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Editors Selection IGR 15-1
Experimental Glaucoma: Inner retinal cell and RGC loss in glaucoma
Comment by Andrew Huberman on:
53129 Elevated intraocular pressure causes inner retinal dysfunction before cell loss in a mouse model of experimental glaucoma, Frankfort BJ; Khan AK; Tse DY et al., Investigative Ophthalmology and Visual Science, 2013; 54: 762-770
What are the changes in retinal structure and function that occur in glaucoma and how can our understanding about the nature and timing of those changes be used to better detect and treat the disease? Many groups are now adopting the 'microbead occlusion model' developed by Calkins and co-workers1 to experimentally mimic glaucoma in laboratory animals. The bead model has many advantages, not the least of which is the fact that it recreates the modest increases in intraocular pressure and gradual loss of retinal ganglion cells (RGCs) observed in many glaucoma patients. This in turn opens the door for careful investigation of anatomical and electrophysiological changes that occur in the retina and brain at various stages of the disease.
Frankfort et al. Used a modified version of the bead model to discover that shortly after IOP elevation and long before RGCs start dying, the b-wave of the electroretinogram (ERG) is significantly increased. The authors attribute this increase to alterations in amacrine cell and/or RGC function. They speculate that altered inhibitory feedback from a particular type of amacrine cell- the AII amacrine, onto bipolar cells is the culprit. In addition to providing careful quantitation of the timing and degree of RGC loss caused by modest and long-lasting IOP elevation, this study adds to a growing number of findings that RGC loss is a relatively late consequence of glaucoma that follows defects in RGC axonal transport2 and dismantling of inner retinal circuitry. Indeed, the findings of Frankfort et al., point to the distinct possibility that RGC dysfunction and loss in glaucoma may actually be a secondary effect of changes that occur in amacrine or bipolar cells. If so, that would challenge the simple notion of glaucoma as a 'ganglion cell disease'.
RGC dysfunction and loss in glaucoma may actually be a secondary effect of changes that occur in amacrine or bipolar cells. If so, that would challenge the simple notion of glaucoma as a 'ganglion cell disease'
It is now crucial to pinpoint the exact nature of the earliest defects in glaucoma. Does elevated pressure cause AII-amacrines to lose synapses and if so, is that because RGCs are sick? Or do amacrines initiate the cascade of RGC injury? The answers to these questions await experimental evaluation. Fortunately, there are now dozens of commercially available immunohistochemical and genetic tools for probing the structure and function of specific retinal cell types at high resolution.3 Such tools should greatly aid that effort to answer these and related questions. Discovering which cell types are the first to take a hit in glaucoma should eventually lead to enhanced detection and treatments for the disease. One can imagine designing visual field tests that probe the health of these specific cells. A non-mutually exclusive approach would be to develop imaging tools and probes to visualize and count specific retinal cell types in the intact human eye during routine eye exams.
References
- Sappington RM, Carlson BJ, Crish SD, Calkins DJ. The microbead occlusion model: a paradigm for induced ocular hypertension in rats and mice. Invest Ophthalmol Vis Sci 2010; 51(1): 207-216
- Calkins DJ, Horner PJ. The cell and molecular biology of glaucoma: axonopathy and the brain. Invest Ophthalmol Vis Sci 2012; 53(5): 2482-1484
- Siegert S, Scherf BG, Del Punta K, Didkovsky N, Heintz N, Roska B. Genetic address book for retinal cell types. Nat Neurosci 2009; 12(9): 1197-1204
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