appear to be in the intersection of OMS and local-edge-detector RGCs. Although postsynaptic inhibition and spike thresholds sharpen the tuning of W3-RGCs, similar to other OMS and local-edge-detector RGCs, key response properties appear to be inherited from their excitatory input (van Wyk et al., 2006; Baccus et al., 2008; Russell and Werblin, 2010; Zhang et al., 2012). This suggests that feature selectivity arises presynaptic to W3-RGCs. Where and how object motion is first detected remains to be determined.

Typically, RGCs receive excitatory input from bipolar cells (Euler et al., 2014) and inhibitory input from amacrine cells (ACs). ACs are the most diverse class of neurons in the retina, encompassing 30–50 cell types (MacNeil and Masland, 1998; Helmstaedter et al., 2013) that serve task-specific functions in vision (Dacheux and Raviola, 1986; Yoshida et al., 2001; Euler et al., 2002; Munch et al., 2009; Grimes et al., 2010; Chen and Li, 2012). Although most ACs release γ-Aminobutyric acid (GABA) or glycine, a wide range of neurotransmitters and neuromodulators can be found in different cell types including one expressing the vesicular glutamate transporter 3 (VGluT3) (gene: Slc17a8, protein: VGluT3, AC: VG3) (Fyk-Kolodziej et al., 2004; Haverkamp and Wassle, 2004; Johnson et al., 2004). VG3-ACs are conserved from rodents to primates. Recent studies found that VG3-ACs respond to light increments (ON) and decrements (OFF) (Grimes et al., 2011), show strong surround suppression, and following optogenetic or electrical stimulation can release glutamate (Lee et al., 2014). However, what specific features of the visual world VG3-ACs detect and how, as well as their interactions with RGCs during sensory processing remain unknown.

Here, we generate and obtain transgenic mouse lines to genetically label VG3-ACs and target them under 2-photon guidance for whole-cell patch-clamp recordings in retinal flat mount preparations. We find that VG3-ACs, like W3-RGCs, combine properties of OMS and local-edge-detector neurons and selectively detect movements of small objects. Using biolistics, we show that many excitatory synapses on W3-RGCs are apposed by boutons of VG3-ACs, and in whole-cell recordings from W3-RGCs, find that properties of their excitatory input match VG3-AC responses. Finally, we show amplitude and object motion preference of synaptic excitation and spike responses of W3-RGCs are reduced in VGluT3 knockout mice (VGluT3^−/− mice) (Seal et al., 2008). Thus, we identify VG3-ACs as object motion detectors, characterize the synaptic mechanisms underlying this computation, and show that VG3-ACs provide feature-selective excitatory input to W3-RGCs.

To analyze the morphology of VG3-ACs, we generated bacterial artificial chromosome (BAC) transgenic mice expressing a ligand-activated Cre recombinase under control of regulatory sequences of the Slc17a8 gene (VG3-CreERT2 mice) and crossed them to a fluorescent reporter strain (Ai9) (Madisen et al., 2010). After tamoxifen injection, a subset of VG3-ACs expresses tdTomato in VG3-CreERT2 Ai9 mice (Figure 1—figure supplement 1). Neurites of VG3-ACs stratify broadly in the center of the inner plexiform layer (Grimes et al., 2011), occupy medium-sized lateral territories (Figure 1A and Figure 1—figure supplement 2, 7662 ± 211 μm², n = 39), and as a population, cover the retina approximately seven times (coverage: 6.88). To characterize light responses, we obtained VG3-Cre mice (Grimes et al., 2011) in which all VG3-ACs express Cre (Figure 1—figure supplement 1), crossed them to Ai9, and targeted fluorescent somata in the inner nuclear layer (INL) for whole-cell patch-clamp recordings. Consistent with previous results, we find that VG3-ACs respond transiently to light increments and decrements, depolarizing to small and hyperpolarizing to large stimuli (Lee et al., 2014) (Figure 1B,C). Voltage-clamp recordings revealed that this switch in response polarity is caused by a combination of pre- and post-synaptic surround inhibition (Figure 1D–F). Excitatory and voltage-response receptive fields are well fit by Difference-of-Gaussians models (Enroth-Cugell and Robson, 1966; McMahon et al., 2004), whereas a single Gaussian is sufficient to describe the monotonic rise of inhibition with stimulus size. For all components, OFF responses exceed ON responses, and for voltage responses and excitatory inputs, ON receptive fields are larger in diameter than their OFF counterparts. We characterized the temporal tuning of VG3-AC responses and underlying synaptic inputs in more detail using white noise stimuli (Figure 1—figure supplement 3).

