Preserving inhibition with a disinhibitory microcircuit in the retina

Previously, we found that in the mammalian retina, inhibitory inputs onto starburst amacrine cells (SACs) are required for robust direction selectivity of On-Off direction-selective ganglion cells (On-Off DSGCs) against noisy backgrounds (Chen et al., 2016). However, the source of the inhibitory inputs to SACs and how this inhibition confers noise resilience of DSGCs are unknown. Here, we show that when visual noise is present in the background, the motion-evoked inhibition to an On-Off DSGC is preserved by a disinhibitory motif consisting of a serially connected network of neighboring SACs presynaptic to the DSGC. This preservation of inhibition by a disinhibitory motif arises from the interaction between visually evoked network dynamics and short-term synaptic plasticity at the SAC-DSGC synapse. Although the disinhibitory microcircuit is well studied for its disinhibitory function in brain circuits, our results highlight the algorithmic flexibility of this motif beyond disinhibition due to the mutual influence between network and synaptic plasticity mechanisms.

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Stimulus-dependent recruitment of lateral inhibition underlies retinal direction selectivity

eLife ◽

10.7554/elife.21053 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 28

Author(s):

Qiang Chen ◽

Zhe Pei ◽

David Koren ◽

Wei Wei

Keyword(s):

Lateral Inhibition ◽

Gaba Receptors ◽

Ganglion Cells ◽

Amacrine Cells ◽

Gaba Release ◽

Direction Selectivity ◽

Optimal Direction ◽

Inhibitory Mechanisms ◽

Mammalian Retina ◽

Starburst Amacrine Cells

The dendrites of starburst amacrine cells (SACs) in the mammalian retina are preferentially activated by motion in the centrifugal direction, a property that is important for generating direction selectivity in direction selective ganglion cells (DSGCs). A candidate mechanism underlying the centrifugal direction selectivity of SAC dendrites is synaptic inhibition onto SACs. Here we disrupted this inhibition by perturbing distinct sets of GABAergic inputs onto SACs – removing either GABA release or GABA receptors from SACs. We found that lateral inhibition onto Off SACs from non-SAC amacrine cells is required for optimal direction selectivity of the Off pathway. In contrast, lateral inhibition onto On SACs is not necessary for direction selectivity of the On pathway when the moving object is on a homogenous background, but is required when the background is noisy. These results demonstrate that distinct sets of inhibitory mechanisms are recruited to generate direction selectivity under different visual conditions.

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GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1803490115 ◽

2018 ◽

Vol 115 (51) ◽

pp. E12083-E12090 ◽

Cited By ~ 5

Author(s):

Adam Bleckert ◽

Chi Zhang ◽

Maxwell H. Turner ◽

David Koren ◽

David M. Berson ◽

...

Keyword(s):

Ganglion Cells ◽

Selective Reduction ◽

Amacrine Cells ◽

Gaba Release ◽

Direction Selectivity ◽

Inhibitory Synapses ◽

Retinal Ganglion ◽

Gabaergic Transmission ◽

Starburst Amacrine Cells ◽

Receptor Clusters

Synaptic inhibition controls a neuron’s output via functionally distinct inputs at two subcellular compartments, the cell body and the dendrites. It is unclear whether the assembly of these distinct inhibitory inputs can be regulated independently by neurotransmission. In the mammalian retina, γ-aminobutyric acid (GABA) release from starburst amacrine cells (SACs) onto the dendrites of on–off direction-selective ganglion cells (ooDSGCs) is essential for directionally selective responses. We found that ooDSGCs also receive GABAergic input on their somata from other amacrine cells (ACs), including ACs containing the vasoactive intestinal peptide (VIP). When net GABAergic transmission is reduced, somatic, but not dendritic, GABAA receptor clusters on the ooDSGC increased in number and size. Correlative fluorescence imaging and serial electron microscopy revealed that these enlarged somatic receptor clusters are localized to synapses. By contrast, selectively blocking vesicular GABA release from either SACs or VIP ACs did not alter dendritic or somatic receptor distributions on the ooDSGCs, showing that neither SAC nor VIP AC GABA release alone is required for the development of inhibitory synapses in ooDSGCs. Furthermore, a reduction in net GABAergic transmission, but not a selective reduction from SACs, increased excitatory drive onto ooDSGCs. This increased excitation may drive a homeostatic increase in ooDSGC somatic GABAA receptors. Differential regulation of GABAA receptors on the ooDSGC’s soma and dendrites could facilitate homeostatic control of the ooDSGC’s output while enabling the assembly of the GABAergic connectivity underlying direction selectivity to be indifferent to altered transmission.

