The mechanism of kainic acid neurotoxicity

The putative excitatory transmitters glutamate and aspartate, as well as their excitatory analogues, can kill neurones in the central nervous system and may thus be involved in the pathogenesis of various neurodegenerative disorders. Several studies have suggested that postsynaptic receptors are important in the mechanism of toxicity. However, presynaptic factors might also be involved because, in some brain areas, the neurotoxicity of kainate (a potent structural analogue of glutamate) is greatly reduced following elimination of afferent excitatory innervation, even though the postsynaptic excitatory potency of kainate may be unaltered in these conditions. The supply of glutamate from the afferent nerve endings has been suggested to be a necessary factor. Recently, Ferkany, Zaczec and Coyle concluded from studies on slices of mouse cerebellum that kainate activates presynaptic kainate receptors on parallel fibre terminals to release glutamate and that it is the postsynaptic interaction between kainate and the released amino acid that is instrumental in causing neuronal necrosis. The more direct evidence we report here does not support these conclusions.