Glaucoma, a progressive optic neuropathy characterised by the loss of retinal ganglion cells (RGC), is one of the leading causes of irreversible blindness worldwide, with a global prevalence of 3.54% (Tham et al., 2014). As the world population ages, the number of people affected is expected to increase to more than 110 million by 2040. The disease is complex, multifactorial and encompasses numerous subtypes, with primary open angle glaucoma (POAG) being the most common. Many risk factors have been implicated, including ageing, high intraocular pressure (IOP), thin central corneal thickness, decreased ocular blood flow and myopia. In particular, the genetic component of glaucoma pathogenesis is well recognized, with more than half of all POAG patients reporting a positive family history and first degree relatives have an approximately 10-fold increased risk of developing glaucoma compared to the general population (Wolfs et al., 1998).

Over the past decade, genome wide association studies (GWAS) have identified a myriad of single-nucleotide polymorphism (SNPs) that are linked to glaucoma. However, the vast majority of SNPs are located in non-coding regions of the genome and may confer disease risk by exerting regulatory effects on other genes, including distant ones beyond their immediate loci. The potential multiple interactions between various susceptibility genes make it challenging to assign causality to any specific variant among the large numbers detected by GWAS studies. Nevertheless, they are still useful in identifying potential genes and pathways involved in disease pathogenesis.

While in vitro assays can be used to validate new candidate genes for glaucoma, animal models are still critical to provide proof of causative phenotype. Not only do they enable the study of how a particular gene and/or pathway can contribute to disease physiology, animal models also create a platform for pre-clinical development and testing of potential disease therapies. Various animal models have been utilised to understand glaucoma disease mechanisms, including mice, rats, rabbits, chickens, dogs, monkeys, and zebrafish (Iglesias et al., 2015). Rodents, in particular mice, have been favoured due to their fecundity and comparatively short life cycles. Furthermore, the genomes of rodents and humans are highly conserved, and the murine eye largely recapitulates human ocular anatomy and physiology. Rodents are also amenable to genetic and experimental manipulation, allowing for the creation of transgenic animals with specific human disease alleles and conditional knockouts. However, rodent models do have their limitations. Firstly, there are a few anatomical differences between the murine and human eye. For instance, unlike humans, mouse eyes lack a collagenous lamina cribosa, but instead contain astrocytes that organise into glial lamina (Howell et al., 2007). There are also significant differences in the structure of the retina between humans and rodents. For example, rodent retinas do not possess a fovea and hence have a slightly different neuronal circuitry (Huberman and Niell, 2011; Volland et al., 2015). Mice also contain a large number of displaced amacrine cells in the RGC layer (Pérez De Sevilla Müller et al., 2007). Furthermore, the small size of rodent eyes render certain experimental procedures technically challenging. Nevertheless, rodent models have been an indispensable tool in the study of human ocular disease.

Rodent models fall into two categories: inducible models of glaucoma and genetically modified animals. For the former, various techniques have been employed to simulate glaucomatous optic nerve damage, either by pressure dependent mechanisms (such as intracameral injection of magnetic microbeads and sclerosis of aqueous outflow pathways) or pressure independent methods such as optic nerve crush (Pang and Clark, 2020). In this review, however, we will only focus on genetic rodent models of glaucoma and how they have illuminated disease mechanisms that contribute to the pathogenesis of various glaucoma subtypes.