A Laser-induced Mouse Model of Chronic Ocular Hypertension to Characterize Visual Defects

Abstract

Glaucoma, frequently associated with elevated intraocular pressure (IOP), is one of the leading causes of blindness. We sought to establish a mouse model of ocular hypertension to mimic human high-tension glaucoma. Here laser illumination is applied to the corneal limbus to photocoagulate the aqueous outflow, inducing angle closure. The changes of IOP are monitored using a rebound tonometer before and after the laser treatment. An optomotor behavioral test is used to measure corresponding changes in visual capacity. The representative result from one mouse which developed sustained IOP elevation after laser illumination is shown. A decreased visual acuity and contrast sensitivity is observed in this ocular hypertensive mouse. Together, our study introduces a valuable model system to investigate neuronal degeneration and the underlying molecular mechanisms in glaucomatous mice.

Progressive Degeneration of Retinal and Superior Collicular Functions in Mice With Sustained Ocular Hypertension

“…The procedure of laser illumination has been described previously. 17,18 In brief, 2-to 3-month-old mice were anesthetized by an intraperitoneal injection of ketamine (100 mg/kg; Butler Schein Animal Health, Dublin, OH, USA) and xylazine (10 mg/kg; Lloyd, Inc., Iowa, Shenandoah, IA, USA). Approximately 80 to 100 laser spots (514-nm wavelength and 200-lm diameter, Ultima 2000 SE; Coherent, Inc., Santa Clara, CA, USA) were applied to the corneal limbus of the right eye.…”

“…Approximately 80 to 100 laser spots (514-nm wavelength and 200-lm diameter, Ultima 2000 SE; Coherent, Inc., Santa Clara, CA, USA) were applied to the corneal limbus of the right eye. 17,18 To achieve the long-term ocular hypertension (>10 weeks), we combined laser photocoagulation with microbead injection. One microliter of polystyrene microbeads (10-lm diameter, 14.4 3 10 6 beads/ mL in PBS; Life Technologies, Eugene, OR, USA) was immediately injected into the anterior chamber of the same eye by a Hamilton syringe right after laser illumination.…”

“…6,7 Among the models are episcleral venous occlusion, which induces IOP elevation for several days 8,9 ; injection of polystyrene beads, which leads to IOP elevation for 2 to 4 weeks [10][11][12][13][14] ; and laser photocoagulation of the outflow of aqueous humor, 15,16 which-in our hands-results in IOP elevation for 2 months in mice. 17,18 Progressive RGC loss has been demonstrated in these different models of experimental glaucoma, and many studies suggest that different types of RGCs may respond to the glaucomatous insult differently. 12,14,[18][19][20] In mice, there are more than 20 types of RGCs, each with a unique dendritic morphology and function, 21,22 making it challenging to profile how each RGC type degenerates and dies in experimental glaucoma.…”

Psychophysical testing in rodent models of glaucomatous optic neuropathy

“…Therefore, using the aforementioned behavioral techniques in rodent models that display disease etiology that is similar to humans, such as the DBA/2 mouse, allows us to conduct studies that obtain valuable information on disease mechanisms and therapeutic strategies at considerably lower cost with more data points. We can use these techniques in mice to evaluate therapeutic intervention in rodent models of disease (Adamus et al, 2012; Cahill et al, 2011; Krempler et al, 2011; Savigni et al, 2013), and RGC axon regeneration (de Lima et al, 2012), test variables such as age and gender (van Alphen et al, 2009), neuronal and RGC disease mechanisms in glaucomatous mice (Burroughs et al, 2011; Feng et al, 2013; Kaja et al, 2011), similar to the assessment of visual deficits in other animal models of disease (Pinto et al, 2007; Pinto et al, 2005; Puk et al, 2009; Richards et al, 2008; Roeser and Baier, 2003; Schmucker and Schaeffel, 2006; Umino and Solessio, 2013). Such data contribute to the pre-clinical development of promising therapeutic interventions prior to human clinical trials and benefit from their non-invasive and comprehensive nature resembling many of the aspects of human clinical trials.…”

Age of Rats Seriously Affects the Degree of Retinal Damage Induced by Acute High Intraocular Pressure

“…By now, IOP reduction is the only treatment strategy for all types of glaucoma. 4 In order to investigate the neuropathologic mechanism of glaucoma and develop effective therapeutic interventions, many kinds of experimental glaucoma models were formed by elevating IOP or changing gene MYOC or a1 subunit of collagen type 1 in rats, 6,7 mice, 8,9 monkeys, 10,11 dogs, 12 cats, 12 and several other species. 12 Studies based on these animal models have shown that neuropathology is related with deprivation of target neurotrophic factor, 13,14 oxidative stress, 15,16 mitochondrial dysfunction, 17 excitotoxic damage, [18][19][20] and inflammation, 21 activation of apoptotic signals, 22,23 ischemia.…”