Characteristic Patterns of Dendritic Remodeling in Early-Stage Glaucoma: Evidence from Genetically Identified Retinal Ganglion Cell Types

El-Danaf, Rana N.; Huberman, Andrew D.

doi:10.1523/jneurosci.1419-14.2015

Cited by 201 publications

(238 citation statements)

References 53 publications

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“…The magnitude of this shift is similar to that seen by other investigators using similar methods (8). These changes could arise from IOP-induced alteration of the RGC dendrites in the OFF sublaminae (8,23,24). In addition to the RGC dendrites, other upstream retinal cell types, such as BCs or amacrine cells (ACs), are thought to mediate IOPinduced functional changes to RGCs (11).…”

Section: Discussionsupporting

confidence: 77%

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: Discussionsupporting

confidence: 77%

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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“…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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“…In many of these models, glaucoma is induced by disrupting aqueous humour dynamics, resulting in the elevation of IOP. Occlusion models, in which microbeads or other substances are injected into the anterior chamber of the eye to block aqueous drainage, have gained popularity in recent years partly due to their relative ease to increase IOP [4][5][6][7][8][9][10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice

Itō

Belforte

Vargas

et al. 2016

JoVE

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The use of rodent models of glaucoma has been essential to understand the molecular mechanisms that underlie the pathophysiology of this multifactorial neurodegenerative disease. With the advent of numerous transgenic mouse lines, there is increasing interest in inducible murine models of ocular hypertension. Here, we present an occlusion model of glaucoma based on the injection of magnetic microbeads into the anterior chamber of the eye using a modified microneedle with a facetted bevel. The magnetic microbeads are attracted to the iridocorneal angle using a handheld magnet to block the drainage of aqueous humour from the anterior chamber. This disruption in aqueous dynamics results in a steady elevation of intraocular pressure, which subsequently leads to the loss of retinal ganglion cells, as observed in human glaucoma patients. The microbead occlusion model presented in this manuscript is simple compared to other inducible models of glaucoma and also highly effective and reproducible. Importantly, the modifications presented here minimize common issues that often arise in occlusion models. First, the use of a bevelled glass microneedle prevents backflow of microbeads and ensures that minimal damage occurs to the cornea during the injection, thus reducing injury-related effects. Second, the use of magnetic microbeads ensures the ability to attract most beads to the iridocorneal angle, effectively reducing the number of beads floating in the anterior chamber avoiding contact with other structures (e.g., iris, lens). Lastly, the use of a handheld magnet allows flexibility when handling the small mouse eye to efficiently direct the magnetic microbeads and ensure that there is little reflux of the microbeads from the eye when the microneedle is withdrawn. In summary, the microbead occlusion mouse model presented here is a powerful investigative tool to study neurodegenerative changes that occur during the onset and progression of glaucoma.

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Characteristic Patterns of Dendritic Remodeling in Early-Stage Glaucoma: Evidence from Genetically Identified Retinal Ganglion Cell Types

Cited by 201 publications

References 53 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

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice

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