Melatonin alleviates pyroptosis of retinal neurons following acute intraocular hypertension

Background: Glaucoma is a multifactorial optic neuropathy progressive characterized by structural loss of retinal ganglion cells (RGCs) and irreversible loss of vision. High intraocular pressure (HIOP) is a high risk factor for glaucoma. It has been reported that the manners of RGCs’ loss are in-depth explored after acute HIOP injury, such as, apoptosis, autophagy and necrosis. However, pyroptosis, a novel type of pro-inflammatory cell programmed necrosis, rarely reported after acute HIOP injury. Researches also showed that melatonin (MT) possesses substantial anti-inflammatory properties. However, whether melatonin could alleviate retinal neurons death, especially pyroptosis, by acute HIOP injury is unclear. Objective: This study explored pyroptosis of retinal neurons and the effects of MT preventing retinal neurons form pyroptosis after acute HIOP injury. Method: Establish acute HIOP model in rat by increasing the IOP and then reperfusion. Western Blot (WB) was adopted to detect molecules related to pyroptosis at the protein level, such as GasderminD (GSDMD), GasderminDp32 (GSDMDp32), Caspase-1 (Casp-1) and Caspase-1p20 (Casp-1p20), and the products of inflammatory reactions, as interleukin-18 (IL-18) and interleukin-1β (IL-1β) as well. At the same time, Immunofluorescence (IF) was used to co-localize Casp-1with retinal neurons to determine the position of Casp-1 expression. Morphologically, Ethidium homodimer-III staining, a method commonly used for judging cell death, was carried out to stain dead cells. Subsequently, Lactate Dehydrogenase (LDH) cytotoxicity assay kit was used to quantitative analysis the LDH released after cell disruption. Results: The results suggested that pyroptosis played a vital role in retinal neurons death, especially in the ganglion cell layer, by acute HIOP injury and peaked at 6h after acute HIOP injury. Furthermore, it was found that MT might prevent retinal neurons from pyroptosis via NF-κB/NLRP3 axis after acute HIOP injury in rats. Conclusion: MT treatment might be considered a new strategy for protecting retinal neurons against pyroptosis following acute HIOP injury.

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Architecture of retinal projections to the central circadian pacemaker

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1523629113 ◽

2016 ◽

Vol 113 (21) ◽

pp. 6047-6052 ◽

Cited By ~ 53

Author(s):

Diego Carlos Fernandez ◽

Yi-Ting Chang ◽

Samer Hattar ◽

Shih-Kuo Chen

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Microscopic Analysis ◽

Brain Regions ◽

Retinal Ganglion ◽

Circadian Pacemaker ◽

Retinal Neurons ◽

Retinal Input ◽

Innervation Patterns ◽

Left And Right

The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.

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Radial migration: Retinal neurons hold on for the ride

The Journal of Cell Biology ◽

10.1083/jcb.201609135 ◽

2016 ◽

Vol 215 (2) ◽

pp. 147-149 ◽

Cited By ~ 4

Author(s):

Jeremy N. Kay

Keyword(s):

Nervous System ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Newborn Neuron ◽

Radial Migration ◽

Biological Basis ◽

Cell Biol

Newborn neuron radial migration is a key force shaping the nervous system. In this issue, Icha et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201604095) use zebrafish retinal ganglion cells as a model to investigate the cell biological basis of radial migration and the consequences for retinal histogenesis when migration is impaired.

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Transcriptional logic of cell fate specification and axon guidance in early born retinal neurons revealed by single-cell mRNA profiling

10.1101/497081 ◽

2018 ◽

Author(s):

Quentin Lo Giudice ◽

Marion Leleu ◽

Pierre J. Fabre

Keyword(s):

Axon Guidance ◽

Cell Fate ◽

Ganglion Cells ◽

Amacrine Cells ◽

Retinal Ganglion ◽

Cell Fate Specification ◽

Retinal Neurons ◽

Fate Specification ◽

Guidance Cues ◽

Insight Into

ABSTRACTRetinal ganglion cells (RGC), together with cone photoreceptors, horizontal cells (HC) and amacrine cells (AC), are the first classes of neurons produced in the retina. Here we have profiled 5348 single retinal cells and provided a comprehensive transcriptomic atlas showing the broad diversity of the developing retina at the time when the four early-born cells are being produced. Our results show the transcriptional sequences that establish the hierarchical ordering of early cell fate specification in the retina. RGC maturation follows six waves of gene expression, giving new insight into the regulatory logic of RGC differentiation. Early-generated RGCs transcribe an increasing amount of guidance cues for young peripheral RGC axons that express the matching receptors. Finally, spatial signatures in sub-populations of RGCs allowed to define novel molecular markers that are spatially restricted during the development of the retina. Altogether this study is a valuable resource that identifies new players in mouse retinal development, shedding light on transcription factors sequence and guidance cues dynamics in space and time.

