Article

Quantification of Deficits in Spatial Visual Function of Mouse Models for Glaucoma

Department of Ophthalmology, University of Missouri - Kansas City, Kansas City, Missouri, United States
Investigative ophthalmology & visual science (Impact Factor: 3.66). 02/2011; 52(6):3654-9. DOI: 10.1167/iovs.10-7106
Source: PubMed

ABSTRACT DBA/2J mice are a standard preclinical glaucoma model, which spontaneously developed mutations resulting in chronic age-related pigmentary glaucoma. The goals of this study were to identify the degree of visual impairment in DBA/2J mice before and after disease onset by quantifying the optokinetic reflex responses and to compare them to the less-researched strain of DBA/2NHsd mice.
Visual performance was measured in healthy, nonglaucomatous, and glaucomatous male DBA/2NHsd or DBA/2J mice using a visuospatial testing box. The optokinetic reflex resulting in optomotor head tracking was manually detected. Measured threshold levels equate to the maximum contrast or spatial frequency the mouse responds to. Intraocular pressure (IOP) was measured by applanation tonometry.
IOP increased with age in both DBA/2J and DBA/2NHsd mice and was not different between the two substrains. Both visual acuity and ability to detect contrast decreased significantly, and similarly with age in both substrains. However, DBA/2NHsd had poorer visual acuity even at a younger age compared to age-matched DBA/2J mice.
Both DBA/2J and DBA/2NHsd mice show a progressive glaucomatous phenotype of age-related increases in IOP and loss of visual acuity and contrast sensitivity when compared to other inbred or outbred strains. Given the similar increases in IOP and contrast sensitivity threshold and loss of visual acuity between these two DBA/2 substrains, we also conclude that DBA/2NHsd mice are a suitable alternative model for pigmentary glaucoma.

0 Followers
 · 
100 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular pathways contributing to visual signal transduction in the retina generate a high energy demand that has functional and structural consequences such as vascularization and high metabolic rates contributing to oxidative stress. Multiple signaling cascades are involved to actively regulate the redox state of the retina. Age-related processes increase the oxidative load, resulting in chronically elevated levels of oxidative stress and reactive oxygen species, which in the retina ultimately result in pathologies such as glaucoma or age-related macular degeneration, as well as the neuropathic complications of diabetes in the eye. Specifically, oxidative stress results in deleterious changes to the retina through dysregulation of its intracellular physiology, ultimately leading to neurodegenerative and potentially also vascular dysfunction. Herein we will review the evidence for oxidative stress-induced contributions to each of the three major ocular pathologies, glaucoma, age-related macular degeneration, and diabetic retinopathy. The premise for neuroprotective strategies for these ocular disorders will be discussed in the context of recent clinical and preclinical research pursuing novel therapy development approaches.
    International Journal of Molecular Sciences 02/2014; 15(2):1865-86. DOI:10.3390/ijms15021865 · 2.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroprotection in glaucoma as a curative strategy complementary to current therapies to lower intraocular pressure (IOP) is highly desirable. This study was designed to investigate neuroprotection by 17β-estradiol (E2) to prevent retinal ganglion cell (RGC) death in a glaucoma model of surgically elevated IOP in rats. We found that daily treatment with E2-containing eye drops resulted in significant E2 concentration in the retina with concomitant profound neuroprotective therapeutic benefits, even in the presence of continually elevated IOP. The number of apoptotic cells in the RGC layer was significantly decreased in the E2-treated group, when compared to the vehicle-treated controls. Deterioration in visual acuity in these animals was also markedly prevented. Using mass spectrometry-based proteomics, beneficial changes in the expression of several proteins implicated in the maintenance of retinal health were also found in the retina of E2-treated animals. On the other hand, systemic side effects could not be avoided with the eye drops, as confirmed by the measured high circulating estrogen levels and through the assessment of the uterus representing a typical hormone-sensitive peripheral organ. Collectively, the demonstrated significant neuroprotective effect of topical E2 in the selected animal model of glaucoma provides a clear rationale for further studies aiming at targeting E2 into the eye while avoiding systemic E2 exposure to diminish undesirable off-target side effects.
    Molecular Pharmaceutics 07/2013; 10(8):3253–3261. DOI:10.1021/mp400313u · 4.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: The rd12 mouse was reported as a recessively inherited Rpe65 mutation. We asked if the rd12 mutation resides in Rpe65 and how the mutation manifests. Methods: A complementation test was performed by mating Rpe65(KO/KO) (KO/KO) and rd12/rd12 mice together. Visual function of wild type (+/+), KO/+, rd12/+, KO/KO, rd12/rd12, and KO/rd12 mice was measured by OKT and ERG. Morphology was assessed by retinal cross section. qRT-PCR quantified Rpe65 mRNA levels. Immunoblotting measured the size and level of RPE65 protein. Rpe65 mRNA localization was visualized with fluorescence in situ hybridization (FISH). Fractions of Rpe65 mRNA-bound proteins were separated by linear sucrose gradient fractionation. Results: The KO and rd12 alleles did not complement. The rd12 allele induced a negative semidominant effect on visual function; OKT responses became undetectable 120 days earlier in rd12/rd12 mice compared to KO/KO mice. rd12/+ mice lost ~21% visual acuity by P210. rd12/rd12 mice had fewer cone photoreceptor nuclei than KO/KO mice at P60. rd12/rd12 mice expressed 71% +/+ levels of Rpe65 mRNA, but protein was undetectable. Mutant mRNA was appropriately spliced, exported to the cytoplasm, trafficked, and contained no other coding mutation aside from the known nonsense mutation. Mutant mRNA was enriched on ribosome-free messenger ribonucleoproteins (mRNPs) while wild type mRNA was enriched on actively translating polyribosomes. Conclusions: The rd12 lesion is in Rpe65. The rd12 mutant phenotype inherits in a semidominant manner. The effects of the mutant mRNA on visual function may result from inefficient binding to ribosomes for translation.
    Investigative ophthalmology & visual science 03/2014; 55(4). DOI:10.1167/iovs.13-13574 · 3.66 Impact Factor

Full-text (2 Sources)

Download
6 Downloads
Available from
Feb 19, 2015