Day 60MicroneuromasRod anomalies

Purpose: Our goal was to assess the nature, scope and chronology of remodeling in the neural retina in non-genetic retinal degeneration triggered by light damage (LD) in the albino rat, in comparison with over fifteen different genetic models (Jones et al. 2003, J Comp Neurol: in press) Our hypothesis is that all retinas evince incipient plasticity upon deafferentation, regardless of the mode of photoreceptor loss.

Methods: Over 90 albino Sprague-Dawley rat retinas were analyzed by computational molecular pheno-typing (Jones and Marc, 2002, J Neurosci 22:413-427) after light exposures (Organisciak et al.,1998, IOVS 39:1107-1116) of varied durations, pre-adaptation states, circadian phases, and survival times. Post-euthanasia, enucleated eyes were rapidly fixed in glutaraldehyde, resin-embedded and thin sections serially probed for key retinal metabolites and markers (e.g. amino acids, glutathione and rhodopsin).

Results: Within 14 days of even a brief, 3 hr LD treatment, focal photoreceptor loss was accompanied by irregular 2-4 fold increases in RPE glutamine and rod aspartate levels, perhaps presaging cell death. The onset of Müller cell (MC) remodeling (formation of a fibrotic glial seal in regions of extensive rod/cone cell death) is accompanied by a dramatic >10-fold increase in MC glutamine. This occurs only in MCs engaged in seal formation; MCs a mere 0.1 mm away are normal. The neural retina remains stable until about 120-240 days post-LD, when both neuronal migration on hypertrophic MC columns and synaptic remodeling are initiated. Synaptic remodeling is evidenced by neuropil arising from new neurites in the remnant distal retina containing GABAergic, glycinergic, and glutamatergic synapses in novel circuits. Distal migration of MC nuclei, MC hypertrophy and disorganization of the inner nuclear layer, including cell loss, match remodeling processes in advanced genetic forms of retinal degeneration, including human retinitis pigmentosa. By 240 days post-LD there is extensive emigration of MCs and neurons into the remnant choroid, similar to that described by Sullivan et al. (IOVS 44, 2003) for the aged ambient-LD rat.

Conclusions: All insults that kill photoreceptors represent sensory deafferentations that trigger retinal remodeling akin to CNS plasticities, including neuronal loss, growth of new neurites, formation of new synapses, and reorganization of the neuronal and glial somatic positions. LD is a fast, effective trigger of large-scale remodeling (perhaps due to the high temporal coherence of the insult) and will enable study of circuitry defects emergent from remodeling.

Commercial Relationship: BW Jones, None;  CB Watt, None;  DK Vaughan, None;  DT Organisciak, None; RE Marc, Signature Immunologics F, E.

Abstract 1811 B783 Retinal Remodeling Triggered by Light Damage in the Albino Rat BW Jones, CB Watt, RE Marc • Univ Utah Moran Eye Center, Salt Lake City, UT • NIH EY02576 & Research to Prevent BlindnessDK Vaughan • Biology, University of Wisconsin Oshkosh, Oshkosh, WIDT Organisciak • Biochemistry and Molecular Biology, Wright State Univ, Dayton, OH • NIH EY01959

γGE(Rho) → rgb(α) mapping

τQE(J) → rgb(α) mapping

Müller cell death/evacuation

Neural retinal border

Neural retinal borderCell emigration to choroid

γGE → rgb

τQE → rgb

τQE → rgb

Choroidal Atrophy

Choroidal Atrophy

Glial Seal

Glial Seal

Glial Seal

Choroidal Atrophy

τQE → rgbmapping

monochromeglutamine signal

100 µm 100 µm

normalchoriocapillaris

atrophicchoriocapillaris

RPE

totalRPEloss

ventralretinanormalroddensity

centralretinaroddeath

Day 60 Complete glial seal • Small microneuromas • IPL border instability • Fluid channel formation

Day 120 Large Microneuromas • Initial neuron loss • Initial cell migration • Initial cell emigration to choroid

γGE → rgb

γGE → rgb

Day 240 Microneuromas • Neuron loss • Neuron migration • Extensive emigration to choroid • Collapse of retinal signals in the emigration zone

Day 14 Photoreceptor and RPE death • Evolution of the glial seal • choriocapillaris atrophy

ventral retina

ventral retina

central retina

central retina

Day 240 Gradient of rod-cone survival → seal zone → emigration zone

rpe

← seal zone → ← emigration zone … →

← emigration zone … →← seal zone →

fluidchannel

fluidchannel

γGE → rgb