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

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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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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Evidence for novel transient clusters of cholinergic ganglion cells in the neonatal mouse retina

10.1101/2019.12.27.888792 ◽

2019 ◽

Author(s):

Jean de Montigny ◽

Vidhyasankar Krishnamoorthy ◽

Fernando Rozenblit ◽

Tim Gollisch ◽

Evelyne Sernagor

Keyword(s):

Ganglion Cells ◽

Amacrine Cells ◽

Bipolar Cells ◽

Neonatal Mouse ◽

Mouse Retina ◽

Retinal Ganglion ◽

Electrical Imaging ◽

Subplate Neurons ◽

Starburst Amacrine Cells ◽

Cholinergic Cell

AbstractWaves of spontaneous activity sweep across the neonatal mouse retinal ganglion cell (RGC) layer, driven by directly interconnected cholinergic starburst amacrine cells (the only known retinal cholinergic cells) from postnatal day (P) 0-10, followed by waves driven by glutamatergic bipolar cells. We found transient clusters of cholinergic RGC-like cells around the optic disc during the period of cholinergic waves. They migrate towards the periphery between P2-9 and then they disappear. Pan-retinal multielectrode array recordings reveal that cholinergic wave origins follow a similar developmental center-to-periphery pattern. Electrical imaging unmasks hotspots of dipole electrical activity occurring in the vicinity of wave origins. We propose that these activity hotspots are sites for wave initiation and are related to the cholinergic cell clusters, reminiscent of activity in transient subplate neurons in the developing cortex, suggesting a universal hyper-excitability mechanism in developing CNS networks during the critical period for brain wiring.

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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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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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Spontaneous Oscillatory Activity of Starburst Amacrine Cells in the Mouse Retina

Journal of Neurophysiology ◽

10.1152/jn.00279.2005 ◽

2005 ◽

Vol 94 (3) ◽

pp. 1770-1780 ◽

Cited By ~ 20

Author(s):

Jerome Petit-Jacques ◽

Béla Völgyi ◽

Bernardo Rudy ◽

Stewart Bloomfield

Keyword(s):

Feedback Inhibition ◽

Glutamate Release ◽

Amacrine Cells ◽

Bipolar Cells ◽

Kainate Receptors ◽

Oscillatory Activity ◽

Mouse Retina ◽

Inner Plexiform Layer ◽

Experimental Conditions ◽

Starburst Amacrine Cells

Using patch-clamp techniques, we investigated the characteristics of the spontaneous oscillatory activity displayed by starburst amacrine cells in the mouse retina. At a holding potential of –70 mV, oscillations appeared as spontaneous, rhythmic inward currents with a frequency of ∼3.5 Hz and an average maximal amplitude of ∼120 pA. Application of TEA, a potassium channel blocker, increased the amplitude of oscillatory currents by >70% but reduced their frequency by ∼17%. The TEA effects did not appear to result from direct actions on starburst cells, but rather a modulation of their synaptic inputs. Oscillatory currents were inhibited by 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX), an antagonist of AMPA/kainate receptors, indicating that they were dependent on a periodic glutamatergic input likely from presynaptic bipolar cells. The oscillations were also inhibited by the calcium channel blockers cadmium and nifedipine, suggesting that the glutamate release was calcium dependent. Application of AP4, an agonist of mGluR6 receptors on on-center bipolar cells, blocked the oscillatory currents in starburst cells. However, application of TEA overcame the AP4 blockade, suggesting that the periodic glutamate release from bipolar cells is intrinsic to the inner plexiform layer in that, under experimental conditions, it can occur independent of photoreceptor input. The GABA receptor antagonists picrotoxin and bicuculline enhanced the amplitude of oscillations in starburst cells prestimulated with TEA. Our results suggest that this enhancement was due to a reduction of a GABAergic feedback inhibition from amacrine cells to bipolar cells and the resultant increased glutamate release. Finally, we found that some ganglion cells and other types of amacrine cell also displayed rhythmic activity, suggesting that oscillatory behavior is expressed by a number of inner retinal neurons.

