The bugeye mutant zebrafish exhibits visual deficits that arise with the onset of an enlarged eye phenotype.

Glaucoma comprises a heterogeneous group of disorders that progressively lead to blindness due to loss of retinal ganglion cells (RGCs) and damage to the optic nerve.1 It is the second leading cause of blindness and the leading cause of irreversible blindness worldwide.2–4 Mutations in single genes, such as myocilin, have been found to be associated with an increased prevalence in one type of glaucoma (primary open-angle glaucoma, or POAG).5 However, it is now clear that glaucoma is a complex eye disease resulting from a confluence of multiple alleles and environmental factors.6 Nonetheless, both human glaucoma and mammalian glaucoma models are characterized by important risk factors. These include elevated intraocular pressure, age, family history, and myopia. While there is substantial evidence of the importance of elevated intraocular pressure (IOP) as a significant risk factor for and cause of glaucomatous pathologies, the importance of the relationship between glaucoma and myopia is not well understood. Based on correlation studies in patients with POAG, after controlling for elevated intraocular pressure, myopia has been identified as a significant risk factor.7 Several independent studies have supported this conclusion,8,9 but another study has reported no correlation between glaucoma and myopia,10 possibly because they did not account for the degree of myopia.11 The exact link between myopia and POAG pathology remains unknown, and there is currently no animal model in which this relationship has been investigated. The zebrafish is an attractive model with which to study glaucoma phenotypes because of its fast development and the similarity of its nervous system, including the retina, to that of other vertebrates.12 One of the major advantages is the precedence of well-established methods of studying retinal function and vision in the zebrafish.13 The zebrafish is a highly visual animal with several well-characterized visually driven behaviors, which are more robust and innate than similar behaviors in the nocturnal mouse. These behaviors include the optokinetic reflex (OKR), optomotor response (OMR), prey capture, visual startle response, and the escape response.14,15 Another important advantage is the availability of genetically altered mutant zebrafish, such as the bugeye mutant. The bugeye mutant exhibits several glaucoma-like phenotypes, which include elevated intraocular pressure and enlarged eyes, resembling buphthalmos (John SW, et al. IOVS 2003;44:ARVO E-Abstract 1125).16 In this study, we further characterized this mutant and investigated the progressive loss of visual function by electrophysiology and visual behavioral testing. Using histologic techniques, we also demonstrated that the bugeye mutant exhibits a substantial loss of RGCs and significant thinning of all the cellular layers of the retina. In addition bugeye mutants exhibit a high degree of myopia that is associated with the enlarged eye phenotype. Thus, the bugeye mutant provides an opportunity for the study of several aspects of glaucoma, especially myopia-associated glaucoma.