The role of starburst amacrine cells in visual signal processing

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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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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A role for 5HT3 receptors in visual processing in the mammalian retina

Visual Neuroscience ◽

10.1017/s0952523800004727 ◽

1993 ◽

Vol 10 (3) ◽

pp. 511-522 ◽

Cited By ~ 12

Author(s):

William J. Brunken ◽

Xiao-Tao Jin

Keyword(s):

Visual Processing ◽

Ganglion Cells ◽

Cell Activity ◽

Phosphatidyl Inositol ◽

Amacrine Cells ◽

Bipolar Cells ◽

Reciprocal Effect ◽

Mammalian Retina ◽

Messenger System

AbstractWe investigated the role of 5HT3 receptors in the mammalian retina using electrophysiological techniques to monitor ganglion cell activity. Activation of 5HT3 receptors with the selective agonist 1-phenylbiguanide (PBG) increased the ON responses of ON-center ganglion cells, while decreasing the OFF responses of OFF-center cells. The application of a selective 5HT3 antagonist had a reciprocal effect, namely it reduced the center response in ON-center cells and concomitantly increased the center responses in OFF-center cells. Since putative serotoninergic amacrine cells in the retina are connected specifically to the rod bipolar cell, these agents most likely affect the rod bipolar terminal. These data, together with previous studies, suggest that both 5HT2 and 5HT3 receptors mediate an excitatory influence which serves to facilitate the output from rod bipolar cells, the former via a phosphatidyl inositol second-messenger system, and the latter via a direction channel.

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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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Pharmacology of Directionally Selective Ganglion Cells in the Rabbit Retina

Journal of Neurophysiology ◽

10.1152/jn.1997.77.2.675 ◽

1997 ◽

Vol 77 (2) ◽

pp. 675-689 ◽

Cited By ~ 122

Author(s):

Christopher A. Kittila ◽

Stephen C. Massey

Keyword(s):

Ganglion Cells ◽

Amacrine Cells ◽

Gaba Release ◽

Excitatory Input ◽

Directional Selectivity ◽

Dependent Manner ◽

Rabbit Retina ◽

Response Curves ◽

Wide Range ◽

Starburst Amacrine Cells

Kittila, Christopher A. and Stephen C. Massey. Pharmacology of directionally selective ganglion cells in the rabbit retina. J. Neurophysiol. 77: 675–689, 1997. In this report we describe extracellular recordings made from on and on-off directionally selective (DS) ganglion cells in the rabbit retina during perfusion with agonists and antagonists to acetylcholine (ACh), glutamate, and γ-aminobutyric acid (GABA). Nicotinic ACh agonists strongly excited DS ganglion cell in a dose-dependent manner. Dose-response curves showed a wide range of potencies, with (±)-exo-2-(6-chloro-3pyridinyl)-7-azabicyclo[2.2.1] heptane dihydrochloride (epibatidine) ≫ nicotine > 1,1-dimethyl-4-phenylpiperazinium iodide = carbachol. In addition, the mixed cholinergic agonist carbachol produced a small excitation, mediated by muscarinic receptors, that could be blocked by atropine. The specific nicotinic antagonists hexamethonium bromide (100 μM), dihydro-β-erythroidine (50 μM), mecamylamine (50 μM), and tubocurarine (50 μM) blocked the responses to nicotinic agonists. In addition, nicotinic antagonists reduced the light-driven input to DS ganglion cells by ∼50%. However, attenuated responses were still DS. We deduce that cholinergic input is not required for directional selectivity. These experiments reveal the importance of bipolar cell input mediated by glutamate. N-methyl-d-aspartic acid (NMDA) excited DS ganglion cells, but NMDA antagonists did not abolish directional selectivity. However, a combined cholinergic and NMDA blockade reduced the responses of DS ganglion cells by >90%. This indicates that most of the noncholinergic excitatory input appears to be mediated by NMDA receptors, with a small residual made upb y α - a m i n o - 3 - h y d r o x y - 5 - m e t h y l - 4 - i s o x a z o l e p r o p i o n i c a c i d(AMPA)/kainate (KA) receptors. Responses to AMPA and KA were highly variable and often evoked a mixture of excitation and inhibition due to the release of ACh and GABA. Under cholinergic blockade AMPA/KA elicited a strong GABA-mediated inhibition in DS ganglion cells. AMPA/KA antagonists, such as 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline dione and GYKI-53655, promoted null responses and abolished directional selectivity due to the blockade of GABA release. We conclude that GABA release, mediated by non-NMDA glutamate receptors, is an essential part of the mechanism of directional selectivity. The source of the GABA is unknown, but may arise from starburst amacrine cells.