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Dark-adapted response threshold of OFF ganglion cells is not set by OFF bipolar cells in the mouse retina

Journal of Neurophysiology ◽

10.1152/jn.01202.2011 ◽

2012 ◽

Vol 107 (10) ◽

pp. 2649-2659 ◽

Cited By ~ 27

Author(s):

A. Cyrus Arman ◽

Alapakkam P. Sampath

Keyword(s):

Ganglion Cells ◽

Amacrine Cells ◽

Bipolar Cells ◽

Response Threshold ◽

Mouse Retina ◽

Signal Flow ◽

Visual Threshold ◽

Aii Amacrine Cells ◽

Aii Amacrine ◽

Cone Bipolar Cells

The nervous system frequently integrates parallel streams of information to encode a broad range of stimulus strengths. In mammalian retina it is generally believed that signals generated by rod and cone photoreceptors converge onto cone bipolar cells prior to reaching the retinal output, the ganglion cells. Near absolute visual threshold a specialized mammalian retinal circuit, the rod bipolar pathway, pools signals from many rods and converges on depolarizing (AII) amacrine cells. However, whether subsequent signal flow to OFF ganglion cells requires OFF cone bipolar cells near visual threshold remains unclear. Glycinergic synapses between AII amacrine cells and OFF cone bipolar cells are believed to relay subsequently rod-driven signals to OFF ganglion cells. However, AII amacrine cells also make glycinergic synapses directly with OFF ganglion cells. To determine the route for signal flow near visual threshold, we measured the effect of the glycine receptor antagonist strychnine on response threshold in fully dark-adapted retinal cells. As shown previously, we found that response threshold for OFF ganglion cells was elevated by strychnine. Surprisingly, strychnine did not elevate response threshold in any subclass of OFF cone bipolar cell. Instead, in every OFF cone bipolar subclass strychnine suppressed tonic glycinergic inhibition without altering response threshold. Consistent with this lack of influence of strychnine, we found that the dominant input to OFF cone bipolar cells in darkness was excitatory and the response threshold of the excitatory input varied by subclass. Thus, in the dark-adapted mouse retina, the high absolute sensitivity of OFF ganglion cells cannot be explained by signal transmission through OFF cone bipolar cells.

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Unique functional properties of the APB sensitive and insensitive rod pathways signaling light decrements in mouse retinal ganglion cells

Visual Neuroscience ◽

10.1017/s0952523806231110 ◽

2006 ◽

Vol 23 (1) ◽

pp. 127-135 ◽

Cited By ~ 8

Author(s):

GUO-YONG WANG

Keyword(s):

Functional Properties ◽

Ganglion Cells ◽

Amacrine Cells ◽

Bipolar Cells ◽

Mouse Retina ◽

Clear Cut ◽

Types Of Information ◽

Rod Bipolar Cells ◽

Rod Pathway ◽

Cone Bipolar Cells

Light decrements are mediated by two distinct groups of rod pathways in the dark-adapted retina that can be differentiated on the basis of their sensitivity to the glutamate agonist DL-2-amino-phosphonobutyric (APB). By means of the APB sensitive pathway, rods transmit light decrementsviarod bipolar cells to AII amacrine cells, then to Off cone bipolar cells, which in turn innervate the dendrites of Off ganglion cells. APB hyperpolarizes rod bipolar cells, thus blocking this rod pathway. With APB insensitive pathways, rods either directly synapse onto Off cone bipolar cells, or rods pass light decrement signal to cones by gap junctions. In the present study, whole-cell patch-clamp recordings were made from ganglion cells in the dark-adapted mouse retina to investigate the functional properties of APB sensitive and insensitive rod pathways. The results revealed several clear-cut differences between the APB sensitive and APB insensitive rod pathways. The latency of Off responses to a flashing spot of light was significantly shorter for the APB insensitive pathways than those for the APB sensitive pathway. Moreover, Off responses of the APB insensitive pathways were found to be capable of following substantially higher stimulus frequencies. Nitric oxide was found to selectively block Off responses in the APB sensitive rod pathway. Collectively, these results provide evidence that the APB sensitive and insensitive rod pathways can convey different types of information signaling light decrements in the dark-adapted retina.

