Abstract
Purpose :
Glaucoma, a disorder characterized by optic neuropathy, is a leading cause of blindness worldwide. Due to the multiple forms of glaucoma, modeling the disease with precision in animals can be challenging. This study aims to establish the novel BXD51 mouse strain from the heterogeneous polygenic BXD family as a model to represent the progression of primary closed angle glaucoma (PCAG) in humans.
Methods :
To select BXD strains for a possible PCAG phenotype, data on intraocular pressure (IOP), number of axons, and optic neuropathy were assessed. We selected against strains with the pigmentary dispersion-inducing Gpnmb and Tyrp1 mutations.
BXD51 mice were chosen as the best PCAG candidate and, every 3 months from 1 month to 12 months of age, were subjected to anatomical/functional analyses including full field and pattern electroretinograms (ERGs/PERGs), visual acuity/contrast sensitivity (VA/CS) assessments by optokinetic nystamography (OKN), IOP measurements, and optical coherence tomography (OCT). At 12 months of age, the mice were euthanized and eyes with optic nerves were paraffin-embedded and sectioned for immunohistochemistry (IHC). C57B/6J (B6) and DBA/2J (D2) were also analyzed.
Results :
The B6 control exhibited unchanged IOP at 12M, while the D2 and BXD51 mice showed a statistically significant increase in IOP by 12M. OKN showed age-dependent loss of VA in all strains while the D2 and BXD51 mice showed a significant decrease in both VA and CS by 12M. Iridocorneal angle OCT showed 0% closure in B6, while the D2 and BXD51 mice both exhibited 100% closed angles by 12 months. The ERG and PERG amplitudes decreased with age across all strains, D2 and BXD51 showed lower amplitudes than B6 at baseline through 12 months. Compared to B6, IHC and histology showed decreases in markers for RGC dendrites and axons (Microtubule-associated protein 1(MAP1), microtubule-associated protein 2 (MAP2), and Beta-III-Tubulin (TUBB3)) in D2 and BXD51 along with a highly thinned inner plexiform layer and iris-corneal adherence in BXD51.
Conclusions :
The BXD51 strain demonstrated functional and structural similarities to PCAG. BXD51 showed a significant increase in IOP and significant decreases in VA, CS, ERG a and b waves, PERG P1 and N2 waves, IHC, and closure of the iridocorneal angle. These results are suggestive of the inbred strain BXD 51 as an adequate experimental model for PCAG.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.