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Epiretinal stimulation with local returns enhances selectivity at cellular resolution

10.1101/275958 ◽

2018 ◽

Author(s):

Victoria H. Fan ◽

Lauren E. Grosberg ◽

Sasidhar S. Madugula ◽

Pawel Hottowy ◽

Wladyslaw Dabrowski ◽

...

Keyword(s):

Ganglion Cells ◽

Electrode Array ◽

Artificial Vision ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Cellular Resolution ◽

Electrode Recording ◽

Current Spread ◽

Evoked Activity

AbstractObjectiveEpiretinal prostheses are designed to restore vision in people blinded by photoreceptor degenerative diseases, by directly activating retinal ganglion cells (RGCs) using an electrode array implanted on the retina. In present-day clinical devices, current spread from the stimulating electrode to a distant return electrode often results in the activation of many cells, potentially limiting the quality of artificial vision. In the laboratory, epiretinal activation of RGCs with cellular resolution has been demonstrated with small electrodes, but distant returns may still cause undesirable current spread. Here, the ability of local return stimulation to improve the selective activation of RGCs at cellular resolution was evaluated.ApproachA custom multi-electrode array (512 electrodes, 10 μm diameter, 60 μm pitch) was used to simultaneously stimulate and record from RGCs in isolated primate retina. Stimulation near the RGC soma with a single electrode and a distant return was compared to stimulation in which the return was provided by six neighboring electrodes.Main resultsLocal return stimulation enhanced the capability to activate cells near the central electrode (<30 μm) while avoiding cells farther away (>30 μm). This resulted in an improved ability to selectively activate ON and OFF cells, including cells encoding immediately adjacent regions in the visual field.SignificanceThese results suggest that a device that restricts the electric field through local returns could optimize activation of neurons at cellular resolution, improving the quality of artificial vision.Novelty & SignificanceThe effectiveness of local return stimulation for enhancing the electrical activation of retinal neurons was tested using high-density multi-electrode recording and stimulation in isolated macaque retina. The results suggest that local returns may reduce unwanted evoked activity and thus optimize the selectivity of stimulation at cellular resolution. Similar patterns could be implemented in a future high-resolution prosthesis to permit a more faithful replication of normal retinal activity for the treatment of incurable blindness.

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Channeling Vision: CaV1.4—A Critical Link in Retinal Signal Transmission

BioMed Research International ◽

10.1155/2018/7272630 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 10

Author(s):

D. M. Waldner ◽

N. T. Bech-Hansen ◽

W. K. Stell

Keyword(s):

Synaptic Vesicles ◽

Ganglion Cells ◽

Signal Transmission ◽

Visual Signals ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Biological Functions ◽

Voltage Gated Calcium Channels ◽

Neural Tissues ◽

Rod And Cone Photoreceptors

Voltage-gated calcium channels (VGCC) are key to many biological functions. Entry of Ca2+into cells is essential for initiating or modulating important processes such as secretion, cell motility, and gene transcription. In the retina and other neural tissues, one of the major roles of Ca2+-entry is to stimulate or regulate exocytosis of synaptic vesicles, without which synaptic transmission is impaired. This review will address the special properties of one L-type VGCC,CaV1.4, with particular emphasis on its role in transmission of visual signals from rod and cone photoreceptors (hereafter called “photoreceptors,” to the exclusion of intrinsically photoreceptive retinal ganglion cells) to the second-order retinal neurons, and the pathological effects of mutations in theCACNA1Fgene which codes for the pore-formingα1Fsubunit ofCaV1.4.

