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Purpose: The Ts65Dn mouse is the most complete widely available animal model of Down syndrome (DS). Quantitative information was generated about visual function in the Ts65Dn mouse by investigating their visual capabilities by means of electroretinography (ERG) and patterned visual evoked potentials (pVEPs)., Methods: pVEPs were recorded directly from specific regions of the binocular visual cortex of anesthetized mice in response to horizontal sinusoidal gratings of different spatial frequency, contrast, and luminance generated by a specialized video card and presented on a 21-in. computer display suitably linearized by gamma correction., Results: ERG assessments indicated no significant deficit in retinal physiology in Ts65Dn mice compared with euploid control mice. The Ts65Dn mice were found to exhibit deficits in luminance threshold, spatial resolution, and contrast threshold, compared with the euploid control mice. The behavioral counterparts of these parameters are luminance sensitivity, visual acuity, and the inverse of contrast sensitivity, respectively., Conclusions: DS includes various phenotypes associated with the visual system, including deficits in visual acuity, accommodation, and contrast sensitivity. The present study provides electrophysiological evidence of visual deficits in Ts65Dn mice that are similar to those reported in persons with DS. These findings strengthen the role of the Ts65Dn mouse as a model for DS. Also, given the historical assumption of integrity of the visual system in most behavioral assessments of Ts65Dn mice, such as the hidden-platform component of the Morris water maze, the visual deficits described herein may represent a significant confounding factor in the interpretation of results from such experiments.

Mutations in the beta-subunit of cGMP-phosphodiesterase (PDE6beta) can lead to either progressive retinal disease, such as human retinitis pigmentosa (RP), or stationary disease, such as congenital stationary night blindness (CSNB). Individuals with CSNB in the Rambusch pedigree were found to carry the H258N allele of PDE6B (MIM# 180072); a similar mutation was not found in RP patients. This report describes an individual carrying the H258N allele, who presented with generalized retinal dysfunction affecting the rod system and a locus of dysfunction at the rod-bipolar interface. Also described are preclinical studies in which transgenic mice with the H258N allele were generated to study the pathophysiological mechanisms of CSNB. While Pde6b(rd1)/Pde6b(rd1) mice have severe photoreceptor degeneration, as in human RP, the H258N transgene rescued these cells. The cGMP-PDE6 activity of dark-adapted H258N mice showed an approximate three-fold increase in the rate of retinal cGMP hydrolysis: from 130.1 nmol x min(-1) x nmol(-1) rhodopsin in wild-type controls to 319.2 nmol x min(-1) x nmol(-1) rhodopsin in mutants, consistent with the hypothesis that inhibition of the PDE6beta activity by the regulatory PDE6gamma subunit is blocked by this mutation. In the albino (B6CBA x FVB) F2 hybrid background, electroretinograms (ERG) from H258N mice were similar to those obtained from affected Rambusch family members, as well as humans with the most common form of CSNB (X-linked), demonstrating a selective loss of the b-wave with relatively normal a-waves. When the H258N allele was introduced into the DBA background, there was no evidence of selective reduction in b-wave amplitudes; rather a- and b-wave amplitudes were both reduced. Thus, factors other than the PDE6B mutation itself could contribute to the variance of an electrophysiological response. Therefore, caution is advisable when interpreting physiological phenotypes associated with the same allele on different genetic backgrounds. Nevertheless, such animals should be of considerable value in further studies of the molecular pathology of CSNB.

Purpose: To report a novel mouse model of achromatopsia with a cpfl3 mutation found in the ALS/LtJ strain., Methods: The effects of a cpfl3 mutation were documented using fundus photography, electroretinography (ERG), and histopathology. Genetic analysis was performed using linkage studies and PCR gene identification., Results: Homozygous cpfl3 mice had poor cone-mediated responses on ERG at 3 weeks that became undetectable by 9 months. Rod-mediated waveforms were initially normal, but declined with age. Microscopy of the retinas revealed progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers showed progressive loss of labeling for alpha-transducin, but the cone outer segments in the oldest mice examined remained intact and positive with peanut agglutinin (PNA). The cpfl3 mapped to mouse chromosome 3 at the same location as human GNAT2, known to cause achromatopsia. Sequence analysis revealed a missense mutation due to a single base pair substitution in exon 6 in cpfl3., Conclusions: The Gnat2(cpfl3) mutation leads to cone dysfunction and the progressive loss of cone alpha-transducin immunolabeling. Despite a poor cone ERG signal and loss of cone alpha-transducin label, the cones survive at 14 weeks as demonstrated by PNA staining. This mouse model of achromatopsia will be useful in the study of the development, pathophysiology, and treatment of achromatopsia and other cone degenerations. The gene symbol for the cpfl3 mutation has been changed to Gnat2(cpfl3).

Recent advances in genetic technologies have greatly accelerated our ability to find disease-related genes and to generate animal models. The availability of ocular tissues with known genetic diseases are greatly contributing to our understanding of retinal disease processes including age-related macular degeneration (AMD), and panretinal and cone degenerations. While the macula is a highly specialised area of the retina not present in many mammals, the use of animal models such as mouse strains will give basic physiology and visual processing genetics relevant to human AMD. This review aims to provide a framework for better understanding some of the existing animal models and the knowledge that has been derived from their evaluations.

