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Editors Selection IGR 23-4

Basic Science: learnings from a classic rodent model

Comment by Robert Nickells on:

108575 Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis, Amato R; Cammalleri M; Melecchi A; Melecchi A et al., Cells, 2023; 12:

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Progressive degeneration of the optic nerve and retinal ganglion cells (RGCs) is a hallmark of glaucomatous pathology. While there is consensus that an increase in intraocular pressure (IOP) above physiological levels is the major initiator of pathology, principally at the level of the optic nerve head, there is still uncertainty of what the actual pathological mechanisms are that elicit the degenerative response. Enter our limited understanding of the roles that glial cells have in both moderating and exasperating these signals. The retina and optic nerve combined contain at least four different glial cell populations, including astrocytes, Muller cells, microglia/monocytes, and oligodendrocytes. All these cells are likely important actors in this overall process, creating a complex dance that is only slowly being dissected in our quest to understand the link between IOP-induced mechanical stress and RGC pathology.

Amato and colleagues have tackled this dissection by correlating four metrics of (1) IOP change; (2) RGC loss; (3) macroglial (astrocyte and Muller cell) reactivity; and (4) vascular changes over a time course of glaucomatous pathology in the DBA/2J mouse model. Progression of pathology in DBA/2J mice has been studied for over 20 years. These animals exhibit an increase in IOP beginning at seven to eight months of age with optic nerve degeneration and RGC loss quickly following suit. By ten months of age, at least 40% of eyes have reached end-stage disease and by 15 months, most eyes are severely affected.^1,2 The group assessed changes of each of these four metrics in groups of DBA/2J mice at the ages of two, six, ten, and 15 months, thereby bracketing the major period of IOP increase. They found that ocular hypertension correlates with RGC loss, astrocyte reactivity, and vascular pathology including a breakdown of the blood retinal barrier as a function of ZO-1 decreases. Importantly, they observed Muller cell reactivity and the production of HIF-1a and VEGF at six months of age, two factors that can contribute to vascular permeability. Collectively, the authors suggest that non-IOP related factors are contributing to RGC pathology, although the precise role of Müller cells in this process, whether being an early protective event or a pathological event remain to be elucidated.

This study is compelling, showing a potential contribution of Müller cells changes that precede statistically significant elevations in IOP

There are some caveats associated with this work that should be kept in mind when considering it. Firstly, DBA/2J glaucoma is both highly variable and asymmetric^1,2 and relatively few eyes were actually used for each set of experiments. When making comparisons between two or more metrics, it is important not to use generalized data and instead use stratified comparisons (one eye for two metrics compared, etc.). Secondly, the critical time points of IOP elevation were not included in the study, which may have an impact on interpretation. Thirdly, any evaluation of glial responses in glaucoma should consider reactivity of microglia. In the DBA/2J model, for example, microglial responses have been reported as early as 3 months of age.³ Fourthly, the authors used GFAP staining as the single marker of glial reactivity. While this often appears in the literature, it does not appreciate the complexity of the reactive response and instead assumes that glial cells respond monolithically and not as a continuum of varying phenotypes.⁴ Nevertheless, this study is compelling, showing a potential contribution of Muller cells changes that precede statistically significant elevations in IOP.

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