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Editors Selection IGR 9-4

Retinal ganglion cells: GLAST and EAAC1 deficiency

Comment by Rosario Hernandez on:

19249 The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma, Harada T; Harada C; Nakamura K et al., Journal of Clinical Investigation, 2007; 117: 1763-1770

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Harada et al. (862) investigated the role of glutamate transporters in retinal ganglion cell (RGC) survival by using mice with deletions of the Muller cell glutamate transporter, GLAST; deletion of the neuronal excitatory amino acid carrier, EAAC1 on RGCs and amacrine cells; and deletion of Glut-1, a neuronal glutamate transporter on bipolar cells and a subset of photoreceptors. The authors performed a variety of quantitative analyses, including retrograde labeling and counting of RGCs, optic nerve axon counts, optic nerve head histology, retinal glutathione levels and multi-focal ERG. GLAST and EAAC1 deficiency caused marked loss of RGCs in eight months old mice without elevation of intraocular pressure (IOP). However, there was probably loss of displaced amacrine cells; thus, the loss of RGCs is not specific in the GLAST knockout mice. Furthermore, in Figure 2A, there appears to be degeneration in all retinal layers. The authors should have addressed the loss of an un-competitive inhibitor of the activated NMDA receptor (Lipton 2007) that is currently being tested clinically in neuroprotection for glaucoma. Figure 7 presents data that memantine prevented RGC loss. However, RGC protection is during a postnatal period when there is massive degeneration of RGCs as part of normal development. Memantine was not tested in eight months old GLAST deficient mice, when there is the reported loss of RGCs demonstrated in Figure 2. The authors did not find the expected increase in glutamate levels in the vitreous of the mutant mice and, therefore, suggest that mechanisms other than glutamate excitotoxicity caused RGC loss in these mutant mice. Results indicate that oxidative stress due to glutathione (GSH) depletion in Muller cells lacking GLAST is the cause of RGC loss. Glutamate is essential for synthesis of retinal GSH by Muller cells, the major source of GSH in the retina. However, the data presented in Figure 8C-E are again from postnatal RGCs and may or may not relate to the loss of RGCs at eight months in vivo.

Older GLAST deficient mice have significant loss of RGCs in the absence of elevated pressure

This paper underscores the role of Muller cells as the key glia in the retina because of its relationship with all retinal neurons. The authors have made an important contribution by studying older GLAST deficient mice and reporting significant loss of RGCs in the absence of elevated pressure. However, the use of GLAST mutants as a model of normal tension glaucoma remains uncertain.

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