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The arbor size of VG3-AC neurites suggests that they receive input from >50 bipolar cells, which each sample a smaller region of visual space (Wassle et al., 2009; Morgan and Kerschensteiner, 2011). Third order neurons that receive convergent rectified input from bipolar cells can detect motion and other changes in patterns with structure on the scale of bipolar cells' receptive fields even when the average luminance across their own receptive fields does not change (i.e., nonlinear spatial integration) (Victor and Shapley, 1979; Demb et al., 2001; Schwartz et al., 2012). To evaluate input rectification of VG3-ACs, we presented sinusoidally modulated split-field stimuli in which the receptive field center was divided evenly or in a biased manner (Figure 1G). We then compared the power of excitatory postsynaptic current (EPSC) responses at once (F1) and twice (F2) the frequency of modulation (2 Hz, Figure 1H,I). Excitatory input to biased split-field stimuli is modulated primarily at the stimulus frequency and recapitulates the OFF-preference of VG3-ACs. The F2-dominant responses to even split-field stimulation indicate that this excitatory input is provided by rectified bipolar cells (Grimes et al., 2014). To test whether inhibition, like excitation, is driven by rectified receptive field subunits and to measure their spatial extent, we sinusoidally modulated square-wave gratings with different bar widths in an annular region overlaying the receptive field surround (Figure 1J). Inhibitory postsynaptic currents (IPSCs) show frequency-doubled (F2) responses characteristic of rectified input (Figure 1K,L). F2 power increases in a step-like fashion between bar widths of 25 μm and 50 μm, suggesting that bipolar cells are likely the cellular substrate for nonlinear subunits (Victor and Shapley, 1979; Demb et al., 2001; Schwartz et al., 2012). Thus, VG3-ACs receive rectified excitatory input from transient ON and OFF bipolar cells, and inhibition from ACs, which themselves appear to be driven by rectified input from possibly the same types of bipolar cells.

The receptive field mechanisms described so far—convergence of transient ON and OFF inputs, strong surround inhibition, and rectified receptive field subunits—led us to hypothesize that VG3-ACs may selectively detect the movements of small objects. To test this hypothesis, we evaluated voltage responses and synaptic inputs of VG3-ACs in differential motion (Baccus et al., 2008; Zhang et al., 2012) and edge detection stimulus paradigms (Levick, 1967; van Wyk et al., 2006). When square-wave gratings overlaying center and surround regions of their receptive field were shifted separately or together (Figure 2A) (Baccus et al., 2008; Zhang et al., 2012), VG3-ACs depolarized robustly to differential motion in the center, but hyperpolarized to synchronous movements in center and surround (i.e., global motion) and differential motion in the surround (Figure 2B,C). Voltage-clamp recordings revealed that this response pattern is caused by preferential excitation during center-only motion and strong inhibition elicited whenever motion includes the surround (Figure 2B,E,D). Since the average luminance in center and surround regions does not change in this stimulus, the observed responses provide further evidence that both are composed of rectified subunits, allowing VG3-ACs to detect when an object moves at a different time than the background irrespective of the precise spatial patterns involved, a defining feature of OMS neurons (Olveczky et al., 2003; Baccus et al., 2008).

