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Nature Communications Apr 2024VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells...
VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells (RGCs, outputs). Because these input and output connections are intermixed on the same dendrites, making sense of VG3 circuitry requires comparing the distribution of synapses across their arbors to the subcellular flow of signals. Here, we combine subcellular calcium imaging and electron microscopic connectomic reconstruction to analyze how VG3s integrate and transmit visual information. VG3s receive inputs from all nearby bipolar cell types but exhibit a strong preference for the fast type 3a bipolar cells. By comparing input distributions to VG3 dendrite responses, we show that VG3 dendrites have a short functional length constant that likely depends on inhibitory shunting. This model predicts that RGCs that extend dendrites into the middle layers of the inner plexiform encounter VG3 dendrites whose responses vary according to the local bipolar cell response type.
Topics: Mice; Animals; Amacrine Cells; Retina; Retinal Ganglion Cells; Synapses; Microscopy, Electron; Dendrites
PubMed: 38580652
DOI: 10.1038/s41467-024-46996-0 -
Classification and analysis of retinal interneurons by computational structure under natural scenes.BioRxiv : the Preprint Server For... May 2024Inhibitory neurons are diverse across the brain, but for the visual system we lack the ability to functionally classify these neurons under complex natural stimuli. Here...
Inhibitory neurons are diverse across the brain, but for the visual system we lack the ability to functionally classify these neurons under complex natural stimuli. Here we take the approach of classifying retinal amacrine cell responses to natural scenes using optical recording and an interpretable neural network model. We fit mouse amacrine cell responses to a two-layer convolutional neural network model of a class shown previously to accurately capture salamander ganglion cell responses to natural scenes. Using an approach from interpretable machine learning, we determined for each stimulus the model interneurons that generated each amacrine response, analogous to the set of bipolar cells that target the amacrine population. From this analysis we clustered amacrine cells not by their natural scene responses, but by the model presynaptic neurons that constructed those responses, conservatively finding approximately seven groups by this approach. By analyzing the set of model presynaptic input neurons for each amacrine cluster, we find that distributed rather than dedicated inputs generate natural scene responses for different amacrine cell types. Additional analyses revealed distinct transient and sustained modes exhibited by the network during the response to simple flashes. These results give insight into the computational structure of how the diverse amacrine cell population responds to natural scenes, and generate multiple quantitative hypotheses for how synaptic inputs generate those responses.
PubMed: 38562848
DOI: 10.1101/2024.03.18.585364 -
Cell Reports Apr 2024The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and...
The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and tensin homolog (Pten) controls starburst amacrine cell spacing by modulating vesicular trafficking of cell adhesion molecules and Wnt proteins. Single-cell transcriptomics and double-mutant analyses revealed that Pten and Down syndrome cell adhesion molecule Dscam) are co-expressed and function additively to pattern starburst amacrine cell mosaics. Mechanistically, Pten loss accelerates the endocytic trafficking of DSCAM, FAT3, and MEGF10 off the cell membrane and into endocytic vesicles in amacrine cells. Accordingly, the vesicular proteome, a molecular signature of the cell of origin, is enriched in exocytosis, vesicle-mediated transport, and receptor internalization proteins in Pten conditional knockout (Pten) retinas. Wnt signaling molecules are also enriched in Pten retinal vesicles, and the genetic or pharmacological disruption of Wnt signaling phenocopies amacrine cell patterning defects. Pten thus controls vesicular trafficking of cell adhesion and signaling molecules to establish retinal amacrine cell mosaics.
Topics: Animals; PTEN Phosphohydrolase; Retina; Wnt Signaling Pathway; Cell Adhesion; Mice; Endocytosis; Amacrine Cells; Mice, Knockout; Protein Transport; Wnt Proteins; Cell Adhesion Molecules
PubMed: 38551961
DOI: 10.1016/j.celrep.2024.114005 -
Pharmaceuticals (Basel, Switzerland) Mar 2024Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress...
Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress is correlated to NADPH oxidase (NOX), a major source of Reactive Oxygen Species (ROS), and glutamate metabolism impairments. This study investigated the role of NOX2 and the novel NOX2 inhibitor, GLX7013170, in two models of a) retinal AMPA excitotoxicity [AMPA+GLX7013170 (10 M, intravitreally)] and b) early-stage DR paradigm (ESDR), GLX7013170: 14-day therapeutic treatment (topically, 20 μL/eye, 10 mg/mL (300 × 10 M), once daily) post-streptozotocin (STZ)-induced DR. Immunohistochemical studies for neuronal markers, nitrotyrosine, micro/macroglia, and real-time PCR, Western blot, and glutamate colorimetric assays were conducted. Diabetes increased NOX2 expression in the retina. NOX2 inhibition limited the loss of NOS-positive amacrine cells and the overactivation of micro/macroglia in both models. In the diabetic retina, GLX7013170 had no effect on retinal ganglion cell axons, but reduced oxidative damage, increased Bcl-2, reduced glutamate levels, and partially restored excitatory amino acid transporter (EAAT1) expression. These results suggest that NOX2 in diabetes is part of the triad, oxidative stress, NOX, and glutamate excitotoxicity, key players in the induction of DR. GLX7013170 is efficacious as a neuroprotective/anti-inflammatory agent and a potential therapeutic in retinal diseases, including ESDR.
