Differential Progression of Structural and Functional Alterations in Distinct Retinal Ganglion Cell Types in a Mouse Model of Glaucoma

Santina, Luca Della; Inman, Denise M.; Lupien, C.; Horner, Philip J.; Wong, Rachel

doi:10.1523/jneurosci.5461-12.2013

Cited by 231 publications

(328 citation statements)

References 72 publications

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“…The optic nerve has been recognized as the initial site of damage leading to death of RGCs in glaucoma, classifying it as an axogenic disease (1, 2). Emerging evidence, however, indicates that morphological and functional changes in RGCs may occur prior to the optic nerve degeneration (46)(47)(48). Interestingly, the protection afforded to the optic nerve in microbead-injected Cx36 -/-animals is intriguing, in that Cx36 protein is not expressed there, suggestand their CxWT littermates were made under control conditions and then 8 weeks after microbead injection to assess changes in spatial acuity and contrast sensitivity.…”

Section: Cx36mentioning

confidence: 99%

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Akopian¹,

Kumar²,

Ramakrishnan³

et al. 2017

Journal of Clinical Investigation

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The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.

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Section: Cx36mentioning

confidence: 99%

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Akopian¹,

Kumar²,

Ramakrishnan³

et al. 2017

Journal of Clinical Investigation

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“…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)(6)(7). Before these changes, functional properties, such as RGC light sensitivity and photopic receptive field (RF) center size, are altered (8)(9)(10)(11)(12). A better understanding of these functional changes may help to detect human disease before irreversible cell death.…”

mentioning

confidence: 96%

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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“…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).…”

mentioning

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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Differential Progression of Structural and Functional Alterations in Distinct Retinal Ganglion Cell Types in a Mouse Model of Glaucoma

Cited by 231 publications

References 72 publications

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

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

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

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