Strategies for studies of neurotoxic mechanisms involving deficient transport of L-glutamate: Antisense knockout in rat brain in vivo and changes in the neurotransmitter metabolism following inhibition of glutamate transportin guinea pig brain slices

This communication briefly reviews characteristics of glutamate transport i n the central nervous system and discusses the hypothesis that deficient gl utamate transport is involved in the aetiology of slow neurodegenerative di seases. Data in the literature suggest that antisense oligonucleotides targ eted against glutamate transporters and administered in vivo over a period of days could be used to test the hypothesis. Data from our laboratory have indicated that single intraventricular doses of antisense oligonucleotides can also result in significant reductions in the numbers of substrate bind ing sites associated with glutamate transporters and may even cause subtle changes in their characteristics. In order to study possible effects of def icient glutamate transport on the metabolism in brain tissue, we have used C-13-nuclear magnetic resonance spectroscopy to analyse extracts of slices of guinea pig cerebral cortex exposed to glutamate transport inhibitor L-an ti,endo-methanopyrrolidine dicarboxylate (L-a,e-MPDC). The results have sho wn-for the first time in an experimental model that preserves the relations hip between glia and neurones within the context of brain tissue-that inhib ition of L-glutamate transport can exert a significant influence on neurotr ansmitter-related metabolism. These findings suggest that metabolic disturb ances caused by deficient glutamate transport could play a significant role in the death of neurones under pathological conditions in vivo. (C) 2000 E lsevier Science Inc.