Realistic retinal modeling unravels the differential role of excitation and inhibition to starburst amacrine cells in direction selectivity

Retinal direction-selectivity originates in starburst amacrine cells (SACs), which display a centrifugal preference, responding with greater depolarization to a stimulus expanding from soma to dendrites than to a collapsing stimulus. Various mechanisms were hypothesized to underlie SAC centrifugal preference, but dissociating them is experimentally challenging and the mechanisms remain debatable. To address this issue, we developed the Retinal Stimulation Modeling Environment (RSME), a multifaceted data-driven retinal model that encompasses detailed neuronal morphology and biophysical properties, retina-tailored connectivity scheme and visual input. Using a genetic algorithm, we demonstrated that spatiotemporally diverse excitatory inputs–sustained in the proximal and transient in the distal processes–are sufficient to generate experimentally validated centrifugal preference in a single SAC. Reversing these input kinetics did not produce any centrifugal-preferring SAC. We then explored the contribution of SAC-SAC inhibitory connections in establishing the centrifugal preference. SAC inhibitory network enhanced the centrifugal preference, but failed to generate it in its absence. Embedding a direction selective ganglion cell (DSGC) in a SAC network showed that the known SAC-DSGC asymmetric connectivity by itself produces direction selectivity. Still, this selectivity is sharpened in a centrifugal-preferring SAC network. Finally, we use RSME to demonstrate the contribution of SAC-SAC inhibitory connections in mediating direction selectivity and recapitulate recent experimental findings. Thus, using RSME, we obtained a mechanistic understanding of SACs’ centrifugal preference and its contribution to direction selectivity.

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Retinal Direction Selectivity: Role of Starburst Amacrine Cells

Encyclopedia of Neuroscience ◽

10.1007/978-3-540-29678-2_5104 ◽

2008 ◽

pp. 3501-3507

Author(s):

Susanne Hausselt ◽

Thomas Euler

Keyword(s):

Amacrine Cells ◽

Direction Selectivity ◽

Starburst Amacrine Cells

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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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Retinal Direction Selectivity: Role of Starburst Amacrine Cells

10.1007/springerreference_118652 ◽

2012 ◽

Keyword(s):

Amacrine Cells ◽

Direction Selectivity ◽

Starburst Amacrine Cells

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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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Conditional Knock-Out of Vesicular GABA Transporter Gene from Starburst Amacrine Cells Reveals the Contributions of Multiple Synaptic Mechanisms Underlying Direction Selectivity in the Retina

Journal of Neuroscience ◽

10.1523/jneurosci.0933-15.2015 ◽

2015 ◽

Vol 35 (38) ◽

pp. 13219-13232 ◽

Cited By ~ 44

Author(s):

Z. Pei ◽

Q. Chen ◽

D. Koren ◽

B. Giammarinaro ◽

H. Acaron Ledesma ◽

...

Keyword(s):

Amacrine Cells ◽

Direction Selectivity ◽

Transporter Gene ◽

Gaba Transporter ◽

Knock Out ◽

Starburst Amacrine Cells ◽

Synaptic Mechanisms

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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 after targeted laser ablation of starburst amacrine cells

Nature ◽

10.1038/38723 ◽

1997 ◽

Vol 389 (6649) ◽

pp. 378-382 ◽

Cited By ~ 96

Author(s):

Shigang He ◽

Richard H. Masland

Keyword(s):

Laser Ablation ◽

Amacrine Cells ◽

Direction Selectivity ◽

Starburst Amacrine Cells

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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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