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Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact

eLife ◽

10.7554/elife.34241 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 13

Author(s):

Thomas A Ray ◽

Suva Roy ◽

Christopher Kozlowski ◽

Jingjing Wang ◽

Jon Cafaro ◽

...

Keyword(s):

Synapse Formation ◽

Ganglion Cells ◽

Plexiform Layer ◽

Surface Protein ◽

Amacrine Cells ◽

Direction Selectivity ◽

Mouse Retina ◽

Inner Plexiform Layer ◽

Starburst Amacrine Cells ◽

Developing Neurons

A common strategy by which developing neurons locate their synaptic partners is through projections to circuit-specific neuropil sublayers. Once established, sublayers serve as a substrate for selective synapse formation, but how sublayers arise during neurodevelopment remains unknown. Here, we identify the earliest events that initiate formation of the direction-selective circuit in the inner plexiform layer of mouse retina. We demonstrate that radially migrating newborn starburst amacrine cells establish homotypic contacts on arrival at the inner retina. These contacts, mediated by the cell-surface protein MEGF10, trigger neuropil innervation resulting in generation of two sublayers comprising starburst-cell dendrites. This dendritic scaffold then recruits projections from circuit partners. Abolishing MEGF10-mediated contacts profoundly delays and ultimately disrupts sublayer formation, leading to broader direction tuning and weaker direction-selectivity in retinal ganglion cells. Our findings reveal a mechanism by which differentiating neurons transition from migratory to mature morphology, and highlight this mechanism’s importance in forming circuit-specific sublayers.

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Antagonistic center-surround mechanisms for direction selectivity in the retina

10.1101/831453 ◽

2019 ◽

Author(s):

Lea Ankri ◽

Elishai Ezra-Tsur ◽

Shir R. Maimon ◽

Nathali Kaushansky ◽

Michal Rivlin-Etzion

Keyword(s):

Receptive Field ◽

Sensory Processing ◽

Ganglion Cells ◽

Amacrine Cells ◽

Direction Selectivity ◽

Repetitive Stimulation ◽

Spatiotemporal Model ◽

Starburst Amacrine Cells ◽

Modeling Data

SummaryA key feature in sensory processing is center-surround receptive field antagonism. Retinal direction-selectivity (DS) relies on asymmetric inhibition from starburst amacrine cells (SAC) to direction selective ganglion cells (DSGC). SAC exhibit antagonistic center-surround, depolarizing to light increments and decrements in their center and surround, respectively, but the role of this property in DS remains elusive. We found that a repetitive stimulation exhausts SAC center and enhances its surround and used it to distinguish center-from surround-mediated responses. Center, but not surround stimulation, induced direction-selective responses in SAC, as predicted by an elementary spatiotemporal model. Nevertheless, both SAC center and surround elicited direction-selective responses in DSGCs, but to opposite directions. Physiological and morphology-based modeling data show that the opposed responses resulted from inverted DSGC’s excitatory-inhibitory temporal balance, indicating that SAC response time rules DS. Our findings reveal antagonistic center-surround mechanisms for DS, and demonstrate how context-dependent center-surround reorganization enables flexible computations.

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Receptive field properties of bipolar cell axon terminals in direction-selective sublaminas of the mouse retina

Journal of Neurophysiology ◽

10.1152/jn.00283.2014 ◽

2014 ◽

Vol 112 (8) ◽

pp. 1950-1962 ◽

Cited By ~ 29

Author(s):

Minggang Chen ◽

Seunghoon Lee ◽

Silvia J. H. Park ◽

Loren L. Looger ◽

Z. Jimmy Zhou

Keyword(s):

