scholarly journals Impaired light adaptation of ON-sustained ganglion cells in early diabetes is attributable to diminished dopamine D4 receptor sensitivity

2020 ◽  
Author(s):  
Michael D. Flood ◽  
Andrea J. Wellington ◽  
Erika D. Eggers
Keyword(s):  
Light Adaptation ◽  
Ganglion Cells ◽  
Plexiform Layer ◽  
Mouse Retina ◽  
Dopamine D4 Receptor ◽  
Receptor Sensitivity ◽  
Early Diabetes ◽  
Cellular Machinery ◽  
D4 Receptor

AbstractPurpose: It has been known for some time that normal retinal signaling is disrupted early on in diabetes, before the onset of the vascular pathologies associated with diabetic retinopathy. There is growing evidence that levels of retinal dopamine, a neuromodulator that mediates light adaptation, may also be reduced in early diabetes. Previously, we have shown that after six weeks of diabetes in a mouse model, light adaptation is impaired at the level of ON-sustained (ON-s) ganglion cells. The purpose of this study was to determine whether changes in dopamine receptor sensitivity contribute to this dysfunction. Here we used single cell retinal patch-clamp recordings from the mouse retina to determine how activating dopamine type D4 receptors (D4Rs) changes the light-evoked and spontaneous excitatory inputs to ON-s ganglion cells, in both control and diabetic animals. We also used in-situ fluorescent hybridization to assess whether D4R expression was impacted by diabetes. We found that D4R activation had a smaller impact on light-evoked excitatory inputs to ON-s ganglion cells in diabetic retinas compared to controls. This impaired D4R signaling is not attributable to a decline in D4R expression, as we found increased D4R mRNA density in the outer plexiform layer in diabetic retinas. This suggests that the cellular machinery of dopaminergic signaling is itself disrupted in early diabetes and may be amenable to chronic dopamine supplementation therapy.

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

eLife ◽  
2018 ◽  
Vol 7 ◽  
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.

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

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.

Differential expression of glycine receptor subunits in the retina of the rat: A study using immunohistochemistry and in situ hybridization

1994 ◽  
Vol 11 (4) ◽  
pp. 721-729 ◽  
Author(s):  
U. Greferath ◽  
J. H. Brandstätter ◽  
H. Wässle ◽  
J. Kirsch ◽  
J. Kuhse ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Differential Expression ◽  
Ganglion Cell Layer ◽  
Ganglion Cells ◽  
Cell Layer ◽  
Glycine Receptor ◽  
Plexiform Layer ◽  
Inner Plexiform Layer ◽  
Subunit Mrna

AbstractImmunohistochemistry and in situ hybridization were used to study the distribution of glycine receptor (GlyR) subunits and the GlyR-associated protein gephyrin in the rat retina. Monoclonal antibodies against the α and β subunits of the GlyR and gephyrin showed a strong punctate labeling pattern in the inner plexiform layer. Glycine receptor mRNAs were found in the inner nuclear layer and the ganglion cell layer. The α 1 subunit mRNA is predominantly present in the outer half of the INL and on some but not all ganglion cells. GlyR α2 subunit mRNA is predominantly present in the inner half of the INL and on nearly all cells in the ganglion cell layer. GlyR α3–, GlyR β-, and gephyrin-mRNAs are present in the entire INL and in cells in the ganglion cell layer. The differential expression of glycine receptor subunits indicates a functional diversity of glycine receptors in the retina.

scholarly journals Dopamine D1 and D4 receptors contribute to light adaptation in ON-sustained retinal ganglion cells

2020 ◽  
Author(s):  
Michael D. Flood ◽  
Erika D. Eggers
Keyword(s):  
Light Adaptation ◽  
Dynamic Range ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Mouse Retina ◽  
Retinal Ganglion ◽  
Cell Responses ◽  
Light Levels ◽  
Excitatory Activity ◽  
Effect Of Light

AbstractAdaptation of ganglion cells to increasing light levels is a crucial property of the retina. The retina must respond to light intensities that vary by 10-12 orders of magnitude, but the dynamic range of ganglion cell responses only covers ~1000 orders of magnitude. Dopamine is a crucial neuromodulator for light adaptation and activates receptors in the D1 family – D1Rs that are expressed on horizontal cells and some bipolar and ganglion cells- and the D2 family – D2Rs that are expressed on dopaminergic amacrine cells and D4Rs that are primarily expressed on photoreceptors. However, how these receptors change the synaptic properties of the inputs to ganglion cells is not yet clear. Here we used single cell retinal patch-clamp recordings from the mouse retina to determine how activating D1Rs and D4Rs changed the light-evoked and spontaneous excitatory inputs to ON-sustained (ON-s) ganglion cells. We found that both D1R and D4R activation decrease the light-evoked excitatory inputs to ON-s ganglion cells, but that only the sum of activating the two receptors was similar to the effect of light adaptation to a rod-saturating background. The largest effects on spontaneous excitatory activity of both D1R and D4R agonists was on the frequency of events, suggesting that D1Rs and D4Rs are acting upstream of the ganglion cells.