PubMed: 38543179
DOI: 10.3390/ph17030393 -
Animals : An Open Access Journal From... Mar 2024The specific arrangement and distribution of photoreceptors in the retina can vary among different fish species, with each species exhibiting adaptations related to its...
The specific arrangement and distribution of photoreceptors in the retina can vary among different fish species, with each species exhibiting adaptations related to its habitat, behavior, and visual requirements. , a diurnal fish, was the focus of this study. The retinas of a total of eighteen Molly fish were investigated utilizing light and electron microscopy. The retina exhibited a square mosaic pattern of the inner segments of cones. This pattern comprised double cones positioned along the sides of a square, with two types of single cones situated at the center and corners of the square arrangement across the entire retina. The corner cones were slightly shorter than the central ones. Additionally, the outer plexiform layer contained both cone pedicles and rod spherules. The rod spherule consisted of a single synaptic ribbon arranged in a triad or quadrat junctional arrangement within the invaginating free ends of the horizontal and bipolar cell processes. On the other hand, cone pedicles have more than one synaptic ribbon in their junctional complex. The inner nuclear layer consisted of the amacrine, bipolar, Müller, and horizontal cell bodies. Müller cell processes, expressing GFAP, extended across all retinal layers, segmenting the deeper retina into alternating fascicles of optic axons and ganglion cells. The outer and inner plexiform layers showed many astrocyte cell processes expressing GFAP. In conclusion, the current study is the first record of the retinal structures of Molly fish. This study illustrated the mosaic arrangement of photoreceptors and GFAP expression patterns of astrocytes and Müller cells. The presence of three cone types, coupled with a sufficient number of rods, likely facilitates motion awareness for tasks like finding food and performing elaborate mating ceremonies.
PubMed: 38540038
DOI: 10.3390/ani14060939 -
Journal of Parkinson's Disease 2024Parkinson's disease (PD) patients experience visual symptoms and retinal degeneration. Studies using optical coherence tomography (OCT) have shown reduced thickness of...
BACKGROUND
Parkinson's disease (PD) patients experience visual symptoms and retinal degeneration. Studies using optical coherence tomography (OCT) have shown reduced thickness of the retina in PD, also a key characteristic of glaucoma.
OBJECTIVE
To identify the presence and pattern of retinal changes in de novo, treatment-naive PD patients compared to healthy controls (HC) and early primary open angle glaucoma (POAG) patients.
METHODS
Macular OCT data (10×10 mm) were collected from HC, PD, and early POAG patients, at the University Medical Center Groningen. Bayesian informative hypotheses statistical analyses were carried out comparing HC, PD-, and POAG patients, within each retinal cell layer.
RESULTS
In total 100 HC, 121 PD, and 78 POAG patients were included. We showed significant reduced thickness of the inner plexiform layer and retinal pigment epithelium in PD compared to HC. POAG patients presented with a significantly thinner retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, outer plexiform layer, and outer photoreceptor and subretinal virtual space compared to PD. Only the outer segment layer and retinal pigment epithelium were significantly thinner in PD compared to POAG.
CONCLUSIONS
De novo PD patients show reduced thickness of the retina compared to HC, especially of the inner plexiform layer, which differs significantly from POAG, showing a more extensive and widespread pattern of reduced thickness across layers. OCT is a useful tool to detect retinal changes in de novo PD, but its specificity versus other neurodegenerative disorders has to be established.
Topics: Humans; Parkinson Disease; Tomography, Optical Coherence; Male; Female; Aged; Middle Aged; Glaucoma, Open-Angle; Retina; Retinal Pigment Epithelium
PubMed: 38517802
DOI: 10.3233/JPD-223481 -
The Journal of Neuroscience : the... May 2024An organizational feature of neural circuits is the specificity of synaptic connections. A striking example is the direction-selective (DS) circuit of the retina. There...
