Differential role of synaptic an extrasynaptic NMDA receptors in glutamate mediated neuronal injury

Abstract

It has been known for 30 years that high concentrations of glutamate induce cell death in vitro and that similar extracellular concentrations are present in the rodent brain during ischaemia. It was subsequently shown that NMDA receptors mediate most of the glutamate-induced cell death in vitro and in vivo. Taken together, these data suggested that administration of NMDA antagonists in human beings could prevent cell death and confer neuroprotection after stroke. However, discouraging news started to accumulate as the clinical trials were terminated. Despite these developments, the theory of glutamate-induced excitotoxicity, the major power that forced NMDA receptor antagonists into human trials, has not been questioned. So it is possible that a fundamental misunderstanding of the pathophysiological roles of NMDA receptors may have been at the origin of absence of efficacy of glutamate antagonists in the treatment of stroke in Man. In the present study, we investigate the influence of NMDA receptors cellular locations on excitotoxicity.