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Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium derived factor. Intravitreal injection of cilliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the central nervous system associated with glial dysfunction.

No abstract

Aim-To describe the early formation of drusen and their relation to normal aging changes at the macula and to the development of age related maculopathy (ARM). Method-Histopathological features of 353 eyes without histological evidence of ARM are described and correlated with the clinical appearance. In addition, 45 of these eyes were examined by transmission electron microscopy. Results-Drusen were detected histopathologically in 177 (50%) eyes but were seen clinically in only 34% of these. Drusen were mainly small hard drusen with an occasional soft distinct drusen: no soft indistinct drusen were seen. Only those drusen deposits larger than 25-30 µm in diameter were detectable clinically. Preclinical drusen in eyes with only an occasional drusen were seen on electron microscopy as entrapment sites of coated membrane bound bodies which formed adjacent to the inner collagenous zone of Bruch's membrane. In contrast, preclinical drusen deposits in eyes with many drusen were seen as accumulations of amorphous material which appeared hyalinised by light microscopy. A distinct feature were rows of dense hyalinised microdrusen (1-2 µm in diameter), over which larger globular hyalinised drusen formed. Conclusion-Histological and ultrastructural examination can recognise and distinguish the earliest drusen formed as a result of normal aging from those associated with ARM. In eyes without diVuse deposits, histologically all drusen were of the hard hyalinised variety or their derivatives; no soft drusen composed of membranous debris were found. These findings support and explain those of other authors who do not consider the presence of a few small hard drusen to be a risk factor for the development of ARM. (Br J Ophthalmol 1999;83:358-368)

The pathways by which soft drusen are formed are illustrated by representative clinical and clinicopathological cases. One type is derived from small hard drusen which first tend to aggregate into clusters and then fuse, forming larger deposits termed hard clusters. Breakdown of the hard drusen results in varying degrees of softening and confluence. These soft clusters may appear in middle age and, like the preceding hard drusen, remain a focal pathology. Soft clusters commonly lead to the atrophic form of age-related macular degeneration. Another type of soft drusen is formed from membranous debris as part of a diffuse disturbance of the retinal pigment epithelium. These membranous soft drusen first appear in the seventh decade and are commonly associated with choroidal neovascularisation.