Defective cone photoreceptor cytoskeleton, alignment, feedback, and energetics can lead to energy depletion in macular degeneration

Eckmiller, Marion Sangster

doi:10.1016/j.preteyeres.2004.04.005

Cited by 50 publications

(29 citation statements)

References 179 publications

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“…Currently, there is no evidence for this phenomenon in mammalian retinas. However, adaptive alignment and realignment toward the direction of highest light intensity (pupil) has been described and attributed to the activity of IS cytoskeletal elements, actin fibers, and microtubules (33,34). We cannot exclude that minute light-induced motor responses could contribute to the optical reflectivity changes observed in the IS͞OS of the PR.…”

Section: Discussionmentioning

confidence: 91%

Optophysiology: Depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography

Bizheva

Pflug

Hermann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

204

140

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Noncontact, depth-resolved, optical probing of retinal response to visual stimulation with a <10-m spatial resolution, achieved by using functional ultrahigh-resolution optical coherence tomography (fUHROCT), is demonstrated in isolated rabbit retinas. The method takes advantage of the fact that physiological changes in dark-adapted retinas caused by light stimulation can result in local variation of the tissue reflectivity. fUHROCT scans were acquired from isolated retinas synchronously with electrical recordings before, during, and after light stimulation. Pronounced stimulusrelated changes in the retinal reflectivity profile were observed in the inner͞outer segments of the photoreceptor layer and the plexiform layers. Control experiments (e.g., dark adaptation vs. light stimulation), pharmacological inhibition of photoreceptor function, and synaptic transmission to the inner retina confirmed that the origin of the observed optical changes is the altered physiological state of the retina evoked by the light stimulus. We have demonstrated that fUHROCT allows for simultaneous, noninvasive probing of both retinal morphology and function, which could significantly improve the early diagnosis of various ophthalmic pathologies and could lead to better understanding of pathogenesis.electroretinogram ͉ functional optical coherence tomography ͉ inner plexiform layer ͉ photoreceptors ͉ retinal imaging T he vertebrate retina consists of several distinct layers: nuclear layers containing cell bodies can be differentiated from plexiform layers with axons and dendrites forming the neuronal network that preprocesses light-evoked signals before transmission to the brain. Early stages of retinal disorders are often confined to one of these layers and are manifested by both morphological abnormalities and impaired physiological responses. Detection of such pathologies requires high-resolution imaging methods. Various imaging modalities such as fundus photography, ultrasound imaging, and optical coherence tomography (OCT) are clinically used for imaging retinal morphology. OCT is an emerging imaging technique that allows for noncontact, in vivo visualization of biological tissue morphology with a micrometer-scale resolution at imaging depths of 1-2 mm (1-3). Currently, electrophysiological tests such as electroretinography (ERG) (4) and multifocal ERG (5) are used for clinical assessment of retinal function.More then 25 years ago, it was observed that the isolated retina when stimulated with visible light changes the amount of transmitted near-infrared light (NIR) (6, 7). Photoreceptors (PRs) were determined to be the main source of this effect, and in the following years, this method was used for investigation and quantitative evaluation of the activation of the PR G protein transducin and the time course of transduction events (8-10 and reviewed in ref. 11). In the last few years, other physiological processes at the cellular and subcellular level such as membrane depolarization (12), cell swelling (13), and altered metabolism...

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Section: Discussionmentioning

confidence: 91%

Optophysiology: Depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography

Bizheva

Pflug

Hermann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

204

140

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“…A disturbance in the microtubule-based cytoskeleton within photoreceptor outer segments may contribute to a loss of photoreceptors. 9 Because the greatest photoreceptor loss occurs in the macula, 14,23 it is reasonable to postulate that the decreased levels of microtubule proteins corresponds directly to the disease-induced loss in photoreceptors. However, our data showed a significant decrease in content of microtubule proteins in both regions suggesting that changes are not exclusive to photoreceptors.…”

Section: Iovsmentioning

confidence: 99%

“…For example, the population of photoreceptors is clearly distinct in each region; the macula contains a proportionately higher density of cones than does the periphery. 9 The increased metabolic activity, elevated blood flow in the choroid, and exposure to focused light energy also distinguish the macula from the periphery. 19 Although these differences have been well described, further investigations to explain the molecular basis for the region-specific differences in susceptibility to degeneration are needed.…”

mentioning

confidence: 99%

The Proteome of Central and Peripheral Retina with Progression of Age-Related Macular Degeneration

Ethen

Reilly

Feng

et al. 2006

Invest. Ophthalmol. Vis. Sci.