Purpose: To report the phenotype and characterization of a new, naturally occurring mouse model of hereditary retinal degeneration (rd12)., Methods: The retinal phenotype of rd12 mice were studied using serial indirect ophthalmoscopy, fundus photography, electroretinography (ERG), genetic analysis including linkage studies and gene identification, immunohistochemistry, and biochemical analysis., Results: Mice homozygous for the rd12 mutation showed small punctate white spots on fundus examination at 5 months of age. The retina in the rd12 homozygote had a normal appearance at the light microscopic level until 6 weeks of age when occasional voids appeared in the outer segments (OS) of the photoreceptor (PR) cells. The outer nuclear layer (ONL) appeared normal until 3 months of age though more obvious voids were detected in the OS. By 7 months of age, 6 to 8 layers of ONL remained in the mutant retina, and the OS were obviously shorter. The first sign of retinal degeneration was detected at the electron microscopic level around 3 weeks of age when occasional small lipid-like droplets were detected in the retinal pigment epithelium (RPE). By 3 months of age, much larger, lipid-like droplets accumulated in RPE cells accompanied by some OS degeneration. While the histology indicated a relatively slow retinal degeneration in the rd12 homozygous mutant mice, the rod ERG response was profoundly diminished even at 3 weeks of age. Genetic analysis showed that rd12 was an autosomal recessive mutation and mapped to mouse chromosome 3 closely linked to D3Mit19, a location known to be near the mouse Rpe65 gene. Sequence analysis showed that the mouse retinal degeneration is caused by a nonsense mutation in exon 3 of the Rpe65 gene, and the gene symbol for the rd12 mutation has been updated to Rpe65rd12 to reflect this. No RPE65 expression, 11-cis retinal, or rhodopsin could be detected in retinas from rd12 homozygotes, while retinyl esters were found to accumulate in the retinal pigment epithelium (RPE)., Conclusions: Mutations in the retinal pigment epithelium gene encoding RPE65 cause an early onset autosomal recessive form of human retinitis pigmentosa, known as Leber congenital amaurosis (LCA), which results in blindness or severely impaired vision in children. A naturally arising mouse Rpe65 mutation provides a good model for studying the pathology of human RPE65 mutations and the effects of retinyl ester accumulation.

Purpose: To characterize the phenotype and report a reliable genetic model of retinal angiogenesis and subretinal neovascularization in the mouse., Methods: The mouse phenotype was characterized using ophthalmoscopy, fundus photography, fluorescein angiography, electroretinography, histology, gene sequencing, and linkage analysis., Results: Scattered pink-gray retinal lesions were found on ophthalmoscopy and were confirmed to be subretinal neovascularization on fluorescein angiography. On histologic examination, outer plexiform retinal neovascularization with growth into the subretinal space was found as early as postnatal Day 15. On genetic analysis, homozygosity of the Vldlr mutation always segregated with the retinal angiogenesis, whereas normal and heterozygous mice had no neovascularization. The histologic studies 15 to 18 days consistently showed new outer plexiform neovascular vessels drawn to the subretinal space by 20 days, and by 30 to 50 days, subretinal hemorrhages and choroidal anastomoses were common. Mice by 8 months had increased vascularity of the iris and ciliary body., Conclusions: The Vldlr mutation in the mouse provides a good model for retinal angiogenesis and subretinal neovascularization. Finding a strong association between retinal angiogenesis and a very low density lipid receptor mutation is new, and study of lipid receptor physiology may broaden the understanding of retinal angiogenesis.

Purpose: To characterize the genetics and phenotype of a new mouse mutant with retinal degeneration, rd6, that is associated with extensive, scattered, small white retinal dots seen ophthalmoscopically., Methods: The phenotype was characterized using ophthalmoscopy, fundus photography, electroretinography, light microscopy, immunocytochemistry, and electron microscopy. Genetic characterization and linkage analysis studies were performed using standard methods., Results: The inheritance pattern of rd6 is autosomal recessive. Linkage analysis mapped rd6 to mouse Chromosome 9 approximately 24 cM from the centromere, suggesting that the human homolog may be on chromosome 11q23. Ophthalmoscopic examination of mice homozygous for rd6 revealed discrete subretinal spots oriented in a regular pattern across the retina. The retinal spots appeared by 8 to 10 weeks of age and persisted through advanced stages of retinal degeneration. Histologic examination revealed large cells in the subretinal space, typically juxtaposed to the retinal pigment epithelium. The white dots seen on fundus examination corresponded both in distribution and size to these large cells. By 3 months of age, the cells were filled with membranous profiles, lipofuscin-like material, and pigment. These cells reacted strongly with an antibody directed against a mouse macrophage-associated antigen. Photoreceptor cells progressively degenerated with age, and an abnormal electroretinogram was initially detected between 1 and 2 months of age., Conclusions: The fundi of mice homozygous for rd6 exhibit phenotypic similarities to the human flecked retinal disorder retinitis punctata albescens. Thus, rd6/rd6 mice may be a model for understanding the etiology of this or similar disorders. The relationship between the aberrant subretinal cells and the concomitant photoreceptor degeneration remains to be established.