Loss of retinal function in aged DBA/2J mice – New insights into retinal neurodegeneration

doi:10.1016/j.exer.2010.09.001

Experimental Eye Research

Volume 91, Issue 5, November 2010, Pages 779-783

https://doi.org/10.1016/j.exer.2010.09.001 Get rights and content

Abstract

The DBA/2J mouse is a common animal model of glaucoma. The intraocular pressure increases with age, and retinal ganglion cells (RGC) degenerate, usually starting at an age of approximately six months. In this study, we used two-year-old DBA/2J mice presuming an end-point of RGC degeneration. We investigated visual function in these animals using electroretinography (ERG) and visual evoked potentials (VEP), and we checked the number of remaining RGC by retrograde staining. Almost no RGC were left in the retina, and VEP were hardly recordable. Surprisingly, also ERG amplitudes of scotopic a-waves and b-waves, photopic b-waves and oscillatory potentials were decreased significantly by approximately 40% compared to amplitudes measured in age-matched C57BL/6J mice. The latencies were not changed in DBA/2J mice compared to C57BL/6J mice, and so were the ratios between amplitudes of a-waves, b-waves and oscillatory potentials. Our results indicate that, in addition to degeneration of RGC, also photoreceptors are affected by pathological processes in the eye caused by the mutations present in DBA/2J mice.

Introduction

The DBA/2J mouse is a widely used inbred strain in cardiovascular biology, neurobiology, and sensorineural research, as well as for the pigment dispersion glaucoma, where pigment particles that normally are located on the iris get loose and distribute inside the anterior chamber (John et al., 1998). Pigment dispersion and iris atrophy were observed in DBA/2J mice usually at an age of six to eight months (John et al., 1998, Libby et al., 2005).

As a consequence of the glaucoma developing in DBA/2J mice, the nerve fibre layer becomes thinner, and the number of RGC is greatly depleted, accompanied by optic nerve atrophy and disorganisation (John et al., 1998). The majority of mice suffer increase of IOP, loss of RGC and optic nerve atrophy by 22 months of age (Jakobs et al., 2005, Libby et al., 2005, Schlamp et al., 2006). This consistency in glaucoma development in DBA/2J mouse makes this strain a useful tool to study this disease (Schuettauf et al., 2002).

The clear-cut way to determine functional loss in the case of RGC loss is to measure visual evoked potentials (VEP). However, no studies are published so far where VEP measurements were applied to study loss of RGC function in DBA/2J mice.

Therefore, we examined two-year-old DBA/2J mice that can be considered a kind of “end-point” regarding the degeneration process caused by the disease. Our aim was to evaluate the extent of RGC degeneration in such old DBA/2J mice, and we were interested whether visual function on both retinal and cortical levels could still be recorded. For this purpose, we performed Ganzfeld ERG and VEP measurements in aged DBA/2J mice and age-matched C57BL/6J mice as a control strain and labelled RGC retrogradely to quantify them.

Section snippets

Materials and methods

All mice were handled according to German animal protection laws, and all experiments were conducted in accordance with the Association for Research in Vision and Ophthalmology. DBA/2J and C57BL/6J mice were obtained from the European distributor of Jackson Laboratories mice (Charles River Laboratories) and were bred here for a maximum of two generations. All mice were kept under specific pathogen-free conditions at room temperature in a 12 h light/12 h dark cycle. For the DBA/2J strain, a

Results

In the electroretinographic waveforms obtained in aged DBA/2J mice and age-matched C57BL/6J mice, a clear impairment of retinal function in DBA/2J mice can be recognised at first sight; all waveforms of DBA/2J mice show considerably smaller amplitudes, as shown for scotopic ERG in Fig. 1A.

Numerical evaluation of the ERG parameters shows that amplitudes of a-waves are significantly smaller in DBA/2J mice at light intensities above 0.01 cd·s/m² (p ≤ 0.027), and the same is true for the amplitudes

Discussion

We found a dramatically decreased number of RGC in retinal whole-mounts of aged DBA/2J mice, in an extent that the retina was almost devoid of RGC. Already in one year-old DBA/2J mice, Jakobs et al. (2005) observed severe loss of RGC by retrograde labelling, with large areas of the retina completely devoid of RGC.

Moreover, visual evoked potentials in the old DBA/2J mice were extremely reduced. It was difficult to determine the values of the VEP amplitudes at all in several of the aged DBA/2J

Conclusion

As a summarising conclusion, we investigated visual function in two-year-old DBA/2J mice. There were only weak visual evoked potentials recordable, which was not surprising given the extremely low number of RGC found in the retina. However, also flash ERG amplitudes were decreased clearly. Whether only the function of photoreceptors is impaired or if there are also structural deficits in the photoreceptors of old DBA/2J mice, remains to be elucidated.

Acknowledgements

The authors thank the Else Kröner-Fresenius-Stiftung (P40/08//A32/08) for supporting Sven Schnichels. Jan Kremers (Department of Ophthalmology, University Hospital Erlangen, University of Erlangen–Nuremberg) is acknowledged for critically reading the manuscript. All authors disclose any commercial interest in the subject of the manuscript or in entities discussed in the manuscript.

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Letter to the EditorLoss of retinal function in aged DBA/2J mice – New insights into retinal neurodegeneration

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusion

Acknowledgements

Gene Expr. Patterns

Vis. Res.

A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy

Brain

Electrophysiological deficits in the retina of the DBA/2J mouse

Doc. Ophthalmol.

Electrophysiological and histologic assessment of retinal ganglion cell fate in a mouse model for OPA1-associated autosomal dominant optic atrophy

Invest. Ophthalmol. Vis. Sci.

Rod phototransduction in retinitis pigmentosa: estimation and interpretation of parameters derived from the rod a-wave

Invest. Ophthalmol. Vis. Sci.

Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma

J. Cell. Biol.

Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice

J. Cell. Biol.

Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice

Invest. Ophthalmol. Vis. Sci.

Primary open angle glaucoma is not associated with photoreceptor loss

Invest. Ophthalmol. Vis. Sci.

Letter to the Editor
Loss of retinal function in aged DBA/2J mice – New insights into retinal neurodegeneration