Quantification of deficits in spatial visual function of mouse models for glaucoma.

Glaucoma is a major leading cause of blindness worldwide and is defined as a heterogeneous group of optic neuropathies manifesting as progressive damage to the optic nerve head (ONH), irreversible loss of retinal ganglion cells (RGCs), and ultimately visual field loss.1–5 Glaucoma has a distinctive pattern of visual field loss for which increased intraocular pressure (IOP) is an important risk factor.4,6 The molecular mechanisms of glaucoma are still poorly understood, and elevated IOP is the only variable risk factor.7 Thus, current medical treatments for glaucoma solely target increased IOP. Rodents represent a smaller, inexpensive alternative to animal models such as the Argon laser-induced monkey and rabbit models and have similar optic nerve morphology to humans. DBA/2J mice8 are the standard, most widely published, and well-characterized preclinical glaucoma model, which spontaneously developed mutations resulting in chronic age-related pigmentary glaucoma that shares many similarities with the human condition.9 Disease onset in DBA/2J mice can vary, largely depending on environmental factors.8,10 IOP levels are reported to increase linearly between 2 and 10 months of age;11 however, similar to human pigmentary glaucoma,12 not all DBA/2J mice display elevated IOP with age.11 Interestingly, however, animals with elevated IOP levels display a similar loss of RGC axons and increased corneal thickness regardless of age.11 In addition to elevated IOP levels, DBA/2J mice suffer iris disease that typically manifests at 6–8 months of age9 as well as progressive structural changes that include the thinning of the inner and outer retina as well as a reduction of the ONH width by 11 months of age.5 Furthermore, DBA/2J mice show deficits in axonal transport that occur early during the disease (at 3 to 5 months of age)13 as well as optic nerve degeneration resulting from elevated IOP and progressively diminishing metabolic capacity.14 Given that glaucomatous retinopathy directly affects visual performance and that DBA/2J mice are the best characterized of glaucoma mouse models, it is surprising that visual function has not been investigated in this strain in more detail. Therefore, one aim of this study was to provide a detailed report of visual function and the visuospatial responses of DBA/2J mice. Visual function can be measured in rodents by exploiting two natural reflexes: eye movement (optokinetic nystagmus) and head movement (optomotor tracking), in response to rotating stimuli of black gratings against a white background.15 In our experiments, we used a specific optokinetic testing apparatus for mice15–17 to investigate visual acuity and contrast sensitivity in DBA/2J mice. Many isogenic substrains of DBA/2 mice exist; however, these have not been studied in the context of glaucoma. For instance, DBA/2NHsd mice have not been investigated for much other than chronic infection.18,19 Therefore, the second aim of this study was to characterize and compare the IOP and visual function of DBA/2NHsd mice with DBA/2J mice, to determine whether the DBA/2NHsd mice may be suitable as a complementary glaucoma mouse model. The present study reports the behavioral outcomes of glaucomatous retinopathy in two substrains of DBA/2 mice using a comprehensive, noninvasive assessment of the full visual system. This knowledge will enable the broader use of these genetic glaucoma models in future studies investigating long-term sustainability of benefits from and efficacy of novel antiglaucoma therapies in longitudinal studies.