| dc.description.abstract |
Due to the large variety of genetically matching mutants, mice are the most widely used
disease models in the preclinical assessment of rod and cone function in ophthalmic
research. However, while their rod system is largely comparable to that of other mammals,
including humans, their cone system does not show the same level of similarity.
In particular, (I) there is a dorsoventral gradient of M- and S-opsins in the mouse retina,
(II) most cones express both visual pigments simultaneously, and (III) S-opsins have
undergone a spectral shift towards the UV range. Furthermore, their retina lacks a
clearly visible outer retinal specialization, which additionally limits their use in diseases
of the central retina. Consequently, the overarching goal of this work was to improve
the preclinical assessment of the cone system in basic research. The first aim was to
develop a refined, mouse-specific diagnostic approach for electroretinographic (ERG)
functional testing in mouse models of hereditary retinal degenerations. The second
objective was the characterization of cone system organization and physiology in an
alternative rodent species, the diurnal Mongolian gerbil (MG), as an improved model
system to assess diseases of the central retina.
The first part focuses on an improvement of the specific functional analysis of cones
in the mouse. We found that so far, ERG recordings in rodents have been performed
almost exclusively with light sources optimized for the human retina (420-550 nm),
which do not match the functional properties of murine cones as their S-opsin sensitivity
peaks at ~365 nm. Thus, while the M-opsin fraction is sufficiently stimulated by
the usual paradigm, the S-opsin fraction in the cones is practically not stimulated at all
(by about three logarithmic units (i.e. 1000x) less). Consequently, we developed a
novel ERG methodology (Patent DE 10 2023 124 080 B3) that includes UV stimuli to
improve cone system responsiveness. In this work, we demonstrate the capabilities of
this enhanced ERG methodology to better characterize the cone system in models of
human retinal degenerations. In this context, we also took a closer look at the opsin
distribution in the murine retina. We found that the S-opsin transitional zone (OTZ),
where the M-dominant part of the retina morphologically transitions into the S-dominant
part, occupied the same relative position in the retina as the visual streak (VS) in MGs.
We therefore suggest that the OTZ, as a homologous region to the VS, resembles the
retinal center in mice.
The second part summarizes the characterization of retinal structure and function in
MGs. We show that MG cones do not share the retinal features typical of mice, such
as (I) and (II), limiting comparability of the cone system to other mammalian species.
Rather, in contrast, gerbils feature a prominent VS dorsal to the optic nerve, which
includes elongated outer segments (OSs) of both photoreceptor types and increased
cone density. Cone system-related responses in MGs were generally larger, faster,
and more sensitive than in mice. Moreover, the rod-to-cone ratio (RCR) in the VS
matched that in the human “macular shoulder” at 1.5 mm eccentricity around the fovea.
RPE cells have a reduced area and are taller, with an overall increase in cell volume
and an increased content of intracellular phagosomes. |
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