The Pattern Electroretinogram as a Tool to Monitor Progressive Retinal Ganglion Cell Dysfunction in the DBA/2J Mouse Model of Glaucoma

Porciatti, Vittorio; Saleh, Maher; Nagaraju, M.

doi:10.1167/iovs.06-0733

Cited by 101 publications

(125 citation statements)

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“…Pattern electroretinography was measured as previously reported (22,23,89). Mice from our colony were shipped in a "masked" fashion to the University of Miami, Miami, Florida, USA.…”

Section: Methodsmentioning

confidence: 99%

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Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma

et al. 2012

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“…Pattern electroretinography was measured as previously reported (22,23,89). Mice from our colony were shipped in a "masked" fashion to the University of Miami, Miami, Florida, USA.…”

Section: Methodsmentioning

confidence: 99%

“…The pattern electroretinogram (PERG; ref. 22) is a measure of RGC function, independent of intact axon function, and is greatly reduced in glaucomatous eyes prior to significant RGC loss (4,23). In irradiated mice, PERG remained normal (Figure 1G).…”

Section: Bone Marrow Transfer Is Not Required For Protectionmentioning

confidence: 99%

Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma

et al. 2012

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“…RGCs from D2.Wld s mice can survive high IOP and have an intact pattern electroretinogram (PERG) (20). Given that PERG amplitude is a sensitive measure of RGC health (32,33), Wld s prevents very early changes. Confirming this effect here, we show that Wld s also prevents other early features of glaucoma, RGC dendrite remodeling, and signs of axon stress.…”

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confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

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

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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“…However, no changes in single RGC or their presynaptic bipolar cell (BC)/AIIAC responses have been reported in experimental glaucoma models. Studies using electroretinogram, STR, and optic nerve recording techniques lack the power to identify or establish cellular and synaptic sites of retinal dysfunction (27,31,32), leaving a disabling gap preventing us from knowing how elevated IOP affects light responses of individual retinal neurons. In this study, we fill this gap by using whole-cell voltage-clamp techniques to study light responses of individual alpha-RGCs (αGCs) and AIIACs, as well as their presynaptic BCs, in two experimental glaucoma mouse models.…”

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confidence: 99%

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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The Pattern Electroretinogram as a Tool to Monitor Progressive Retinal Ganglion Cell Dysfunction in the DBA/2J Mouse Model of Glaucoma

Abstract: The PERG has an adequate signal-to-noise ratio, reproducibility, and dynamic range to monitor the progression of functional changes in the inner retina in DBA/2J mice.

Cited by 101 publications

References 31 publications

Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma

Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

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

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