Müller cell changes precede photoreceptor cell degeneration in the age-related retinal degeneration of the Fischer 344 rat

Previously, we have used descriptive pathology and histomorphometry, as well as functional testing to characterize the age-related retinal degeneration in the Fischer 344 rat. These studies suggested an association between Müller cells and photoreceptor cells in this process. The purpose of the present study was to further investigate the respective roles of these cell types in the development and progression of the retinal degeneration. Retinas from male Fischer 344 rats aged 3-24 months were first studied by light and electron microscopy. Since Müller cells abundantly express GFAP during pathological states, GFAP content was studied by immunocytochemistry and by immunoblotting following one- and two-dimensional gel electrophoresis. Microscopically, at 12 months, Müller cells showed a gradient of immunoreactivity for GFAP that was minimal in the central retina, positive for their radial processes in the equator, and abundantly expressed in the periphery. At this age, the photoreceptor cells were just beginning to degenerate in the far periphery, while they appeared healthy in the equatorial and central regions. By 24 months, Müller cell hypertrophy was seen in the peripheral regions where photoreceptor cell degeneration was most severe, while the immunoreactivity of the Müller cell processes spread further toward the central regions, ahead of the degeneration of the photoreceptor cells. Thus, Müller cell changes actually preceded photoreceptor degeneration in time and location. This phenomenon was confirmed by measurement of GFAP after one- and two-dimensional PAGE. These findings show that Müller cell changes precede chronic photoreceptor cell degeneration in the aging Fischer 344 rat and are consistent with the hypothesis that Müller cell alteration may be the primary mechanism of this age-related retinal degeneration.