Mechanisms of photoreceptor death and survival in mammalian retina

The mammalian retina, like the rest of the central nervous system, is highl y stable and can maintain its structure and function for the full life of t he individual, in humans for many decades. Photoreceptor dystrophies are in stances of retinal instability. Many are precipitated by genetic mutations and scores of photoreceptor-lethal mutations have now been identified at th e codon level. This review explores the factors which make the photorecepto r more vulnerable to small mutations of its proteins than any other cell of the body, and more vulnerable to environmental factors than any other reti nal neurone. These factors include the highly specialised structure and fun ction of the photoreceptors, their high appetite for energy, their self-pro tective mechanisms and the architecture of their energy supply from the cho roidal circulation. Particularly important are the properties of the choroi dal circulation, especially its fast how of near-arterial blood and its ina bility to autoregulate. Mechanisms which make the retina stable and unstabl e are then reviewed in three different models of retinal degeneration, reti nal detachment, photoreceptor dystrophy and light damage. A two stage model of the genesis of photoreceptor dystrophies is proposed, comprising an ini tial "depletion" stage caused by genetic or environmental insult and a seco nd "late" stage during which oxygen toxicity damages and eventually destroy s any photoreceptors which survive the initial depletion. it is a feature o f the model that the second "late" stage of retinal dystrophies is driven b y oxygen toxicity. The implications of these ideas for therapy of retinal d ystrophies are discussed. (C) 1999 Elsevier Science Ltd. All rights reserve d.