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

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.

scholarly journals Dopamine D1 and D4 receptors contribute to light adaptation in ON-sustained retinal ganglion cells

2021 ◽  
Author(s):  
Michael Daniel Flood ◽  
Erika D Eggers
Keyword(s):  
Light Adaptation ◽  
Dynamic Range ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Mouse Retina ◽  
Retinal Ganglion ◽  
Cell Responses ◽  
Light Levels ◽  
Excitatory Activity ◽  
Effect Of Light

The adaptation of ganglion cells to increasing light levels is a crucial property of the retina. The retina must respond to light intensities that vary by 10-12 orders of magnitude, but the dynamic range of ganglion cell responses covers only ~3 orders of magnitude. Dopamine is a crucial neuromodulator for light adaptation and activates receptors in the D1 and D2 families. D1Rs are expressed on horizontal cells and some bipolar, amacrine and ganglion cells. In the D2 family D2Rs are expressed on dopaminergic amacrine cells and D4Rs are primarily expressed on photoreceptors. However, the roles of activating these receptors to modulate the synaptic properties of the inputs to ganglion cells are not yet clear. Here we used single cell retinal patch-clamp recordings from the mouse retina to determine how activating D1Rs and D4Rs changed the light-evoked and spontaneous excitatory inputs to ON-sustained (ON-s) ganglion cells. We found that both D1R and D4R activation decrease the light-evoked excitatory inputs to ON-s ganglion cells, but that only the sum of the peak response decrease due to activating the two receptors was similar to the effect of light adaptation to a rod-saturating background. The largest effects on spontaneous excitatory activity of both D1R and D4R agonists was on the frequency of events, suggesting that both D1Rs and D4Rs are acting upstream of the ganglion cells.

scholarly journals Digital museum of retinal ganglion cells with dense anatomy and physiology

2017 ◽  
Author(s):  
J. Alexander Bae ◽  
Shang Mu ◽  
Jinseop S. Kim ◽  
Nicholas L. Turner ◽  
Ignacio Tartavull ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Imaging Modality ◽  
Plexiform Layer ◽  
Mouse Retina ◽  
Uniform Density ◽  
Inner Plexiform Layer ◽  
Visual Responses ◽  
Digital Museum ◽  
Anatomy And Physiology ◽  
Neurite Density

AbstractMost digital brain atlases have macroscopic resolution and are confined to a single imaging modality. Here we present a new kind of resource that combines dense maps of anatomy and physiology at cellular resolution. The resource encompasses almost 400 ganglion cells from a single patch of mouse retina, and a digital “museum” provides a 3D interactive view of each cell’s anatomy as well as graphs of its visual responses. To demonstrate the utility of the resource, we use it to divide the inner plexiform layer of the retina into four sublaminae defined by a purely anatomical principle of arbor segregation. We also test the hypothesis that the aggregate neurite density of a ganglion cell type should be approximately uniform (“density conservation”). Finally, we find that ganglion cells arborizing in the inner marginal sublamina of the inner plexiform layer exhibit significantly more sustained visual responses on average.

scholarly journals An extracellular biochemical screen reveals that FLRTs and Unc5s mediate neuronal subtype recognition in the retina

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Jasper J Visser ◽  
Yolanda Cheng ◽  
Steven C Perry ◽  
Andrew Benjamin Chastain ◽  
Bayan Parsa ◽  
...  
Keyword(s):  
Visual Processing ◽  
Ganglion Cells ◽  
Expression Patterns ◽  
Plexiform Layer ◽  
Amacrine Cells ◽  
Extracellular Proteins ◽  
Mouse Retina ◽  
Inner Plexiform Layer ◽  
Starburst Amacrine Cells

In the inner plexiform layer (IPL) of the mouse retina, ~70 neuronal subtypes organize their neurites into an intricate laminar structure that underlies visual processing. To find recognition proteins involved in lamination, we utilized microarray data from 13 subtypes to identify differentially-expressed extracellular proteins and performed a high-throughput biochemical screen. We identified ~50 previously-unknown receptor-ligand pairs, including new interactions among members of the FLRT and Unc5 families. These proteins show laminar-restricted IPL localization and induce attraction and/or repulsion of retinal neurites in culture, placing them in an ideal position to mediate laminar targeting. Consistent with a repulsive role in arbor lamination, we observed complementary expression patterns for one interaction pair, FLRT2-Unc5C, in vivo. Starburst amacrine cells and their synaptic partners, ON-OFF direction-selective ganglion cells, express FLRT2 and are repelled by Unc5C. These data suggest a single molecular mechanism may have been co-opted by synaptic partners to ensure joint laminar restriction.

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