CONTRIBUTION OF GLIAL METABOLISM TO NEURONAL DAMAGE CAUSED BY PARTIALINHIBITION OF ENERGY-METABOLISM IN RETINA

Glial cells are relatively resistant to energy impairment, although li ttle is known of the extent to which glial metabolism is affected duri ng partial energy impairment and how this influences neurons. Fluoroci trate has been shown to be a glial specific metabolic inhibitor. Its s elective effect on chick retinal Muller cells was verified by measurin g incorporation of radiolabel from H-3-acetate and U-C-14-glucose into glutamate and glutamine following exposure of isolated embryonic day 15-18 chick retina to 20 mu M fluorocitrate. Fluorocitrate significant ly reduced the incorporation of radiolabel from acetate and glucose in to glutamine, with less effect on incorporation of label from acetate into glutamate and no reduction of label from glucose into glutamate. The relative specific activity (RSA; ratio of glutamine to glutamate) increased between embryonic day 15 and 18 consistent with the increase in glutamine synthetase activity that occurs in Muller cells at this time in chick retinal development. As with previous findings, mild ene rgy stress produced by inhibiting glycolysis with the general inhibito r iodoacetate (IOA) for up to 45 min, caused acute neuronal damage tha t was predominately NMDA receptor mediated and occurred in the absence of a net efflux of excitatory amino acids. Acute NMDA-mediated toxici ty in this preparation is characterized by the selective damage to ama crine and ganglion cells and quantitatively, by GABA release into the medium. When IOA was combined with fluorocitrate, acute toxicity was p otentiated and temporally accelerated. Acute damage was first noted at 15 min, occurred throughout all retinal layers and was accompanied by an overflow of excitatory amino acids at 30 and 45 min. Blocking NMDA receptors with MK-801 during IOA plus fluorocitrate exposure attenuat ed the rise in excitatory amino acids and prevented the swelling in ne uronal, but not Muller cells. Following incorporation of radiolabel fr om acetate and glucose into glutamate and glutamine after different ti mes of exposure to IOA showed that while the effects of incorporation of label from glucose were immediate, glutamine synthesis from acetate was preserved for a longer period of time. These findings suggest tha t during a partial energy impairment, neuronal metabolism is affected to a greater extent than is glial metabolism. Glial cells may play a p rotective role in this situation, and can delay the onset of acute neu ronal damage. (C) 1997 Academic Press Limited.