Abstract
Purpose :
Glaucoma is a key cause of blindness worldwide that results from the death of retinal ganglion cells (RGCs). Due to the many subtypes of the disease, accurately modeling it in animals remains a challenge. The purpose of this study was to identify and characterize a novel mouse strain, specifically the BXD50 strain of mice, as a reliable model to mimic the development and progression of human primary open-angle glaucoma (POAG).
Methods :
Using archived data on axon counts, optic nerve (ON) degeneration, and intraocular pressure (IOP) in the BXD family of mice, multiple strains were selected for a possible POAG phenotype. Strains bearing the DBA/2J (D2) haplotype of Gpnmb and Tyrp1, which induce pigmentary dispersion glaucoma, were excluded from further analysis. BXD50 was chosen as the best POAG candidate and was subjected to anatomical/functional analyses including optokinetic nystagmography (OKN) to measure visual acuity/contrast sensitivity (VA/CS), IOP measurements, full field and pattern electroretinograms (ERG/PERG), and optical coherence tomography (OCT). These measurements were taken every three months from baseline to 12 months of age. At 12 months, animals were euthanized and eyes with optic nerves were paraffin embedded and sectioned for immunohistochemistry (IHC). Parent strains C57B/6J (B6) and D2 also underwent full analyses.
Results :
IOP data was normal for B6 through 12 mos while the D2 and BXD50 had significant increases in IOP by 12 months of age. OKN analysis showed age-dependent VA losses in all strains while only D2 and BXD50 had a loss of CS. Iridocorneal angle OCT showed 0% closure in B6 and BXD50 strains at all ages while the D2 strain showed 45% closure at 6 mos with 100% closure at 12 mos. All strains show ERG and PERG wave amplitude decreases with age, though D2 and BXD50 had lower amplitudes than B6 at baseline through 12 mos. IHC showed decreases in markers of RGC dendrites and axons (microtubule-associated protein 1A (MAP1A), microtubule-associated protein 2 (MAP2), and b-tubulin 3(TUBB3)) in D2 and BXD50 when compared to B6.
Conclusions :
BXD50 mice exhibited phenotypes consistent with those of POAG including significant increases in IOP, decreases in VA, CS, ERG/PERG amplitudes and markers of RGCdendrites/axons while maintaining an open iridocorneal angle. These findings suggest that BXD50 may act as a promising animal model for the progression of POAG.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.