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Next, we tested the ability of VG3-ACs to detect contrast edges. Narrow dark bars moving across the receptive fields of VG3-ACs elicited transient depolarizations as leading and trailing edges cross the receptive field center. Robust edge responses were observed over a wide range of motion speeds (Figure 2G,H) and were indistinguishable for leading and trailing edges in spite of the opposite polarity of the associated temporal contrast. Responses of VG3-ACs are not directionally selective (Figure 2—figure supplement 1). Similar to voltage recordings, transient EPSCs and IPSCs were observed during edge transits (Figure 2I). EPSCs and IPSCs were larger at leading than trailing edges and showed a preference for the faster speeds tested (Figure 2J). However, the ratio of excitation and inhibition remained relatively constant across these conditions, which likely accounts for the greater constancy of edge responses observed in voltage recordings. Local edge detectors are typically stimulated robustly by narrow contrast edges, but not by expansive ones (Levick, 1967; Roska and Werblin, 2001; Zeck et al., 2005; van Wyk et al., 2006). We, therefore, recorded responses of VG3-ACs to bars of varying heights moving across their receptive field at a constant speed (Figure 2K). Edge responses were strongly suppressed for bar heights above 200 μm (Figure 2L,M). Trailing edge responses to the smallest bars were lower than leading edge responses, likely a consequence of the asymmetric size of VG3-ACs' ON and OFF receptive field centers (Figure 1). Similar to voltage responses, excitatory synaptic inputs showed edge response suppression for larger stimuli, whereas inhibition rose and plateaued with increasing bar height (Figure 2N,O), corroborating that surround inhibition acts both pre- and post-synaptic in VG3-ACs. VG3-ACs, thus, show key response features of OMS and local-edge-detector neurons, and through the synaptic mechanisms outlined above, selectively detect movements of small objects.

The data presented so far suggest that pre- and post-synaptic surround inhibition cancel responses of VG3-ACs to global scene shifts and movements of large objects. Surround suppression of the excitatory input to W3-RGCs was found to rely on spiking ACs (Zhang et al., 2012). To test whether surround suppression of VG3-ACs is similarly mediated by spiking ACs and to assess its importance to feature detection, we tested the effect of the sodium channel blocker TTX on VG3-ACs' responses in differential motion and edge detection stimulus paradigms. In the presence of TTX, VG3-ACs depolarized to global motion as well as differential center motion, and hyperpolarizations observed during surround stimulation were abolished (Figure 3A,B). Edge responses elicited by narrow bars moving across the receptive fields of VG3-ACs at a variety of speeds were not changed by TTX (Figure 3C,D), but the suppression observed for larger bars was blocked (Figure 3E,F). Surround inhibition, thus, is critical for the feature detection of VG3-ACs and appears to be mediated by spiking ACs. The use of spikes to signal surround motion likely improves temporal coincidence of inhibitory input with bipolar cell depolarization and excitatory input to VG3-ACs during coherent motion, leading to more effective cancellation of center signals by the surround.

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We next wondered how signals of VG3-ACs are used in the retina. Recent optogenetic experiments and paired recordings suggest that VG3-ACs can release glutamate and activate postsynaptic receptors on several RGC types, including W3-RGCs (Lee et al., 2014). Whether and how VG3-ACs contribute to visual processing in these RGCs remains unknown. Given our results on object-motion detection, we focus here on VG3-ACs' connections with and influence on W3-RGCs. To obtain anatomical evidence for or against excitatory synapses between VG3-ACs and W3-RGCs, we biolistically labeled W3-RGCs with cytosolic cerulean fluorescent protein and PSD95 fused to yellow fluorescent protein (PSD95-YFP) in VG3-Cre Ai9 mice (Figure 4A,B). PSD95-YFP selectively localizes to excitatory synapses on RGC dendrites (Morgan et al., 2008; Kerschensteiner et al., 2009). More than half of the PSD95-YFP puncta on W3-RGCs were apposed by VG3-ACs boutons, whereas few appositions with VG3-ACs were observed when PSD95-YFP puncta were randomly repositioned along the dendrites in Monte Carlo simulations (Figure 4C,D). We next characterized spike responses and synaptic inputs of W3-RGCs with the same differential motion and edge detection stimuli used for VG3-ACs, revealing matching tuning properties of excitatory input to W3-RGCs with responses of VG3-ACs (Figure 4—figure supplement 1).

