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Editors Selection IGR 10-1
Basic research: The lamina cribrosa and initial insult to RGC
Comment by John Danias on:
20483 Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma, Howell GR; Libby RT; Jakobs TC et al., The Journal of Cell Biology, 2007; 179: 1523-1537
Howell et al. (123) have used the DBA/2 mouse model of glaucoma to attempt to confirm 'beyond reasonable doubt' the site of initial insult to retinal ganglion cells in glaucoma. They have first confirmed previous work by other investigators that although the mouse does not have a formed lamina cribrosa (as defined by the presence of extracellular plates typically present in primate) they do have a robust glial lamina equivalent. Howell et al. Then proceed to show by electron microscopy and immunohistochemistry that in very early stages of glaucoma (where no damage can be detected at the optic nerve), changes are already occurring within the glial lamina region. These changes are also evident in animals that express a fluorescent protein in RGCs in the DBA/2 background. The areas of damage within the lamina seem to correspond with areas of eventual RGC loss. Since the first site of degeneration is not a reliable indicator of the site of initial neuronal injury, the authors first confirmed that optic nerve crush in young pre-glaucomatous DBA/2/ Bax deficient mice, allows survival of axons to the level of damage (behind the eye), They then studied aged glaucomatous DBA/2/Bax deficient mice and showed termination of axons at the anterior edge of the laminar region. Furthermore they showed that the Wallerian degeneration slow gene (Wlds) delays (and possibly prevents) axonal loss in DBA/2/Wlds congenic animals and preserves RGC activity as measured by pattern electroretinography (PERG).
This impressive piece of experimental work is a 'tour de force' of the use of mouse genetics to address biologically important ques-tions. It does provide extremely strong data on the importance of lamina cribrosa in glaucoma. However, as the authors themselves recognize, it fails to reach the point of 'beyond reasonable doubt' for lamina being the point of initial insult in glaucoma. The authors suggest that PERG activity change in DBA/2 mice may reflect an even earlier pathologic process than the insult at the laminar level. Although they do not make suggestions as to what that insult may be, a previous publication in collaboration with by the same group1 has implicated innate immunity (in the form of complement) in this process. Despite the apparent failure to 'seal' the case, this work is a very important addition to our understanding of glaucoma and as every significant piece of experimental work raises new questions that will ultimately lead us to complete understanding of the pathophysiology of this complex disease.
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