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Tbr2-expressing retinal ganglion cells are ipRGCs

10.1101/2020.06.17.153551 ◽

2020 ◽

Author(s):

Chai-An Mao ◽

Ching-Kang Chen ◽

Takae Kiyama ◽

Nicole Weber ◽

Christopher M. Whitaker ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Molecular Mechanisms ◽

Ganglion Cells ◽

Amacrine Cells ◽

Primary Component ◽

Retinal Ganglion ◽

Retinal Neurons ◽

T Box ◽

Retinofugal Projections ◽

A Minor

AbstractThe mammalian retina contains more than 40 retinal ganglion cell (RGC) subtypes based on their unique morphologies, functions, and molecular profiles. Among them, intrinsically photosensitive RGCs (ipRGCs) are the first specified RGC type that emerged from a common pool of retinal progenitor cells. Previous work has shown that T-box transcription factor T-brain 2 (Tbr2) is essential for the formation and maintenance of ipRGCs, and Tbr2-expressing RGCs activate Opn4 expression upon native ipRGC loss, suggesting that Tbr2+ RGCs can serve as a reservoir for ipRGCs. However, the identity of Tbr2+ RGCs has not been fully vetted, and the developmental and molecular mechanisms underlying the formation of native and reservoir ipRGCs remain unclear. Here, we showed that Tbr2-expressing retinal neurons include RGCs and GABAergic displaced amacrine cells (dACs). Using genetic sparse labeling, we demonstrated that the majority of Tbr2+ RGCs are intrinsically photosensitive and morphologically indistinguishable from known ipRGC types and have identical retinofugal projections. Additionally, we found a minor fraction of Pou4f1-expressing Tbr2+ RGCs marks a unique OFF RGC subtype. Most of the Tbr2+ RGCs can be ablated by anti-melanopsin-SAP toxin in adult retinas, supporting that Tbr2+ RGCs contain reservoir ipRGCs that express melanopsin at varying levels. When Tbr2 is deleted in adult retinas, Opn4 expression is diminished followed by the death of Tbr2-deficient cells, suggesting that Tbr2 is essential for both Opn4 expression and ipRGC survival. Finally, Tbr2 extensively occupies multiple T-elements in the Opn4 locus, indicating a direct regulatory role for Tbr2 on Opn4 transcription.Significance statementMelanopsin/Opn4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) play fundamental roles in non-image forming vision. Previously we identified Tbr2 as the key transcription regulator for the development and maintenance of ipRGCs. To reveal the full identity of Tbr2-expressing retinal neurons and how Tbr2 acts, we generated a novel mouse line to genetically label and study Tbr2-expressing cells. Our in-depth characterizations firmly established that most Tbr2+ RGCs are indeed ipRGCs and that Tbr2 regulates Opn4 transcription, thus place Tbr2-Opn4 transcription regulatory hierarchy as the primary component in the development and maintenance of the non-image forming visual system.

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Large retinal ganglion cells in the pipid frog Xenopus laevis form independent, regular mosaics resembling those of teleost fishes

Visual Neuroscience ◽

10.1017/s095252380001155x ◽

1997 ◽

Vol 14 (5) ◽

pp. 811-826 ◽

Cited By ~ 9

Author(s):

K. M. Shamim ◽

P. Tóth ◽

J. E. Cook

Keyword(s):

Xenopus Laevis ◽

Nearest Neighbor ◽

Ganglion Cells ◽

Early Stage ◽

Population Based ◽

Retinal Ganglion ◽

Teleost Fishes ◽

Retinal Neurons ◽

Neuronal Populations ◽

Mosaic Analysis

AbstractPopulation-based studies of retinal neurons have helped to reveal their natural types in mammals and teleost fishes. In this, the first such study in a frog, labeled ganglion cells of the mesobatrachian Xenopus laevis were examined in flatmounts. Cells with large somata and thick dendrites could be divided into three mosaic-forming types, each with its own characteristic stratification pattern. These are named αa, αab, and αc, following a scheme recently used for teleosts. Cells of the αa mosaic (~0.4% of all ganglion cells) had very large somata and trees, arborizing diffusely within sublamina a (the most sclerad). Their distal dendrites were sparsely branched but achieved consistent coverage by intersecting those of their neighbors. Displaced and orthotopic cells belonged to the same mosaic, as did cells with symmetric and asymmetric trees. Cells of the αab mosaic (~1.2%) had large somata, somewhat smaller trees that appeared bistratified at low magnification, and dendrites that branched extensively. Their distal dendrites arborized throughout sublamina b and the vitread part of a, tessellating with their neighbors. All were orthotopic; most were symmetric. Cells of the αc mosaic (~0.5%) had large somata and very large, sparse, flat, overlapping trees, predominantly in sublamina c. All were orthotopic; some were asymmetric. Nearest-neighbor analyses and spatial correlograms confirmed that each mosaic was regular and independent, and that spacings were reduced in juvenile frogs. Densities, proportions, sizes, and mosaic statistics are tabulated for all three types, which are compared with types defined previously by size and symmetry in Xenopus and potentially homologous mosaic-forming types in teleosts. Our results reveal strong organizational similarities between the large ganglion cells of teleosts and frogs. They also demonstrate the value of introducing mosaic analysis at an early stage to help identify characters that are useful markers for natural types and that distinguish between within-type and between-type variation in neuronal populations.