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Development of excitatory and inhibitory neurotransmitters in transitory cholinergic neurons, starburst amacrine cells, and GABAergic amacrine cells of rabbit retina, with implications for previsual and visual development of retinal ganglion cells

Visual Neuroscience ◽

10.1017/s0952523810000052 ◽

2010 ◽

Vol 27 (1-2) ◽

pp. 19-42 ◽

Cited By ~ 9

Author(s):

EDWARD V. FAMIGLIETTI ◽

SARAH J. SUNDQUIST

Keyword(s):

Ganglion Cells ◽

Cholinergic Neurons ◽

Amacrine Cells ◽

Visual Development ◽

Adult Rabbit ◽

Inner Plexiform Layer ◽

Rabbit Retina ◽

Ultrastructural Studies ◽

Adult Pattern ◽

Starburst Amacrine Cells

AbstractStarburst amacrine cells (SACs), the only acetylcholine (ACh)-releasing amacrine cells (ACs) in adult rabbit retina, contain GABA and are key elements in the retina’s directionally selective (DS) mechanism. Unlike many other GABAergic ACs, they use glutamic acid decarboxlyase (GAD)67, not GAD65, to synthesize GABA. Using immunocytochemistry, we demonstrate the apoptosis at birth (P0) of transitory putative ACs that exhibit immunoreactivity (IR) for the ACh-synthetic enzyme choline acetyltransferase (ChAT), GAD67, and the GABA transporter, GAT1. Only a few intact, displaced ChAT-immunoreactive SAC bodies are detected at P0. At P2, ChAT-IR is detected in the two narrowly stratified substrata of starburst dendrites in the inner plexiform layer (IPL). Quantitative analysis reveals that in the first postnatal week, only a small fraction of SACs cells express ChAT- and GABA-IR. Not until the end of the second week are they expressed in all SACs. At P0, a three-tiered stratification of GABA-IR is present in the IPL, entirely different from the adult pattern of seven substrata, emerging at P3–P4, and optimally visualized at P13. At P0, GAD65 is detectable in normally placed AC bodies. At P1, GAD65-IR appears in dendrites of nonstarburst GABAergic ACs, and by P5 is robust in the adult pattern of four substrata in the IPL. GAD65-IR never co-localizes with ChAT-IR. In a temporal comparison of our data with physiological, pharmacological, and ultrastructural studies, we suggest that transitory ChAT-immunoreactive cells share with SACs production of stage II (nicotinic) waves of previsual synchronous activity in ganglion cells (GCs). Further, we conclude that (1) GAD65-immunoreactive, non-SAC GABAergic ACs are the most likely candidates responsible for the suppression of stage III (muscarinic/AMPA-kainate) waves and (2) DS responses first appear in DS GCs, when about 50% of SACs express ChAT- and GABA-IR, and in 100% of DS GCs, when expression occurs in all SACs.

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Rapid ‘multi-directed’ cholinergic transmission at central synapses

10.1101/2020.04.18.048330 ◽

2020 ◽

Cited By ~ 4

Author(s):

Santhosh Sethuramanujam ◽

Akihiro Matsumoto ◽

J. Michael McIntosh ◽

Miao Jing ◽

Yulong Li ◽

...

Keyword(s):

Ganglion Cells ◽

Amacrine Cells ◽

Cholinergic Transmission ◽

Starburst Amacrine Cells ◽

Local Direction ◽

The Central Nervous System ◽

Point To Point ◽

Central Synapses ◽

Synaptic Structures ◽

Synaptic Mechanisms

AbstractAcetylcholine (ACh) is a key neurotransmitter that plays diverse roles in many parts of the central nervous system, including the retina. However, assessing the precise spatiotemporal dynamics of ACh is technically challenging and whether ACh transmits signals via rapid, point-to-point synaptic mechanisms, or broader-scale ‘non-synaptic’ mechanisms has been difficult to ascertain. Here, we examined the properties of cholinergic transmission at individual contacts made between direction-selective starburst amacrine cells and downstream ganglion cells in the retina. Using a combination of electrophysiology, serial block-face electron microscopy, and two-photon ACh imaging, we demonstrate that ACh signaling bears the hallmarks of both non-synaptic and synaptic forms of transmission. ACh co-activates nicotinic ACh receptors located on the intersecting dendrites of pairs of ganglion cells, with equal efficiency (non-synaptic)— and yet retains the ability to generate rapid ‘miniature’ currents (∼1 ms rise times: synaptic). Fast cholinergic signals do not appear to depend on anatomically well-defined synaptic structures. We estimate that ACh spread is limited to ∼1-2 µm from its sites of release, which may help starbursts drive local direction-selective cholinergic responses in ganglion cell dendrites. Together, our results establish the functional architecture for cholinergic signaling at a central synapse and propose a novel motif whereby single presynaptic sites can co-transmit information to multiple neurons on a millisecond timescale.

