Differential perturbation of neuronal and glial glutamate transport systems in retinal ischaemia

Glutamate is the major excitatory neurotransmitter in the retina and is rem oved from the extracellular space by an energy-dependent process involving neuronal and glial cell transporters. The radial glial Muller cells express the glutamate transporter, GLAST, and preferentially accumulate glutamate. However, during an ischaemic episode, extracellular glutamate concentratio ns may rise to excitotoxic levels. Is this catastrophic rise in extracellul ar glutamate due to a failure of GLAST? Using immunocytochemistry, we monit ored the transport of the glutamate transporter substrate, D-aspartate, in the retina under normal and ischaemic conditions. Two models of compromised retinal perfusion were compared: (1) Anaesthetised rats had their carotid arteries occluded for 7 days to produce a chronic reduction in retinal bloo d flow. Retinal function was assessed by electroretinography. D-aspartate w as injected into the eye for 45 min, Following euthanasia, the retina was p rocessed for D-aspartate. GLAST and glutamate immunocytochemistry. Although reduced retinal perfusion suppresses the electroretinogram b-wave, neither retinal histology, GLAST expression, nor the ability of Muller cells to up take D-aspartate is affected. As this insult does not appear to cause excit otoxic neuronal damage, these data suggest that GLAST function and glutamat e clearance are maintained during periods of reduced retinal perfusion. (2) Occlusion of the central retinal artery for 60 min abolishes retinal perfu sion, inducing histological damage and electroretinogram suppression. Altho ugh GLAST expression appears to be normal. its ability to transport D-aspar tate into Muller cells is greatly reduced. Interestingly, D-aspartate is tr ansported into neuronal cells, i.e. photoreceptors, bipolar and ganglion ce lls. This suggests that while GLAST is vitally important for the clearance of excess extracellular glutamate, its capability to sustain inward transpo rt is particularly susceptible to an acute ischaemic attack. Manipulation o f GLAST function could alleviate the degeneration and blindness that result from ischaemic retinal disease. (C) 2001 Elsevier Science Ltd, All rights reserved.