Muller cell swelling, glutamate uptake, and excitotoxic neurodegeneration in the isolated rat retina

(W)e characterized morphological effects of the endogenous excitotoxin, glu tamate in ex vivo retinal segments prepared from 30-day-old rats. Initial c hanges induced by glutamate consisted of reversible, sodium-dependent Mulle r cell swelling. This glial swelling was mimicked by glutamate transport su bstrates but not by ionotropic glutamate receptor agonists. Only very high concentrations of exogenous glutamate (3,000 mu M) produced excitotoxic neu ronal damage. The neuronal damage was accompanied by severe glial swelling and was blocked by an antagonist of non-N-methyl-D-aspartate (NMDA) recepto rs but not by an NMDA receptor antagonist. Because glutamate uptake can be influenced by changes in cellular energy levels, we studied the effects of oxidative and glycolytic energy depletion on glutamate-mediated Muller cell swelling. Oxygen deprivation produced little morphological change and did not alter either glutamate-mediated Muller cell swelling or glutamate-induc ed excitotoxicity. In contrast, inhibition of glycolysis by iodoacetate pro duced severe neuronal damage without Muller cell swelling. In the presence of iodoacetate, exogenous glutamate failed to cause glial swelling. The neu ronal damage produced by iodoacetate was inhibited by pyruvate, a substrate that sustains oxidative energy pathways. In the presence of iodoacetate pl us pyruvate, glutamate failed to cause Muller cell swelling but became neur otoxic at low concentrations through activation of non-NMDA receptors. Thes e results indicate that glycolytic energy metabolism plays a critical role in sustaining ionic balances required for Muller cell glutamate uptake and glial uptake helps to prevent glutamate-mediated excitotoxicity. (C) 1999 W iley-Liss, Inc.