The Contribution of Anterior Segment Abnormalities to Changes in Intraocular Pressure in the DBA/2J Mouse Model of Glaucoma: DBA/2J-Gpnmb +/SjJ Mice as Critical Controls.

Landon J. Rohowetz,R. Scott Duncan,Peter Koulen,Sean M. Riordan,Marc E. Mardelli

doi:10.3389/fnins.2021.801184

Landon J. Rohowetz, R. Scott Duncan + Show 3 more

Open Access

https://doi.org/10.3389/fnins.2021.801184

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Abstract

The contributions of anterior segment abnormalities to the development of ocular hypertension was determined in the DBA/2J mouse model of glaucoma. Intraocular pressure (IOP) was measured non-invasively. Iris pigment dispersion (IPD) and corneal calcification were measured weekly starting at 20 weeks of age in DBA/2J and DBA/2J-Gpnmb+/SjJ mice. Thickness, surface area, auto-fluorescence intensity, and perimeter length of calcified regions were measured in postmortem corneas using confocal microscopy. DBA/2J mice developed elevated IOP between 9 and 12 months of age, but DBA/2J-Gpnmb+/SjJ mice did not. Corneal calcification was found at all ages observed and at similar frequencies in both strains with 83.3% of DBA/2J eyes and 60.0% of DBA/2J-Gpnmb+/SjJ eyes affected at 12 months (P = 0.11). Calcification increased with age in both DBA/2J (P = 0.049) and DBA/2J-Gpnmb+/SjJ mice (P = 0.04) when assessed qualitatively and based on mixed-effects analysis. No differences in the four objective measures of calcification were observed between strains or ages. At 12 months of age, DBA/2J mice with corneal calcification had greater mean IOP than DBA/2J mice without corneal calcification. IOP was not correlated with the qualitatively assessed measures of calcification. For the subset of eyes with ocular hypertension, which were only found in DBA/2J mice, IOP was negatively correlated with the qualitative degree of calcification, but was not correlated with the four quantitative measures of calcification. Differences in IOP were not observed between DBA/2J-Gpnmb+/SjJ mice with and without calcification at any age. IPD increased with age and demonstrated a moderate correlation with IOP in DBA/2J mice, but was not observed in DBA/2J-Gpnmb+/SjJ mice. In the DBA/2J mouse model of glaucoma, increased IPD is positively correlated with an increase in IOP and corneal calcification is present in the majority of eyes at and after age 9 months. However, while IPD causes ocular hypertension, corneal calcification does not appear to contribute to the elevation of IOP, as the control strain DBA/2J-Gpnmb+/SjJ exhibits corneal calcification similar to DBA/2J mice, but does not develop ocular hypertension. Corneal calcification, therefore, does not appear to be a contributing factor to the development of elevated IOP in DBA/2J mice.

Highlights

Glaucoma is characterized by progressive dysfunction and degeneration of the optic nerve and is the leading cause of irreversible blindness worldwide, affecting 64.3 million individuals in 2013 (Tham et al, 2014)
Previous reports indicated that DBA/2J mice exhibit falsely elevated
One possible explanation for this artifact was the presence of calcium deposits on the cornea disrupting rebound tonometry

Summary

Introduction

Glaucoma is characterized by progressive dysfunction and degeneration of the optic nerve and is the leading cause of irreversible blindness worldwide, affecting 64.3 million individuals in 2013 (Tham et al, 2014). A separate iris abnormality, iris stromal atrophy (ISA), occurs as a result of a mutation in the tyrosinase related protein 1 gene (Tyrp1b) (Chang et al, 1999; Anderson et al, 2002; Libby et al, 2005; Howell et al, 2007). Homozygosity for both of these genes accounts for the severe iris abnormalities including ISA and IPD seen in DBA/2J mice (Anderson et al, 2002)

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