Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation

AbstractThere is increasing evidence for the vulnerability of specific retinal ganglion cell (RGC) types in those with glaucoma and in animal models. In addition, the P2X7-receptor (P2X7-R) has been suggested to contribute to RGC death following stimulation and elevated IOP, though its role in RGC dysfunction prior to death has not been examined. Therefore, we examined the effect of an acute, non-ischemic intraocular pressure (IOP) insult (50 mmHg for 30 min) on RGC function in wildtype mice and P2X7-R knockout (P2X7-KO) mice. We examined retinal function using electroretinogram recordings and individual RGC responses using multielectrode arrays, 3 days following acute IOP elevation. Immunohistochemistry was used to examine RGC cell death and P2X7-R expression in several RGC types. Acute intraocular pressure elevation produced pronounced dysfunction in RGCs; whilst other retinal neuronal responses showed lesser changes. Dysfunction at 3 days post-injury was not associated with RGC loss or changes in receptive field size. However, in wildtype animals, OFF-RGCs showed reduced spontaneous and light-elicited activity. In the P2X7-KO, both ON- and OFF-RGC light-elicited responses were reduced. Expression of P2X7-R in wildtype ON-RGC dendrites was higher than in other RGC types. In conclusion, OFF-RGCs were vulnerable to acute IOP elevation and their dysfunction was not rescued by genetic ablation of P2X7-R. Indeed, knockout of P2X7-R also caused ON-RGC dysfunction. These findings aid our understanding of how pressure affects RGC function and suggest treatments targeting the P2X7-R need to be carefully considered.

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The coma in glaucoma: Retinal ganglion cell dysfunction and recovery

Progress in Retinal and Eye Research ◽

10.1016/j.preteyeres.2018.04.001 ◽

2018 ◽

Vol 65 ◽

pp. 77-92 ◽

Cited By ~ 26

Author(s):

Lewis E. Fry ◽

Eamonn Fahy ◽

Vicki Chrysostomou ◽

Flora Hui ◽

Jessica Tang ◽

...

Keyword(s):

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Retinal Ganglion ◽

Cell Dysfunction

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IOP-Dependent Retinal Ganglion Cell Dysfunction in Glaucomatous DBA/2J Mice

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.07-0582 ◽

2007 ◽

Vol 48 (10) ◽

pp. 4573 ◽

Cited By ~ 48

Author(s):

Mahesh Nagaraju ◽

Maher Saleh ◽

Vittorio Porciatti

Keyword(s):

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Retinal Ganglion ◽

Cell Dysfunction

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Reversal of Retinal Ganglion Cell Dysfunction after Surgical Reduction of Intraocular Pressure

Yearbook of Ophthalmology ◽

10.1016/j.yoph.2011.03.021 ◽

2011 ◽

Vol 2011 ◽

pp. 89-91

Author(s):

J.S. Myers

Keyword(s):

Intraocular Pressure ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Retinal Ganglion ◽

Cell Dysfunction ◽

Surgical Reduction

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Retinal Ganglion Cell Dysfunction Induced by Hypoxia and Glutamate

Survey of Ophthalmology ◽

10.1016/s0039-6257(99)00054-5 ◽

1999 ◽

Vol 43 ◽

pp. S162-S170 ◽

Cited By ~ 42

Author(s):

Ronald L Gross ◽

Steven H Hensley ◽

F Gao ◽

Samuel M Wu

Keyword(s):

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Retinal Ganglion ◽

Cell Dysfunction

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Retinal ganglion cell dysfunction in humans following post-geniculate lesions: specific spatio–temporal losses revealed by pattern ERG

Vision Research ◽

10.1016/s0042-6989(98)00272-7 ◽

1999 ◽

Vol 39 (9) ◽

pp. 1739-1748 ◽

Cited By ~ 11

Author(s):

Giovanni Porrello ◽

Benedetto Falsini

Keyword(s):

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Pattern Erg ◽

Retinal Ganglion ◽

Cell Dysfunction ◽

Spatio Temporal

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Modeling Retinal Ganglion Cell Dysfunction in Optic Neuropathies

10.20944/preprints202104.0571.v1 ◽

2021 ◽

Author(s):

Vittorio Porciatti ◽

Tsung-Han Chou

Keyword(s):

Cell Death ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Pattern Electroretinogram ◽

Retinal Ganglion ◽

Response Dynamics ◽

Cell Dysfunction ◽

Non Invasive ◽

Neuroprotective Strategies ◽

Cellular Dysfunction

As in glaucoma and other optic neuropathies cellular dysfunction often precedes cell death, sensitive assessment of retinal ganglion cell (RGC) function represents a key outcome measure for neuroprotective strategies aimed at targeting distressed but still viable cells. Here we offer a conceptual framework to identify progressive stages of RGC dysfunction leading to cell death in mouse models of glaucoma and other optic neuropathies based on non-invasive pattern electroretinogram (PERG), to differentiate phenotypic and altered RGC response dynamics, to assess susceptibility to stressors and to assess reversible dysfunction.