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Presynaptic SNAP-25 regulates retinal waves and retinogeniculate projection via phosphorylation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812169116 ◽

2019 ◽

Vol 116 (8) ◽

pp. 3262-3267 ◽

Cited By ~ 1

Author(s):

Yu-Tien Hsiao ◽

Wen-Chi Shu ◽

Pin-Chun Chen ◽

Hui-Ju Yang ◽

Hsin-Yo Chen ◽

...

Keyword(s):

Ganglion Cells ◽

Amacrine Cells ◽

Calcium Transients ◽

Retinal Ganglion ◽

Retinal Waves ◽

Starburst Amacrine Cells ◽

Retinogeniculate Projection ◽

Wave Properties

Patterned spontaneous activity periodically displays in developing retinas termed retinal waves, essential for visual circuit refinement. In neonatal rodents, retinal waves initiate in starburst amacrine cells (SACs), propagating across retinal ganglion cells (RGCs), further through visual centers. Although these waves are shown temporally synchronized with transiently high PKA activity, the downstream PKA target important for regulating the transmission from SACs remains unidentified. A t-SNARE, synaptosome-associated protein of 25 kDa (SNAP-25/SN25), serves as a PKA substrate, implying a potential role of SN25 in regulating retinal development. Here, we examined whether SN25 in SACs could regulate wave properties and retinogeniculate projection during development. In developing SACs, overexpression of wild-type SN25b, but not the PKA-phosphodeficient mutant (SN25b-T138A), decreased the frequency and spatial correlation of wave-associated calcium transients. Overexpressing SN25b, but not SN25b-T138A, in SACs dampened spontaneous, wave-associated, postsynaptic currents in RGCs and decreased the SAC release upon augmenting the cAMP-PKA signaling. These results suggest that SN25b overexpression may inhibit the strength of transmission from SACs via PKA-mediated phosphorylation at T138. Moreover, knockdown of endogenous SN25b increased the frequency of wave-associated calcium transients, supporting the role of SN25 in restraining wave periodicity. Finally, the eye-specific segregation of retinogeniculate projection was impaired by in vivo overexpression of SN25b, but not SN25b-T138A, in SACs. These results suggest that SN25 in developing SACs dampens the spatiotemporal properties of retinal waves and limits visual circuit refinement by phosphorylation at T138. Therefore, SN25 in SACs plays a profound role in regulating visual circuit refinement.

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Preserving inhibition with a disinhibitory microcircuit in the retina

eLife ◽

10.7554/elife.62618 ◽

2020 ◽

Vol 9 ◽

Author(s):

Qiang Chen ◽

Robert G Smith ◽

Xiaolin Huang ◽

Wei Wei

Keyword(s):

Synaptic Plasticity ◽

Mutual Influence ◽

Ganglion Cells ◽

Amacrine Cells ◽

Direction Selectivity ◽

Short Term ◽

Brain Circuits ◽

Mammalian Retina ◽

Starburst Amacrine Cells ◽

Noise Resilience

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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Rapid multi-directed cholinergic transmission in the central nervous system

Nature Communications ◽

10.1038/s41467-021-21680-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Santhosh Sethuramanujam ◽

Akihiro Matsumoto ◽

Geoff deRosenroll ◽

Benjamin Murphy-Baum ◽

J Michael McIntosh ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Ganglion Cells ◽

Release Site ◽

Amacrine Cells ◽

Global Scale ◽

Cholinergic Transmission ◽

Data Set ◽

The Central Nervous System ◽

Synaptic Mechanisms

AbstractIn many parts of the central nervous system, including the retina, it is unclear whether cholinergic transmission is mediated by rapid, point-to-point synaptic mechanisms, or slower, broad-scale ‘non-synaptic’ mechanisms. Here, we characterized the ultrastructural features of cholinergic connections between direction-selective starburst amacrine cells and downstream ganglion cells in an existing serial electron microscopy data set, as well as their functional properties using electrophysiology and two-photon acetylcholine (ACh) imaging. Correlative results demonstrate that a ‘tripartite’ structure facilitates a ‘multi-directed’ form of transmission, in which ACh released from a single vesicle rapidly (~1 ms) co-activates receptors expressed in multiple neurons located within ~1 µm of the release site. Cholinergic signals are direction-selective at a local, but not global scale, and facilitate the transfer of information from starburst to ganglion cell dendrites. These results suggest a distinct operational framework for cholinergic signaling that bears the hallmarks of synaptic and non-synaptic forms of transmission.

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