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Editors Selection IGR 13-2

Basic Science: Animal models II

Comment by Chris Leung on:

Visualizing dendritic and axonal morphologies of retinal ganglion cells (RGCs) is germane to the investigation of RGC degeneration in glaucoma. Using the DBA/2J mouse model of glaucoma, Williams and colleagues performed histological analysis examining dendritic morphology of RGCs in eyes with different degrees of optic nerve damage. Three groups of animals with different levels of axonal damage were compared (no or early, moderate, and severe axonal damage) and two different methods were used to visualize dendritic arborization (DiOlistic labeling and transgenic fluorescent protein labeling (DBA/2J.Thy1(YFP)). The key finding is that RGCs of the DBA/2J mice labeled with DiO coated tungsten particles showed dendritic shrinkage in the eyes with no or early axonal damage compared with the control eyes (DBA/2JGpnmb+ mice). However, there were no significant differences in the dendritic measurements (dendritic field area, Sholl analysis area under the curve) between the eyes with moderate/severe axonal damage and the controls. For the DBA/2J.Thy1(YFP) mice, the authors did not find significant differences in the dendritic measurements among the groups with different levels of axonal damage.

dendritic shrinkage can be detected prior to significant axonal damage

This study provides important data illustrating that dendritic shrinkage can be detected prior to significant axonal damage. Intraocular pressure elevation may induce preferential loss of certain types of RGCs. It is plausible that RGCs with a smaller dendritic field might have been lost in eyes with moderate and severe axonal damage, rendering the dendritic measurements of the surviving RGCs comparable to the controls. The lack of significant differences in the dendritic measurements among the DBA/2J.Thy1(YFP) mice with different degrees of axonal damage, on the other hand, is more difficult to interpret. The authors suggested that a reduced expression of YFP prior to dendritic atrophy consequential to down-regulation of Thy-1 might be accountable for this observation. Tracking the longitudinal changes of dendritic trees after optic nerve crush (Leung CK, Weinreb RN, Li ZW, et al. Invest Ophthalmol Vis Sci 2011; 52: 1539-1547) and acute intraocular pressure elevation (Li ZW, Liu S, Weinreb RN, et al. Invest Ophthalmol Vis Sci 2011; 52: 7205-7212), we showed that it is possible to visualize dendritic shrinkage and measure its rate of change in the Thy-YFP mice. Dendritic shrinkage was observed before loss of the axon and then the cell body. There are different types of RGCs and their responses to the same optic nerve insult may vary. Dendritic shrinkage is challenging to document in cross-sectional studies. Another potential factor contributing to the different results between the eyes with DiOlistic labeling and those with transgenic fluorescent protein labeling is that the extent of dendritic labeling for a single cell might be different between the two techniques. While it is not feasible to study dendritic changes of the same RGCs longitudinally with DiOlistic labeling, in vivo RGC imaging will afford a more definitive answer to the sequence of neuronal degeneration in glaucoma.

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