An organizational feature of neural circuits is the specificity of synaptic connections. A striking example is the direction-selective (DS) circuit of the retina. There are multiple subtypes of DS retinal ganglion cells (DSGCs) that prefer motion along one of four preferred directions. This computation is mediated by selective wiring of a single inhibitory interneuron, the starburst amacrine cell (SAC), with each DSGC subtype preferentially receiving input from a subset of SAC processes. We hypothesize that the molecular basis of this wiring is mediated in part by unique expression profiles of DSGC subtypes. To test this, we first performed paired recordings from isolated mouse retinas of both sexes to determine that postnatal day 10 (P10) represents the age at which asymmetric synapses form. Second, we performed RNA sequencing and differential expression analysis on isolated P10 ON-OFF DSGCs tuned for either nasal or ventral motion and identified candidates which may promote direction-specific wiring. We then used a conditional knock-out strategy to test the role of one candidate, the secreted synaptic organizer cerebellin-4 (Cbln4), in the development of DS tuning. Using two-photon calcium imaging, we observed a small deficit in directional tuning among ventral-preferring DSGCs lacking Cbln4, though whole-cell voltage-clamp recordings did not identify a significant change in inhibitory inputs. This suggests that Cbln4 does not function primarily via a cell-autonomous mechanism to instruct wiring of DS circuits. Nevertheless, our transcriptomic analysis identified unique candidate factors for gaining insights into the molecular mechanisms that instruct wiring specificity in the DS circuit.
Topics: Animals; Mice; Retina; Male; Synapses; Female; Retinal Ganglion Cells; Mice, Inbred C57BL; Amacrine Cells; Motion Perception; Nerve Net; Visual Pathways
PubMed: 38514178
DOI: 10.1523/JNEUROSCI.1461-23.2024 -
International Journal of Molecular... Feb 2024We recently identified PKN1 as a developmentally active gatekeeper of the transcription factor neuronal differentiation-2 (NeuroD2) in several brain areas. Since NeuroD2...
We recently identified PKN1 as a developmentally active gatekeeper of the transcription factor neuronal differentiation-2 (NeuroD2) in several brain areas. Since NeuroD2 plays an important role in amacrine cell (AC) and retinal ganglion cell (RGC) type formation, we aimed to study the expression of NeuroD2 in the postnatal retina of WT and animals, with a particular focus on these two cell types. We show that PKN1 is broadly expressed in the retina and that the gross retinal structure is not different between both genotypes. Postnatal retinal NeuroD2 levels were elevated upon knockout, with retinae showing more NeuroD2 cells in the lower portion of the inner nuclear layer. Accordingly, immunohistochemical analysis revealed an increased amount of AC in postnatal and adult retinae. There were no differences in horizontal cell, bipolar cell, glial cell and RGC numbers, nor defective axon guidance to the optic chiasm or tract upon knockout. Interestingly, we did, however, see a specific reduction in SMI-32 α-RGC in retinae. These results suggest that PKN1 is important for retinal cell type formation and validate PKN1 for future studies focusing on AC and α-RGC specification and development.
Topics: Animals; Retina; Retinal Ganglion Cells; Amacrine Cells; Optic Chiasm; Transcription Factors
PubMed: 38474095
DOI: 10.3390/ijms25052848 -
PLoS Biology Feb 2024In mammals, starburst amacrine cells are centrally involved in motion vision and a new study in PLOS Biology, by Yan and colleagues finds that zebrafish have them, too....
In mammals, starburst amacrine cells are centrally involved in motion vision and a new study in PLOS Biology, by Yan and colleagues finds that zebrafish have them, too. They coexist with a second pair of starburst-like neurons, but neither appears to be strongly motion selective.
Topics: Animals; Amacrine Cells; Zebrafish; Retina; Mammals; Cholinergic Agents
PubMed: 38422167
DOI: 10.1371/journal.pbio.3002538 -
Nature Communications Feb 2024Dendritic mechanisms driving input-output transformation in starburst amacrine cells (SACs) are not fully understood. Here, we combine two-photon subcellular voltage and...
Dendritic mechanisms driving input-output transformation in starburst amacrine cells (SACs) are not fully understood. Here, we combine two-photon subcellular voltage and calcium imaging and electrophysiological recording to determine the computational architecture of mouse SAC dendrites. We found that the perisomatic region integrates motion signals over the entire dendritic field, providing a low-pass-filtered global depolarization to dendrites. Dendrites integrate local synaptic inputs with this global signal in a direction-selective manner. Coincidental local synaptic inputs and the global motion signal in the outward motion direction generate local suprathreshold calcium transients. Moreover, metabotropic glutamate receptor 2 (mGluR2) signaling in SACs modulates the initiation of calcium transients in dendrites but not at the soma. In contrast, voltage-gated potassium channel 3 (Kv3) dampens fast voltage transients at the soma. Together, complementary mGluR2 and Kv3 signaling in different subcellular regions leads to dendritic compartmentalization and direction selectivity, highlighting the importance of these mechanisms in dendritic computation.
Topics: Animals; Mice; Amacrine Cells; Calcium; Receptors, Metabotropic Glutamate; Signal Transduction; Dendrites
PubMed: 38418467
DOI: 10.1038/s41467-024-46234-7