Effects of elevated intraocular pressure on mouse retinal ganglion cells

Ji, Jianzhong; Chang, Peter; Pennesi, Mark E.; Yang, Zhuo; Zhang, Jian; Li, Dequan; Wu, Samuel M.; Gross, Ronald L.

doi:10.1016/j.visres.2004.08.008

Cited by 67 publications

(55 citation statements)

References 26 publications

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“…Our results have shown that functional changes of the DBC R →AIIAC synapses are likely to be a primary source of RGC sensitivity loss in mice with elevated IOP. We found such sensitivity reduction in ON and OFF αGCs as well as in AIIACs in mice with elevated IOP at stages before significant RGC or optic nerve degeneration is observed (12,16). This suggests that physiological response changes may occur before structural damage in early stages of glaucoma, and thus measuring RGC and AIIAC response sensitivity changes may be used as a diagnostic tool for glaucoma at its early stages before any irreversible structural damage occurs.…”

Section: Sensitivity Loss In Inner Retinal Neurons Occurs Before Obsementioning

confidence: 60%

“…2B) and ΔI C and ΔI Cl (Fig. 2 C and D, respectively) of an ONαGC to light steps of various intensities in a darkadapted flat-mounted retina of a mouse with 5-wk elevated IOP (15-24 Hg) (12,16). The average response-intensity (R-Log I) relations of six ONαGCs in H-IOP mouse retinas (with 3-to 7-wk elevated IOP, four with the laser method and two with the microbead method; Materials and Methods) are shown as dotted curves in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Because high IOP (H-IOP) is an important risk factor, many experimental animal models of elevated IOP have been developed in multiple species including monkeys, rats, and mice (16)(17)(18)(19)(20)(21)(22). Most experiments performed in animal models have focused on anatomical and histopathological analyses of RGC death, axon loss, and changes to axonal projections to higher visual centers in the brain (23)(24)(25).…”

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confidence: 99%

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Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Pang

Frankfort

Gross

et al. 2015

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

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Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3-7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.laucoma is a leading cause of irreversible blindness in the United States and the world (1, 2), and is characterized by optic nerve cupping (thinning of the neuroretinal rim at the optic nerve head) and progressive optic nerve and retinal ganglion cell (RGC) degeneration as well as functional deficit revealed by psychophysical tests (3, 4). Although factors causing the eventual RGC death and blindness remain controversial (1, 5-8), increasing evidence from human patients and animal models has shown that the disease is associated with an early mild diffuse loss of retinal sensitivity or inner retinal response decrease (9-14). Although it is unclear whether these functional changes are a prelude or even causal to RGC death and blindness, elucidating the underlying synaptic and cellular mechanisms for such sensitivity/response decline will nevertheless provide novel insights pertaining to early detection and treatment of human glaucoma.Multiple risk factors are associated with glaucomatous diseases, among which elevated intraocular pressure (IOP) is widely accepted as the most significant for both disease onset and progression (2, 15). Because high IOP (H-IOP) is an important risk factor, many experimental animal models of elevated IOP have been developed in multiple species including monkeys, rats, and mice (16)(17)(18)(19)(20)(21)(22). Most experiments performed in animal models have focused on anatomical and histopathological analyses of RGC death, axon loss, and changes to axonal projections ...

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Section: Sensitivity Loss In Inner Retinal Neurons Occurs Before Obsementioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Pang

Frankfort

Gross

et al. 2015

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

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“…A transgenic (Tg) mouse strain with a targeted mutation in the gene for the ␣1 subunit of collagen type I demonstrates a gradual elevation of intraocular pressure (IOP) and progressive optic nerve axon loss (Mabuchi et al, 2004). Other approaches include cauterization of the episcleral and limbal veins leading to elevation of IOP and the loss of RGCs (Ji et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Expression of Mutated Mouse Myocilin Induces Open-Angle Glaucoma in Transgenic Mice

Senatorov¹,

Malyukova²,

Fariss³

et al. 2006

J. Neurosci.

139

112

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“…First, we show that exposing conscious animals to intermittent systemic hypoxia, a noninvasive postconditioning stimulus, can promote glaucoma resistance without the requirement for inducing repetitive anesthesia and/ or repetitive, direct retinal ischemia. Second, we demonstrate postconditioning efficacy in a model of glaucoma exhibiting progressive, time-dependent RGC loss secondary to IOP elevation by a relatively common episcleral vein occlusion approach [9][10][11][39][40][41][42][43][44], in contradistinction to a more obscure model dependent on weekly anterior chamber injections of chondroitin sulfate to elevate IOP [38]. Third, we now document that glaucomatous protection by postconditioning is feasible in mice.…”

Section: Discussionmentioning

confidence: 82%

Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset

et al. 2015

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The neuroprotective efficacy of adaptive epigenetics, wherein beneficial gene expression changes are induced by nonharmful "conditioning" stimuli, is now well established in several acute, preclinical central nervous system injury models. Recently, in a mouse model of glaucoma, we demonstrated retinal ganglion cell (RGC) protection by repetitively "preconditioning" with hypoxia prior to disease onset, indicating an epigenetic approach may also yield benefits in chronic neurodegenerative disease. Herein, we determined whether presenting the repetitive hypoxic stimulus after disease initiation [repetitive hypoxic "postconditioning" (RHPost)] could afford similar functional and morphologic protection against glaucomatous RGC injury. Chronic elevations in intraocular pressure (IOP) were induced unilaterally in adult male C57BL/6 mice by episcleral vein ligation. Mice were randomized to an RH-Post [1 h of systemic hypoxia (11 % oxygen) every other day, starting 4 days after IOP elevation] or an untreated control group. After 3 weeks of experimental glaucoma, the 21-27 % reduction and 5-25 % prolongation in flash visual-evoked potential amplitudes and latencies, respectively, and the 30 % impairment in visual acuity were robustly improved in RH-Post-treated mice, as was the 17 % loss in RGC soma number and 20 % reduction in axon integrity. These protective effects were observed without RH-Post affecting IOP. The present findings demonstrate that functional and morphologic protection of RGCs can be realized by stimulating epigenetic responses during the early stages of disease, and thus constitute a new conceptual approach to glaucoma therapeutics.

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Effects of elevated intraocular pressure on mouse retinal ganglion cells

Cited by 67 publications

References 26 publications

Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Expression of Mutated Mouse Myocilin Induces Open-Angle Glaucoma in Transgenic Mice

Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset

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