Who’s lost first? Susceptibility of retinal ganglion cell types in experimental glaucoma

Santina, Luca Della; Ou, Yvonne

doi:10.1016/j.exer.2016.06.006

Cited by 65 publications

(71 citation statements)

References 43 publications

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“…Some of the class-specific IOP-induced changes we found differ significantly from results in recent papers (33). For example, we find that the RF center size of OFF transient RGCs is unchanged, ON-OFF RGCs are decreased, and the RF sizes were previously found to be reduced and unchanged, respectively (8,9,24).…”

Section: Differential Effects Of Iop On Various Physiological Types Ocontrasting

confidence: 55%

Elevated IOP alters the space–time profiles in the center and surround of both ON and OFF RGCs in mouse

Sabharwal

Seilheimer

Tao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glaucoma is a leading cause of blindness worldwide, and is characterized by progressive retinal ganglion cell (RGC) death. An experimental model of glaucoma has been established by elevating the intraocular pressure (IOP) via microbead occlusion of ocular fluid outflow in mice. Studies in this model have found visual dysfunction that varied with adaptational state, occurred before anatomical changes, and affected OFF RGCs more than ON RGCs. These results indicate subtle alterations in the underlying retinal circuitry that could help identify disease before irreversible RGC changes. Therefore, we looked at how RGC function was altered with elevated IOP under both photopic and scotopic conditions. We first found that responses to light offset are diminished with IOP elevation along with a concomitant decrease in receptive field center size for OFF RGCs. In addition, the antagonistic surround strength and size was reduced in ON RGCs. Furthermore, elevation of IOP significantly accelerated the photopic temporal tuning of RGC center responses in both ON and OFF RGCs. We found that some of the IOP-induced functional changes to OFF RGCs relied on ON cross-over pathways, indicating dysfunction in inner retinal circuitry. Overall, these results suggest that IOP alters multiple functions in the retina depending on the adaptational state. They provide a basis for designing multiple functional tests for early detection of glaucoma and for circuit-specific therapeutic targets in treatment of this blinding disease.retinal ganglion cell | glaucoma | IOP | receptive field | multielectrode array G laucoma is one of the leading causes of blindness worldwide (1). It is a progressive disease and most patients are only identified after an irreversible visual deficit is already present (2). Diagnosing patients with subtle functional deficits that occur before this irreversible visual deficit will significantly improve a patient's ability to preserve normal vision.Elevated intraocular pressure (IOP) is a critical risk factor for glaucoma and the central focus of glaucoma treatment (3, 4). Mouse models of glaucoma are also dependent on raising IOP. One method to elevate IOP is to inject microbeads into the eye to block normal fluid outflow (5). Previous studies on this mouse model have found that high IOP causes changes in retinal ganglion cell (RGC) anatomy and eventual cell death leading to irreversible vision loss as seen in glaucoma (5-7). Before these changes, functional properties, such as RGC light sensitivity and photopic receptive field (RF) center size, are altered (8-12). A better understanding of these functional changes may help to detect human disease before irreversible cell death.In addition to RGC changes, behavioral tests have found that spatiotemporal tuning under photopic and scotopic conditions is altered (10). These behavioral studies suggest alteration in additional functional properties related to spatiotemporal tuning, such as scotopic receptive field size, temporal tuning, and the antagonistic surround.To det...

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Section: Differential Effects Of Iop On Various Physiological Types Ocontrasting

confidence: 55%

Elevated IOP alters the space–time profiles in the center and surround of both ON and OFF RGCs in mouse

Sabharwal

Seilheimer

Tao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This finding supports the idea that a reduction in editing by ADAR2 at the Q/R site is responsible for the increase in CP-AMPAR expression associated with chronic OHT. Robust AMPAR remodeling of α transient Off RGCs observed in the present study is in line with the notion that this cell type is particularly susceptible to OHT (Della Santina and Ou, 2017). Within the first 7 days, α transient Off RGCs undergo extensive dendritic pruning and loss of synaptic contacts, judged by a reduction in PSD-95 puncta (Della Santina et al, 2013; El-Danaf and Huberman, 2015; Ou et al, 2016).…”

Section: Discussionsupporting

confidence: 92%

“…Here we show that two weeks of ocular hypertension (OHT) is sufficient to remodel AMPARs in α On and α transient Off, but not α sustained Off RGCs. Amongst the alpha type RGCs, the Off transient type appears more vulnerable than the others, although there is some subtype variability depending upon the parameters that are being measured (Della Santina and Ou, 2017). AMPARs displayed increased voltage-dependent block by spermine, consistent with increased CP-AMPARs expression (Bowie and Mayer, 1995; Donevan and Rogawski, 1995; Kamboj et al, 1995; Koh et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

Sladek

Nawy

2019

Preprint

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148 words) 1 AMPA receptors in the CNS are normally impermeable to Ca 2+ but aberrant expression of 2 Ca 2+ -permeable AMPA receptors (CP-AMPARs) occurs in pathological conditions such as 3 ischemia or epilepsy, or in degenerative diseases such as ALS. Here we show that select 4 populations of retinal ganglion cells (RGCs) similarly express high levels of CP-AMPARs in 5 a mouse model of glaucoma. CP-AMPAR expression increased dramatically in both α On 6 and α transient Off RGCs, and this increase was prevented by genomic editing of the 7 GluA2 Q/R site. α On RGCs with elevated CP-AMPAR levels displayed profound synaptic 8 depression, which was reduced by selectively blocking CP-AMPARs, buffering Ca 2+ with 9 BAPTA, or with the CB1 antagonist AM251, suggesting that depression was mediated by a 10 retrograde transmitter which might be triggered by influx of Ca 2+ through CP-AMPARs.11 Thus OHT alters the composition of AMPARs and modulates patterns of synaptic activity 12 in select populations of RGCs. 13 14 27 CP-AMPARs, and decrease synaptic gain. We explore the possibility that CP-AMPAR 28 expression and synaptic gain are linked, with CP-AMPARs providing a route of Ca 2+ influx 29 to activate a retrograde messenger that reduces transmitter release from the presynaptic 30 bipolar cell.31 Results 32 5 α transient and sustained Off RGCs express predominantly Ca 2+ -impermeant

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“…In some cases, we identified RGC type specificity among these genes. Of particular interest are genes implicated in POAG, given the current lack of knowledge about whether specific RGC types exhibit selective vulnerability in this disease (63).…”

Section: Mapping Disease Genes To Cell Classes and Typesmentioning

confidence: 99%

Cell Atlas of the Human Fovea and Peripheral Retina

Yan¹,

Peng

Zyl

et al. 2020

Preprint

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Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of ~85,000 cells from the fovea and peripheral retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and nonneuronal cells. Nearly all types are shared between the two retinal regions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 2 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis. We show that over 90% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and provide a foundation for investigating molecular mechanisms underlying visual processing.

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Who’s lost first? Susceptibility of retinal ganglion cell types in experimental glaucoma

Cited by 65 publications

References 43 publications

Elevated IOP alters the space–time profiles in the center and surround of both ON and OFF RGCs in mouse

Elevated IOP alters the space–time profiles in the center and surround of both ON and OFF RGCs in mouse

Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

Cell Atlas of the Human Fovea and Peripheral Retina

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