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A comparison of receptive-field and tracer-coupling size of amacrine and ganglion cells in the rabbit retina

Visual Neuroscience ◽

10.1017/s0952523800011846 ◽

1997 ◽

Vol 14 (6) ◽

pp. 1153-1165 ◽

Cited By ~ 28

Author(s):

Stewart A. Bloomfield ◽

Daiyan Xin

Keyword(s):

Receptive Field ◽

Ganglion Cells ◽

Electrical Coupling ◽

Receptive Fields ◽

Amacrine Cells ◽

Visual Signals ◽

Lateral Spread ◽

Field Size ◽

Electrical Networks ◽

Mammalian Retina

AbstractRecent studies have shown that amacrine and ganglion cells in the mammalian retina are extensively coupled as revealed by the intercellular movement of the biotinylated tracers biocytin and Neurobiotin. These demonstrations of tracer coupling suggest that electrical networks formed by proximal neurons (i.e. amacrine and ganglion cells) may underlie the lateral propagation of signals across the inner retina. We studied this question by comparing the receptive-field size, dendritic-field size, and extent of tracer coupling of amacrine and ganglion cells in the dark-adapted, supervised, isolated retina eyecup of the rabbit. Our results indicate that while the center-receptive fields of proximal neurons are approximately 15% larger than their corresponding dendritic diameters, this slight difference can be explained by factors other than electrical coupling such as tissue shrinkage associated with histological processing. However, the extent of tracer coupling of amacrine and ganglion cells was, on average, about twice the size of the corresponding receptive fields. Thus, the receptive field of an individual proximal neuron matched far more closely to its dendritic diameter than to the size of the tracer-coupled network of cells to which it belonged. The exception to this rule was the AII amacrine cells for which center-receptive fields were 2–3 times the size of their dendritic diameters but matched closely to the size of the tracer-coupled arrays. Thus, with the exception of AII cells, our data indicate that tracer coupling between proximal neurons is not associated with an enlargement of their receptive fields. Our results, then, provide no evidence for electrical coupling or, at least, indicate that extensive lateral spread of visual signals does not occur in the proximal mammalian retina.

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Dendro-somatic synaptic inputs to ganglion cells violate receptive field and connectivity rules in the mammalian retina

10.1101/2021.07.01.450751 ◽

2021 ◽

Author(s):

Miloslav Sedlacek ◽

William Grimes ◽

Morgan Musgrove ◽

Amurta Nath ◽

Hua Tian ◽

...

Keyword(s):

Receptive Field ◽

Ganglion Cells ◽

Plexiform Layer ◽

Amacrine Cells ◽

Cell Types ◽

Excitatory Input ◽

Mouse Retina ◽

Inner Plexiform Layer ◽

Visual Response ◽

Dendritic Arbors

In retinal neurons, morphology strongly influences visual response features. Ganglion cell (GC) dendrites ramify in distinct strata of the inner plexiform layer (IPL) so that GCs responding to light increments (ON) or decrements (OFF) receive appropriate excitatory inputs. This vertical stratification prescribes response polarity and ensures consistent connectivity between cell types, whereas the lateral extent of GC dendritic arbors typically dictates receptive field (RF) size. Here, we identify circuitry in mouse retina that contradicts these conventions. A2 amacrine cells are interneurons understood to mediate 'cross-over' inhibition by relaying excitatory input from the ON layer to inhibitory outputs in the OFF layer. Ultrastructural and physiological analyses show, however, that some A2s deliver powerful inhibition to OFF GC somas and proximal dendrites in the ON layer, rendering their inhibitory RFs smaller than their dendritic arbors. This OFF pathway, avoiding entirely the OFF region of the IPL, challenges several tenets of retinal circuitry.

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