CHRONIC INHIBITION OF GLUTAMATE UPTAKE PRODUCES A MODEL OF SLOW NEUROTOXICITY

Defects in neurotransmitter glutamate transport may be an important co mponent of chronic neurotoxicity in diseases such as amyotrophic later al sclerosis. There are no reliable models of slow glutamate neurotoxi city. Most previous in vitro systems have studied the rapid neurotoxic effects of direct-acting glutamate agonists. Therefore, we developed a model of slow toxicity in cultured organotypic spinal cord slices. T he model was based on selective inhibition of glutamate transport, whi ch continuously raised the concentration of glutamate in the culture m edium. This resulted in the slow degeneration of motor neurons over se veral weeks. Motor neuron toxicity was selectively prevented by non-N- methyl-D-aspartate glutamate receptor antagonists and glutamate synthe sis or release inhibitors but not by N-methyl-D-aspartate receptor ant agonists. Thus, selective inhibition of glutamate transport produces a model of clinically relevant slow neurotoxicity and appears to be med iated by the action of non-N-methyl-D-aspartate receptors. This data s upports the hypothesis that the slow loss of motor neurons in amyotrop hic lateral sclerosis could be due, in part, to defective glutamate tr ansport.