ALTERED GLUTAMATERGIC TRANSMISSION IN NEUROLOGICAL DISORDERS - FROM HIGH EXTRACELLULAR GLUTAMATE TO EXCESSIVE SYNAPTIC EFFICACY

This review is a critical appraisal of the widespread assumption that high extracellular glutamate, resulting from enhanced pre-synaptic rel ease superimposed on deficient uptake and/or cytosolic efflux, is the key to excessive glutamate-mediated excitation in neurological disorde rs. Indeed, high extracellular glutamate levels do not consistently co rrelate with, nor necessarily produce, neuronal dysfunction and death in vivo. Furthermore, we exemplify with spreading depression that the sensitivity of an experimental or pathological event to glutamate rece ptor antagonists does not imply involvement of high extracellular glut amate levels in the genesis of this event. We propose an extension to the current, oversimplified concept of excitotoxicity associated with neurological disorders, to include alternative abnormalities of glutam atergic transmission which may contribute to the pathology, and lead t o excitotoxic injury. These may include the following: (i) increased d ensity of glutamate receptors; (ii) altered ionic selectivity of ionot ropic glutamate receptors; (iii) abnormalities in their sensitivity an d modulation; (iv) enhancement of glutamate-mediated synaptic efficacy (i.e. a pathological form of long-term potentiation); (v) phenomena s uch as spreading depression which require activation of glutamate rece ptors and can be detrimental to the survival of neurons. Such an exten sion would take into account the diversity of glutamate-receptor-media ted processes, match the complexity of neurological disorders pathogen esis and pathophysiology, and ultimately provide a more elaborate scie ntific basis for the development of innovative treatments. (C) 1997 El sevier Science Ltd.