Mechanisms of photoreceptor death and survival in mammalian retina

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Abstract

The mammalian retina, like the rest of the central nervous system, is highly stable and can maintain its structure and function for the full life of the individual, in humans for many decades. Photoreceptor dystrophies are instances of retinal instability. Many are precipitated by genetic mutations and scores of photoreceptor-lethal mutations have now been identified at the codon level. This review explores the factors which make the photoreceptor more vulnerable to small mutations of its proteins than any other cell of the body, and more vulnerable to environmental factors than any other retinal neurone. These factors include the highly specialised structure and function of the photoreceptors, their high appetite for energy, their self-protective mechanisms and the architecture of their energy supply from the choroidal circulation. Particularly important are the properties of the choroidal circulation, especially its fast flow of near-arterial blood and its inability to autoregulate. Mechanisms which make the retina stable and unstable are then reviewed in three different models of retinal degeneration, retinal detachment, photoreceptor dystrophy and light damage. A two stage model of the genesis photoreceptor dystrophies is proposed, comprising an initial “depletion” stage caused by genetic or environmental insult and a second “late” stage during which oxygen toxicity damages and eventually destroys any photoreceptors which survive the initial depleiton. It is a feature of the model that the second “late” stage of retinal dystrophies is driven by oxygen toxicity. The implications of these ideas for therapy of retinal dystrophies are discussed.

Section snippets

Durability and fragility

It is easy to be impressed by both the durability and the fragility of mammalian photoreceptors. In phylogenetic terms their design—each is a neurone of the central nervous system in which the cilium is specialised to bear photosensitive pigments and signal their breakdown—is considered to have been conserved throughout the evolution of vertebrates, thus over hundreds of millions of years. In ontogenetic terms the photoreceptor shares the ability of all central nervous system neurones to

Developmental death of photoreceptors

The generation of photoreceptors and other retinal neurones has been reviewed elsewhere (Stone, 1987; Robinson, 1991; Rapaport and Vietri, 1991; LaVail et al., 1991). Emphasis is given here to a period of death among photoreceptors which appears to be a normal part of their development. During this period (we suggest) the population of photoreceptors is culled from an initial excess to a level appropriate for adult life. Evidence of a cull is reviewed here because regulation of the cull is a

Adaptability of energy sourcing

“The…retina has three unusual properties: it converts glucose to lactic acid with prodigious speed; it consumes oxygen more readily than other tissues; and the formation of lactic acid is rapid even in the presence of oxygen….” Cohen and Noell (1965)

Mechanisms of adult instability: dearth of energy and excess of oxygen

What mechanisms make the adult retina unstable, despite the natural longevity of mammalian CNS neurones and the self-protective mechanisms the retina has evolved? We review here three distinct forms of retinal destabilisation.

A two stage model of retinal dystrophies

The ideas and data presented in Section 4lead to the following model of photoreceptor dystrophies (other than the dystrophy which follows detachment).

Retinal detachment: oxygen supplementation will improve outcomes

The retina's response to detachment is the degeneration of some photoreceptors, degenerative changes in the survivors and a glial proliferation (Section 4.1). From the evidence set out in Section 4.1.2we predict that oxygen supplementation between diagnosis and surgery will be of benefit in corresponding ways: it will rescue photoreceptors in the detached portion of retina, preserve the structure of surviving photoreceptors and reduce the proliferation of glial cells. The clinical outcome

References (182)

  • G.L Fain et al.

    Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis

    Exp. Eye Res.

    (1993)
  • D.B Farber et al.

    The rd mouse story: seventy years of research on an animal model of inherited retinal degeneration

    Progress in Retinal and Eye Research

    (1994)
  • I Ferrer et al.

    Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes

    Neuroscience

    (1990)
  • I Ferrer et al.

    Naturally occurring cell death in the developing cerebral cortex of the rat. Evidence of apoptosis-associated internucleosomal DNA fragmentation

    Neurosci. Lett.

    (1994)
  • H Gao et al.

    Basic fibroblast growth factor in retinal development: Differential levels of bFGF expression and content in normal and retinal degeneration (rd) mutant mice

    Devl. Biol.

    (1995)
  • S-C Hsu et al.

    Glucose metabolism in photoreceptor outer segments. Its role in phototransduction and in NADPH-requiring reactions

    J. Biol. Chem.

    (1994)
  • M.M LaVail et al.

    Retinal pigment epithelial cell transplantation in rcs rats: normal metabolism in rescued photoreceptors

    Exp. Eye Res.

    (1992)
  • M.M LaVail et al.

    Influence of eye pigmentation and light deprivation on inherited retinal dystrophy on the rat

    Exp. Eye Res.

    (1975)
  • G Lewis et al.

    Fate of biotinylated fibroblast growth factor in the retina following intravitreal injection

    Exp. Eye Res.

    (1996)
  • L Li et al.

