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Editors Selection IGR 7-3
Basic science: Excitotoxicity - glutamate
Comment by Larry Wheeler on:
12564 Functional assessment of glutamate clearance mechanisms in a chronic rat glaucoma model using retinal ganglion cell calcium imaging, Hartwick AT; Zhang X; Chauhan BC et al., Journal of Neurochemistry, 2005; 94: 794-807
In glaucoma, retinal ganglion cells (RGCs) are particularly vulnerable to the insult produced by high intraocular pressure (IOP). There is good evidence in animal models of experimental glaucoma that glutamate excitotoxicity contributes significantly to high IOP induced retinal ganglion cell injury. For example, in mouse, rat and monkey glaucoma models, NMDA receptor channel blockers, such as memantine and MK-801, have been shown to attenuate significantly ganglion cell injury.
In this study, Hartwick et al. (830) designed an elegant experiment to assess the function of the glutamate uptake mechanisms in a rat chronic ocular hypertension model. They used free intracellular Ca++ signals in RGCs as a biosensor to assess indirectly the level of glutamate receptor (mostly the NMDA receptors) activation by exogenously applied glutamate. In the normal isolated retina (an ex vivo preparation that has many properties resembling those seen in vivo), due to a strong glutamate uptake mechanism, a much higher exogenous glutamate concentration is needed in order to elicit a threshold Ca++ response in in situ RGCs compared with glutamate concentration needed to elicit a similar response in dissociated RGCs. The difference in glutamate concentrations needed to elicit comparable Ca++ responses in in situ and dissociated RGCs is for the most part a measure of the capacity of the glutamate clearance mechanism in the isolated retina. The authors compared exogenous glutamate elicited Ca++ signals observed in glaucomatous and fellow control retinas from the same rats and found no obvious difference in glutamate effectiveness. They conclude that there was no evidence for a general impairment in the glutamate uptake system in their rat glaucoma model.
While the finding reported by Hartwick et al. is interesting and helpful in evaluating the role of glutamate uptake mechanism in glaucomatous RGC injury, more studies are warranted to determine whether this is a general phenomenon or a model-specific one. In two other recent studies on another rat model of experimental glaucoma in which high IOP is induced by a laser treatment to the aqueous outflow vessels instead of hypertonic saline injection into episcleral veins, a major glutamate transporter (GLAST) in the retina has been shown to be either down-regulated or up-regulated. It would therefore be interesting to determine whether there is any functional alteration in glutamate clearance in other rat or even monkey models of experimental glaucoma. Also, the present study evaluated glutamate clearance at a time point long after most or all of the glaucoma-induced RGC injury has occurred. At this late stage, the surviving RGCs may represent some functionally distinct subset and glutamate clearance may be very different than that present during RGC injury. For this reason, it would be valuable to determine glutamate clearance at earlier time points in glaucomatous retinas.
Note: important contributions to this comment were received from Joe Adorante and William Hare.
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