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Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

Frontiers in Neuroscience ◽

10.3389/fnins.2020.618019 ◽

2020 ◽

Vol 14 ◽

Author(s):

Michael Telias ◽

Scott Nawy ◽

Richard H. Kramer

Keyword(s):

Ganglion Cells ◽

Photoreceptor Cells ◽

Age Related Macular Degeneration ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Age Related ◽

Retinal Remodeling ◽

Blind Individuals ◽

The Brain ◽

Photoreceptor Death

Vision impairment and blindness in humans are most frequently caused by the degeneration and loss of photoreceptor cells in the outer retina, as is the case for age-related macular degeneration, retinitis pigmentosa, retinal detachment and many other diseases. While inner retinal neurons survive degeneration, they undergo fundamental pathophysiological changes, collectively known as “remodeling.” Inner retinal remodeling downstream to photoreceptor death occurs across mammalian retinas from mice to humans, independently of the cause of degeneration. It results in pervasive spontaneous hyperactivity and membrane hyperpermeability in retinal ganglion cells, which funnel all retinal signals to the brain. Remodeling reduces light detection in vision-impaired patients and precludes meaningful vision restoration in blind individuals. In this review, we summarize current hypotheses proposed to explain remodeling and their potential medical significance highlighting the important role played by retinoic acid and its receptor.

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Contrast sensitivity reveals an oculomotor strategy for temporally encoding space

10.1101/388132 ◽

2018 ◽

Author(s):

Antonino Casile ◽

Jonathan Victor ◽

Michele Rucci

Keyword(s):

Contrast Sensitivity ◽

Perception And Action ◽

Spatial Information ◽

Ganglion Cells ◽

Sensitivity Function ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Processing Stage ◽

Response Characteristics ◽

Sensory Processes

AbstractThe contrast sensitivity function (CSF), how sensitivity varies with the spatial frequency of the stimulus, is a fundamental assessment of visual performance. The CSF is generally assumed to be determined by low-level sensory processes. However, the sensitivities of neurons in the early visual pathways, as measured in experiments with immobilized eyes, diverge from psychophysical CSF measurements in primates. Under natural viewing conditions, as in typical psychophysical measurements, humans continually move their eyes, drifting in a seemingly erratic manner even when looking at a fixed point. Here, we show that the resulting transformation of the visual scene into a spatiotemporal flow on the retina constitutes a processing stage that reconciles human CSF and the response characteristics of retinal ganglion cells under a broad range of conditions. Our findings suggest a fundamental integration between perception and action: eye movements work synergistically with the sensitivities of retinal neurons to encode spatial information.

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Laminin receptors in the retina: sequence analysis of the chick integrin alpha 6 subunit. Evidence for transcriptional and posttranslational regulation.

The Journal of Cell Biology ◽

10.1083/jcb.113.2.405 ◽

1991 ◽

Vol 113 (2) ◽

pp. 405-416 ◽

Cited By ~ 102

Author(s):

I de Curtis ◽

V Quaranta ◽

R N Tamura ◽

L F Reichardt

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Developmental Regulation ◽

Cell Types ◽

Laminin Receptor ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Laminin Receptors ◽

Chick Retina ◽

Integrin Alpha 6

The integrin alpha 6 beta 1 is a prominent laminin receptor used by many cell types. In the present work, we isolate clones and determine the primary sequence of the chick integrin alpha 6 subunit. We show that alpha 6 beta 1 is a prominent integrin expressed by cells in the developing chick retina. Between embryonic days 6 and 12, both retinal ganglion cells and other retinal neurons lose selected integrin functions, including the ability to attach and extend neurites on laminin. In retinal ganglion cells, we show that this is correlated with a dramatic decrease in alpha 6 mRNA and protein, suggesting that changes in gene expression account for the developmental regulation of the interactions of these neurons with laminin. In other retinal neurons the expression of alpha 6 mRNA and protein remains high while function is lost, suggesting that the function of the alpha 6 beta 1 heterodimer in these cells is regulated by posttranslational mechanisms.

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