Receptive Field ◽

Ganglion Cells ◽

Amacrine Cells ◽

Direction Selectivity ◽

Bipolar Cells ◽

Visual Signals ◽

Mouse Retina ◽

Patch Clamp Recording ◽

Axon Terminals ◽

Starburst Amacrine Cells

Retinal bipolar cells (BCs) transmit visual signals in parallel channels from the outer to the inner retina, where they provide glutamatergic inputs to specific networks of amacrine and ganglion cells. Intricate network computation at BC axon terminals has been proposed as a mechanism for complex network computation, such as direction selectivity, but direct knowledge of the receptive field property and the synaptic connectivity of the axon terminals of various BC types is required in order to understand the role of axonal computation by BCs. The present study tested the essential assumptions of the presynaptic model of direction selectivity at axon terminals of three functionally distinct BC types that ramify in the direction-selective strata of the mouse retina. Results from two-photon Ca2+ imaging, optogenetic stimulation, and dual patch-clamp recording demonstrated that 1) CB5 cells do not receive fast GABAergic synaptic feedback from starburst amacrine cells (SACs); 2) light-evoked and spontaneous Ca2+ responses are well coordinated among various local regions of CB5 axon terminals; 3) CB5 axon terminals are not directionally selective; 4) CB5 cells consist of two novel functional subtypes with distinct receptive field structures; 5) CB7 cells provide direct excitatory synaptic inputs to, but receive no direct GABAergic synaptic feedback from, SACs; and 6) CB7 axon terminals are not directionally selective, either. These findings help to simplify models of direction selectivity by ruling out complex computation at BC terminals. They also show that CB5 comprises two functional subclasses of BCs.

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Retinal direction selectivity in the absence of asymmetric starburst amacrine cell responses

eLife ◽

10.7554/elife.42392 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 9

Author(s):

Laura Hanson ◽

Santhosh Sethuramanujam ◽

Geoff deRosenroll ◽

Varsha Jain ◽

Gautam B Awatramani

Keyword(s):

Ganglion Cells ◽

Amacrine Cells ◽

Direction Selectivity ◽

Cell Responses ◽

Receptor Knockout Mouse ◽

Starburst Amacrine Cells ◽

Gabaergic Synapses ◽

Novel Strategy ◽

Starburst Amacrine Cell ◽

Differential Connectivity

In the mammalian retina, direction-selectivity is thought to originate in the dendrites of GABAergic/cholinergic starburst amacrine cells, where it is first observed. However, here we demonstrate that direction selectivity in downstream ganglion cells remains remarkably unaffected when starburst dendrites are rendered non-directional, using a novel strategy combining a conditional GABAA α2 receptor knockout mouse with optogenetics. We show that temporal asymmetries between excitation/inhibition, arising from the differential connectivity patterns of starburst cholinergic and GABAergic synapses to ganglion cells, form the basis for a parallel mechanism generating direction selectivity. We further demonstrate that these distinct mechanisms work in a coordinated way to refine direction selectivity as the stimulus crosses the ganglion cell’s receptive field. Thus, precise spatiotemporal patterns of inhibition and excitation that determine directional responses in ganglion cells are shaped by two ‘core’ mechanisms, both arising from distinct specializations of the starburst network.

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The role of starburst amacrine cells in visual signal processing

Visual Neuroscience ◽

10.1017/s0952523811000393 ◽

2012 ◽

Vol 29 (1) ◽

pp. 73-81 ◽

Cited By ~ 46

Author(s):

W.R. TAYLOR ◽

R.G. SMITH

Keyword(s):

Ganglion Cells ◽

Cholinergic Neurons ◽

Amacrine Cells ◽

Gaba Release ◽

Reciprocal Inhibition ◽

Visual Signal ◽

Cholinergic Transmission ◽

Mammalian Retina ◽

Starburst Amacrine Cells

AbstractStarburst amacrine cells (SBACs) within the adult mammalian retina provide the critical inhibition that underlies the receptive field properties of direction-selective ganglion cells (DSGCs). The SBACs generate direction-selective output of GABA that differentially inhibits the DSGCs. We review the biophysical mechanisms that produce directional GABA release from SBACs and test a network model that predicts the effects of reciprocal inhibition between adjacent SBACs. The results of the model simulations suggest that reciprocal inhibitory connections between closely spaced SBACs should be spatially selective, while connections between more widely spaced cells could be indiscriminate. SBACs were initially identified as cholinergic neurons and were subsequently shown to contain release both acetylcholine and GABA. While the role of the GABAergic transmission is well established, the role of the cholinergic transmission remains unclear.

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The functional organization of excitation and inhibition in the dendritic arbors of retinal direction-selective ganglion cells

10.1101/718783 ◽

2019 ◽

Author(s):

Varsha Jain ◽

Benjamin L. Murphy-Baum ◽

Geoff deRosenroll ◽

Santhosh Sethuramanujam ◽

Mike Delsey ◽

...