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To test whether VG3-ACs provide excitatory input to W3-RGCs during visual stimulation, to compare the tuning of VG3- and non-VG3 inputs, and assess VG3-ACs' contribution to object motion signals sent to the brain, we recorded W3-RGCs in mice lacking VGluT3 (VGluT3^−/− mice) (Seal et al., 2008). Removal of VGluT3, which in the retina is only expressed by VG3-ACs, affected neither gross morphological development of the retina (Figure 4—figure supplement 2) nor dendritic patterns of W3-RGCs (Figure 4—figure supplement 3). EPSCs elicited by differential center motion were reduced by approximately 50% in W3-RGCs of VGluT3^−/− compared to wild-type (WT) mice (Figure 4E,F). By contrast, excitation during global motion and tonic excitation revealed by differential surround stimulation were unchanged. A similar pattern was observed in the spike responses of W3-RGCs, which were selectively decreased for differential center but not global motion stimuli (Figure 4G,H). Similarly, EPSCs and spike responses evoked by edges of narrow moving bars (height: 100 μm) were suppressed across a wide range of speeds in VGluT3^−/− mice (Figure 4I–L and data not shown), whereas excitation and spike responses elicited by broader moving bars remained intact in VGluT3^−/− mice (Figure 4I–L). In agreement with anatomical results (Figure 4B,C), VG3-ACs, thus, appear to provide approximately half of the excitatory input to W3-RGCs. Importantly, feature selectivity of this VG3-input is more sharply tuned than the excitatory input remaining in VGluT3^−/− mice—likely provided by ON and OFF bipolar cells—and is required for normal spike responses of W3-RGCs.

In the OMS circuit (Figure 4—figure supplement 4), VG3-ACs serve to amplify and sharpen the tuning of responses to object motion. Multi-tiered inhibition combined with delayed excitation, and successive threshold nonlinearities likely contribute to sharpening. Surround inhibition acts at three levels: bipolar axon terminals, VG3-ACs, and W3-RGCs (Zhang et al., 2012; Lee et al., 2014). Key features—transient ON and OFF input driven by rectified subunits—are similar at all three stages, arguing that inhibition is provided by a single AC type or a shared set of AC types, which remain to be identified. The added level of inhibition onto VG3-ACs compared to conventional pathways through bipolar cells likely contributes to the more complete surround suppression in the OMS circuit. Moreover, channeling of excitation through VG3-ACs introduces a delay not shared by the inhibitory input, which could improve cancellation of center signals by the surround, for example, during global image motion. The sequential arrangement of three thresholding nonlinearities—glutamate release from bipolar cells, glutamate release from VG3-ACs, and spike generation in W3-RGCs—likely further contributes to the increasing selectivity for narrow vs broad edges and differential center vs global texture motion at successive stages of the OMS circuit. Finally, our results support the notion that the diversity of AC types and circuit motifs in which they participate are integral to the diversity of features encoded in the signals the retinal sends to the brain (Masland, 2012; Jadzinsky and Baccus, 2013).

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Author details

1. Tahnbee Kim

   1. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, United States
   2. Graduate Program in Neuroscience, Washington University School of Medicine, Saint Louis, United States

   Contribution

   TK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Florentina Soto

   Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, United States

   Contribution

   FS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Daniel Kerschensteiner

   1. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, United States
   2. Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, United States
   3. Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, United States

   Contribution

   DK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   dkerschensteiner@wustl.edu

   Competing interests

   The authors declare that no competing interests exist.

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