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Bax Contributes to Retinal Ganglion Cell Dendritic Degeneration During Glaucoma

Molecular Neurobiology ◽

10.1007/s12035-021-02675-5 ◽

2022 ◽

Author(s):

Michael L. Risner ◽

Silvia Pasini ◽

Nolan R. McGrady ◽

David J. Calkins

Keyword(s):

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Light Response ◽

B Cell Lymphoma ◽

Glaucomatous Optic Neuropathy ◽

Dendritic Arbor ◽

Retinal Ganglion ◽

Axon Transport ◽

Spatial Acuity ◽

Iop Elevation

AbstractThe BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models of neurodegeneration, including glaucomatous optic neuropathy (glaucoma), which degrades the retinal ganglion cell (RGC) axonal projection to the visual brain. Glaucoma is commonly associated with increased sensitivity to intraocular pressure (IOP) and involves a proximal program that leads to RGC dendritic pruning and a distal program that underlies axonopathy in the optic projection. While genetic deletion of the Bcl2-associated X protein (Bax-/-) prolongs RGC body survival in models of glaucoma and optic nerve trauma, axonopathy persists, thus raising the question of whether dendrites and the RGC light response are protected. Here, we used an inducible model of glaucoma in Bax-/- mice to determine if Bax contributes to RGC dendritic degeneration. We performed whole-cell recordings and dye filling in RGCs signaling light onset (αON-Sustained) and offset (αOFF-Sustained). We recovered RGC dendritic morphologies by confocal microscopy and analyzed dendritic arbor complexity and size. Additionally, we assessed RGC axon function by measuring anterograde axon transport of cholera toxin subunit B to the superior colliculus and behavioral spatial frequency threshold (i.e., spatial acuity). We found 1 month of IOP elevation did not cause significant RGC death in either WT or Bax-/- retinas. However, IOP elevation reduced dendritic arbor complexity of WT αON-Sustained and αOFF-Sustained RGCs. In the absence of Bax, αON- and αOFF-Sustained RGC dendritic arbors remained intact following IOP elevation. In addition to dendrites, neuroprotection by Bax-/- generalized to αON-and αOFF-Sustained RGC light- and current-evoked responses. Both anterograde axon transport and spatial acuity declined during IOP elevation in WT and Bax-/- mice. Collectively, our results indicate Bax contributes to RGC dendritic degeneration and distinguishes the proximal and distal neurodegenerative programs involved during the progression of glaucoma.

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Hydrogen Sulfide and β-Synuclein Are Involved and Interlinked in the Aging Glaucomatous Retina

Journal of Ophthalmology ◽

10.1155/2020/8642135 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Hanhan Liu ◽

Karl Mercieca ◽

Fabian Anders ◽

Verena Prokosch

Keyword(s):

Hydrogen Sulfide ◽

Ganglion Cell ◽

Intravitreal Injection ◽

Retinal Ganglion Cell ◽

Mass Spectrometric ◽

Retinal Ganglion ◽

Proteomics Analysis ◽

Small Proteins ◽

Iop Elevation ◽

Elevation Model

Purpose. Glaucoma, one of the leading causes of irreversible blindness worldwide, is a group of disorders characterized by progressive retinal ganglion cell (RGC) loss. Synucleins, a family of small proteins, have been of interest in studies of neurodegeneration and CNS. However, their roles and functions in glaucoma are still not completely understood and remain to be explored. Our previous studies showed that α-synuclein and H2S play a pivotal role in glaucoma. This study aims to (1) elucidate the potential roles and functions of synucleins in glaucoma throughout aging, (2) investigate the interaction between the synucleins and H2S, and better understand the mechanism of H2S in neuroprotection. Methods. The chronic IOP elevation model was carried out in 12 animals at different ages (3 months and 14 months), and RGCs were quantified by Brn3a staining. Mass spectrometric-assisted proteomics analysis was employed to measure synuclein levels and H2S producing proteins in retina. Secondly, the acute IOP elevation model was carried out in 12 juvenile animals, with or without intravitreal injection of GYY4137 (a H2S donor). RGCs were quantified along with the abundancy of synucleins. Results. RGCs and β-synuclein (SNCB) are significantly changed in old animals. Under chronic IOP elevation, there is a significant RGC loss in old animals, whereas no significant change in young animals; SNCB is significantly downregulated and 3MST is significantly upregulated in young animals due to IOP, while no significant changes in old ones are notable. Under acute IOP elevation (approx. 55 mmHg), a significant RGC loss is observed; exogenous H2S significantly reduced RGC loss and downregulated SNCB levels. Conclusion. The present study indicates a strong link between ageing and SNCB regulation. In young animals SNCB is downregulated going along with less RGC loss. Furthermore, increasing endogenous H2S is effective to downregulate SNCB and is neuroprotective against acute IOP elevation.

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