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“…We show that under hypoglycemic conditions and in 20% oxygen, spontaneous reentrant SD spiral waves propagate around a small lesion for many cycles, leading to an increase in cleavage of procaspase 3 and expansion of the lesion to encompass larger regions of the central retina, which has a large metabolic load (30). Under these conditions, the initial threshold for onset of SD is reduced to the point where SD episodes arise spontaneously with increased frequency.…”

Section: Discussionmentioning

confidence: 90%

Reentrant spiral waves of spreading depression cause macular degeneration in hypoglycemic chicken retina

Yu¹,

Santos²,

Mattiace³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Spreading depression (SD), a slow diffusion-mediated self-sustained wave of depolarization that severely disrupts neuronal function, has been implicated as a cause of cellular injury in a number of central nervous system pathologies, including blind spots in the retina. Here we show that in the hypoglycemic chicken retina, spontaneous episodes of SD can occur, resulting in irreversible punctate lesions in the macula, the region of highest visual acuity in the central region of the retina. These lesions in turn can act as sites of origin for secondary self-sustained reentrant spiral waves of SD that progressively enlarge the lesions. Furthermore, we show that the degeneration of the macula under hypoglycemic conditions can be prevented by blocking reentrant spiral SDs or by blocking caspases. The observation that spontaneous formation of reentrant spiral SD waves leads to the development of progressive retinal lesions under conditions of hypoglycemia establishes a potential role of SD in initiation and progression of macular degeneration, one of the leading causes of visual disability worldwide.diabetes | retinal migraine | scotomas C urrent research has revealed a number of molecular mechanisms underlying the pathophysiology of macular degeneration (1), a disease that involves damage to the central retina, where the higher density of photoreceptors results in maximal visual acuity (2). Macular degeneration is a leading cause of visual disability (1, 2). However, the reasons for the particular sensitivity of the macula remain speculative. A number of patients report the presence of monocular scotomas that gradually enlarge and move across the retinal field, and this phenomenon, which can lead to loss of vision, has been ascribed to retinal migraine (3, 4). Although the occurrence of retinal migraine has been disputed (5), the likely cause is spreading depression (SD), a phenomenon initially described in the central nervous system by Leão (6). SD is a slow diffusion-mediated self-sustained wave of generalized depolarization of gray matter or retina that does not respect synaptic connectivity (7) and severely disrupts neuronal function. SD results in a temporary collapse of transmembrane ionic gradients and membrane potential (8, 9), and is characterized by a negative field potential 10-20 mV in amplitude and 1-2 min in duration, propagating at a velocity of a few millimeters per minute (6-10). The advancing wave front is accompanied by a burst of action potentials and K + efflux into the interstitial space, followed by electrical silence, which is associated with the negative field potential (11, 12). Na + and Cl − enter the cells, causing an influx of water, swelling, and reduction in the volume of the extracellular space. In addition, proinflammatory compounds are released, often accompanied by edema and extravasation of blood proteins (13). Recovery can occur in minutes, but repeated episodes of SD increase neuronal loss surrounding traumatic brain lesions, and have been implicated in other central nervous syst...

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Defective cone photoreceptor cytoskeleton, alignment, feedback, and energetics can lead to energy depletion in macular degeneration

Cited by 50 publications

References 179 publications

Optophysiology: Depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography

Optophysiology: Depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography

The Proteome of Central and Peripheral Retina with Progression of Age-Related Macular Degeneration

Reentrant spiral waves of spreading depression cause macular degeneration in hypoglycemic chicken retina

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