Abstract
Purpose :
Glaucoma is a key cause of blindness worldwide that results from the death of retinal ganglion cells (RGCs). Due to many subtypes of glaucoma, accurate animal models remain a challenge. The purpose of this study was to identify and characterize a novel mouse strain, specifically the BXD87 strain of mice, as a reliable model to mimic the development and progression of human normotensive glaucoma (NTG).
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 possible NTG phenotype. Strains with the DBA/2J (D2) haplotype of Gpnmb and Tyrp1, which induce pigmentary dispersion glaucoma, were excluded from further analysis. BXD87 was chosen as the best candidate for NTG and was subjected to anatomical/functional analysis 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 C57/B16 (B6) and DBA/2J (D2) also underwent full analyses. Statistical analyses were performed using ordinary one-way ANOVA.
Results :
IOP data was normal for B6 and BXD87 through 12 mos while the D2 had significant increase in IOP starting at 9 mos. OKN analysis showed age-dependent VA losses in all strains while only D2 and BXD87 had losses in CS. Iridocorneal angle OCT showed 0% closure in B6 and BXD87 strains at all ages while 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 BXD87 had lower amplitudes than B6 at baseline through 12 mos. When compared to B6 mice, D2 and BXD87 mice showed decreased expression of Microtubule-associated protein 1A (MAP1A), Microtubule-associated protein 2 (MAP2), and Beta-tubulin 3 (TUBB3).
Conclusions :
BXD87 mice exhibited phenotypes consistent with those of NTG including normotensive IOP, decreases in VA, CS, ERG/PERG amplitudes, and markers of RGC dendrites/axons while maintaining an open iridocorneal angle. These findings suggest that BXD87 may act as a promising animal model for the progression of NTG.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.