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Editors Selection IGR 17-4

Basic research: RGC and cell body loss

Comment by James Morgan on:

21099 Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma, Buckingham BP; Inman DM; Lambert W et al., Journal of Neuroscience, 2008; 28: 2735-2744

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The paper by Buckingham et al. (817) address the important issue of the relationship between retinal ganglion cell (RGC) axon damage and cell body loss in glaucoma. The study is based on the DBA2/J mouse model of glau-coma and compares the numbers of cells in the retinal ganglion cell layer with the number of axons in the optic nerve to determine the tem-poral relationship between these events. Using a neuronal marker (NueN) which relates to the RGC population and retrograde tracers (Fluorogold and DiI) which provide an index of axonal integrity they demonstrate significant reductions in RGCs following the onset of axon damage and loss in the optic nerve. Other markers of RGC physiology such as Brn-3b, Sncg and NF-L were quantified to provide an index of RGC damage. This paper follows on from earlier work in the DBA2 mouse model by Jakobs et al.¹ on RGC morphology and by Howell et al.² identifying the optic nerve head as the site of axonal injury. In many ways it highlights the difficulties that can arise when trying to trace neuronal populations in animal glaucoma models. Effective labeling of the RGC population using retrograde tracers can be difficult in healthy animals and different RGC counts can be obtained depending on the tracer used; deficits in labelling can arise from loss of axons or simply indicate dysfunctional uptake mechanisms. The quantification of cell morphology on the basis of nuclear stains such as NueN can also be problematic and the search continues for a neuronal marker that unequivocally labels all the retinal ganglion cells. Furthermore, the results from pooled samples of DBA mice (a proportion of which will not develop glaucomatous damage) require careful interpretation. Although mention is made of IOP measurements using the Tonopen (which may not be ideal in the DBA2 mouse because of changes in corneal morphology that occur with prolonged IOP elevation) the IOPs of the study animals are not presented. It is difficult therefore to draw any conclusions between the level of IOP and RGC changes in this study.

Axon damage precedes RGC dendrite and soma changes in the DBA/2J mouse

What does this mean for our clinical understanding of glaucoma? The authors describe a persuasive time line for retinal ganglion cell damage in which axon damage precedes RGC dendrite and soma changes. In recent years attention has been drawn to the early changes that may occur in RGC structure prior to soma loss. The present study suggests that axon dysfunction and loss remains one of the earliest changes in experimental glaucoma. Clinical studies have not demonstrated marked thinning of the retinal nerve fibre layer with preservation of the retinal ganglion cell layer which suggests that the intra-retinal portion of the axon may persist following loss within the optic nerve. Further detailing of the axonal events in both the optic nerve head and terminal targets such as the superior colliculus are required to determine the site and progress of axon damage. In all these studies we should remain cautious in our search for morphological indicators of RGC damage; the loss of synaptic con-nections in an apparently intact dendritic tree can also generate dysfunction prior to axon loss.

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