Keyword(s):

Functional Organization ◽

Ganglion Cells ◽

Dendritic Tree ◽

Amacrine Cells ◽

Direction Selectivity ◽

Inhibitory Input ◽

Processing Scheme ◽

Fine Grained ◽

Cell Ablation ◽

Starburst Amacrine Cells

SUMMARYRecent studies indicate that the precise timing and location of excitation and inhibition (E/I) within active dendritic trees can significantly impact neuronal function. How excitatory and inhibitory inputs are functionally organized at the subcellular level in intact circuits remains unclear. To address this issue, we took advantage of the retinal direction-selective ganglion cell circuit, in which directionally tuned inhibitory GABAergic input arising from starburst amacrine cells shape direction-selective dendritic responses. We combined two-photon Ca2+ imaging with genetic, pharmacological, and single-cell ablation methods to examine local E/I. We demonstrate that when active dendritic conductances are blocked, direction selectivity emerges semi-independently within unusually small dendritic segments (<10 µm). Impressively, the direction encoded by each segment is relatively homogenous throughout the ganglion cell’s dendritic tree. Together the results demonstrate a precise subcellular functional organization of excitatory and inhibitory input, which suggests that the parallel processing scheme proposed for direction encoding could be more fine-grained than previously envisioned.

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Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact

10.1101/235978 ◽

2017 ◽

Author(s):

Thomas A. Ray ◽

Suva Roy ◽

Christopher Kozlowski ◽

Jingjing Wang ◽

Jon Cafaro ◽

...

Keyword(s):

Synapse Formation ◽

Ganglion Cells ◽

Plexiform Layer ◽

Surface Protein ◽

Amacrine Cells ◽

Direction Selectivity ◽

Mouse Retina ◽

Inner Plexiform Layer ◽

Starburst Amacrine Cells ◽

Developing Neurons

Impact statementSelective synapse formation in a retinal motion-sensitive circuit is orchestrated by starburst amacrine cells, which use homotypic interactions to initiate formation of a dendritic scaffold that recruits projections from circuit partners.SUMMARYA common strategy by which developing neurons locate their synaptic partners is through projections to circuit-specific neuropil sublayers. Once established, sublayers serve as a substrate for selective synapse formation, but how sublayers arise during neurodevelopment remains unknown. Here we identify the earliest events that initiate formation of the direction-selective circuit in the inner plexiform layer of mouse retina. We demonstrate that radially-migrating newborn starburst amacrine cells establish homotypic contacts on arrival at the inner retina. These contacts, mediated by the cell-surface protein MEGF10, trigger neuropil innervation resulting in generation of two sublayers comprising starburst-cell dendrites. This dendritic scaffold then recruits projections from circuit partners. Abolishing MEGF10-mediated contacts profoundly delays and ultimately disrupts sublayer formation, leading to broader direction tuning and weaker direction-selectivity in retinal ganglion cells. Our findings reveal a mechanism by which differentiating neurons transition from migratory to mature morphology, and highlight this mechanism’s importance in forming circuit-specific sublayers.

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Retinal direction selectivity in the absence of asymmetric starburst amacrine cell responses

10.1101/428532 ◽

2018 ◽

Author(s):

Laura Hanson ◽

Santhosh Sethuramanujam ◽

Geoff deRosenroll ◽

Gautam B. Awatramani

Keyword(s):

Ganglion Cells ◽

Amacrine Cells ◽

Direction Selectivity ◽

Cell Responses ◽

Receptor Knockout Mouse ◽

Starburst Amacrine Cells ◽

Gabaergic Synapses ◽

Novel Strategy ◽

Starburst Amacrine Cell ◽

Differential Connectivity

SummaryIn the mammalian retina, asymmetric inhibitory signals arising from the direction-selective dendrites of GABAergic/cholinergic starburst amacrine cells are thought to be crucial for originating direction selectivity. Contrary to this notion, however, we found that direction selectivity in downstream ganglion cells remains remarkably unaffected when starburst output is rendered non-directional (using a novel strategy combining a conditional GABAA α2 receptor knockout mouse with optogenetics). We show that temporal asymmetries between excitation/inhibition, arising from the differential connectivity patterns of starburst cholinergic and GABAergic synapses to ganglion cells, form the basis for a parallel mechanism generating direction selectivity. We further demonstrate that these distinct mechanisms work in a coordinated way to refine direction selectivity as the stimulus crosses the ganglion cell’s receptive field. Thus, precise spatiotemporal patterns of inhibition and excitation that shape directional responses in ganglion cells are shaped by two ‘core’ mechanisms, both arising from distinct specializations of the starburst network.

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