Optic Neuropathy Due to Microbead-Induced Elevated Intraocular Pressure in the Mouse

Glaucoma is a leading cause of blindness worldwide.1 It is characterized by progressive loss of retinal ganglion cells (RGCs), atrophy of optic nerve, and eventual loss of vision.2,3 Although it is known that elevation of intraocular pressure (IOP) is a major risk factor for glaucoma,4 the pathophysiology of the disease remains poorly understood. Current therapy that is directed at lowering IOP cannot completely stop the progression of the disease.5 Thus, further elucidating the mechanisms underlying RGC degeneration and developing new therapies that can prevent or delay progressive optic neuropathy in glaucoma are of critical importance. Progress in understanding the pathogenesis of glaucoma has been largely hampered by the lack of an inducible mouse model of glaucoma. Animal models of glaucoma that simulate the RGC and optic nerve pathology in the human disease are of considerable importance in elucidating the mechanisms of the disease and in evaluating therapies. Although mouse models of glaucoma are uniquely useful because of the development of mouse genetic technology,6 the small size of the mouse eye has made both the induction and the measurement of IOP elevation challenging. In recent years, mice carrying spontaneous mutations that result in chronic age-related glaucoma, such as DBA/2J mice, have been documented.7–9 A distinguishing feature of DBA/2J mice is the development of iris illumination defects associated with pigment dispersion into the anterior chamber and accumulation of pigment granules in the trabecular meshwork that block the drainage system and lead to IOP elevation.8 However, although these are inbred mice carrying a fixed genetic background, they exhibit a high degree of individual variability and asymmetry in disease development.10 Moreover, use of DBA/2J mice has been limited by the difficult and lengthy process of introducing genetic mutations or applying mouse genetic technologies to this mouse line. Development of an effective and reproducible method of inducing chronic IOP elevation and glaucomatous neurodegeneration in mice would prove to be extremely useful.11 A well-studied method for inducing IOP elevation in animals such as monkeys and rats is the application of laser burns to outflow tissues.12 Inducible models of glaucoma in mice have also been reported, using laser photocoagulation of episcleral veins13,14 or sclerosis of episcleral veins by injecting hypertonic saline15 to obstruct aqueous humor outflow. Complications of these methods include thermal damage to the sclera, induction of intraocular inflammation, and irreversible ocular surface damage. Moreover, the small size of the mouse eye poses significant difficulties in applying these approaches to induce consistent elevations of IOP and in using a variety of conventional technologies. A recent study16 described a simple and reproducible means to elevate IOP in the rodent eye by injection of polystyrene microbeads into the anterior chamber. Here, to further develop and characterize a glaucoma model in mice, we applied a modified version of this protocol to elevate IOP and reported that this method induced RGC and axon degeneration similar to that in glaucoma.