    Inherited retinal dystrophy in the RCS rat: prevention of photoreceptor degeneration by pigment epithelial cell transplantation

    Exp Eye Res

    (1988)
  • V.A Alder et al.

    The effect of the retinal circulation on vitreal oxygen tension

    Curr. Eye Res.

    (1985)
  • V.A Alder et al.

    PO2 profiles and oxygen consumption in cat retina with an occluded retinal circulation

    Investigative Ophthalmology and Visual Science

    (1990)
  • A Alm et al.

    The oxygen supply to the retina, II. Effects of high intra-ocular pressure and of increased aterial carbon dioxide tension on uveal and retinal blood flow in cats

    Acta Physiol. Scand.

    (1972)
  • A Ames et al.

    Energy metabolism of rabbit retina as related to function: high cost of Na+ transport

    Journal of Neuroscience

    (1992)
  • D.H Anderson et al.

    Mammalian cones: disc shedding, phagocytosis, and renewal

    Invest. Ophthal. Vis. Sci.

    (1978)
  • D.H Anderson et al.

    Morphological recovery in the reattached retina

    Invest. Ophthal. Vis. Sci.

    (1986)
  • D.H Anderson et al.

    Retinal detachment in the cat: the pigment epithelial-photoreceptor interface

    Invest. Ophthal. Vis. Sci.

    (1983)
  • M.F Barbe et al.

    Hyperthermia protects against light damage in the rat retina

    Science

    (1988)
  • M.M Behbehani et al.

    Preservation of retinal function in the RCS rat by laser treatment

    Retina

    (1984)
  • J Bennett et al.

    Photoreceptor cell rescue in retinal degeneration (rd) mice by in vivo gene therapy

    Nature Medicine

    (1996)
  • L Berglin et al.

    Photoreceptor decay over time and apoptosis in experimental retinal detachment

    Graefes Archive for Clinical and Experimental Ophthalmology

    (1997)
  • E.L Berson

    Light deprivation for early retinitis pigmentosa

    Arch. Ophthal.

    (1971)
  • E.L Berson

    Experimental and therapeutic aspects of photic damage to the retina

    Invest. Ophthal. Vis. Sci.

    (1973)
  • E.L Berson

    Retinitis Pigmentosa. Invest. Ophthal. Vis. Sci.

    (1993)
  • A Bill et al.

    Control of retinal and choroidal blood flow

    Eye

    (1990)
  • A Bill et al.

    Permeability of the intraocular blood vessels

    Trans. ophthal. Soc. U.K.

    (1980)
  • A Bill et al.

    Permeability of the intraocular blood vessels

    Trans. ophthal. Soc. U.K.

    (1980)
  • A Bill et al.

    Physiology of the choroidal vascular bed

    International Ophthalmology

    (1983)
  • F.L Bowers et al.

    The expression of cytochrome oxidase in the photoreceptors of the developing and adult rat

    Proc. Aust. Neuroscience Soc.

    (1998)
  • F Bowers et al.

    Dual rescue effect of oxygen on light induced photoreceptor death in the rat

    Invest. Ophthal. Vis. Sci.

    (1998)
  • R.D Braun et al.

    Oxygen consumption in the inner and outer retina of the cat

    Invest. Ophthal. Vis. Sci.

    (1995)
  • R.D Brown et al.

    Light-induced changes in retinal oxygen consumption

    Invest. Ophthal. Vis. Sci.

    (1996)
  • M.S Burns et al.

    Muller cell GFAP expression exhibits gradient from focus of photoreceptor light damage

    Curr. Eye Res.

    (1990)
  • R.A Bush et al.

    The melatonin receptor antagonist luzindole protects retinal photoreceptors from light damage in rat

    Invest. Ophthal. Vis. Sci.

    (1997)
  • P.A Campochiaro et al.

    Retinal degeneration in transgenic mice with photoreceptor specific expression of a dominant-negative fibroblast growth factor receptor

    J. Neurosci.

    (1996)
  • W Cao et al.

    Development of injury-induced gene expression of bFGF, FGFR-1, CNTF and GFAP in rat retina

    Invest. Ophthal. Vis. Sci.

    (1997)
  • C.J Chang et al.

    Apoptotic photoreceptor cell death after traumatic retinal detachment in humans

    Arch. Ophthal.

    (1996)
  • T Chan-Ling et al.

    Retinopathy of prematurity: Origins in the architecture of the retina

    Prog. Ret. Res.

    (1993)
  • Y Chu et al.

    Immunocytochemical localisation of basic fibroblast growth factor and glial fibrillary acidic protein after laser photocoagulation in the Royal College of Surgeons rat

    Aust. N.Z. J. Ophthal.

    (1998)
  • L.B Clerch et al.

    Tolerance of rats to hyperoxia. Lung antioxidant enzyme gene expression

    J. Clin. Invest.

    (1993)
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