Altered glutamatergic transmission in neurological disorders: from high extracellular glutamate to excessive synaptic...

This review is a critical appraisal of the widespread assumption that high extracellular glutamate, resulting from enhanced pre-synaptic release superimposed on deficient uptake and/or cytosolic efflux, is the key to excessive glutamate-mediated excitation in neurological disorders. Indeed, high extracellular glutamate levels do not consistently correlate 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 receptor antagonists does not imply involvement of high extracellular glutamate 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 glutamatergic transmission which may contribute to the pathology, and lead to excitotoxic injury. These may include the following: (i) increased density of glutamate receptors; (ii) altered ionic selectivity of ionotropic glutamate receptors; (iii) abnormalities in their sensitivity and modulation; (iv) enhancement of glutamate-mediated synaptic efficacy (i.e. a pathological form of long-term potentiation); (v) phenomena such as spreading depression which require activation of glutamate receptors and can be detrimental to the survival of neurons. Such an extension would take into account the diversity of glutamate-receptor-mediated processes, match the complexity of neurological disorders pathogenesis and pathophysiology, and ultimately provide a more elaborate scientific basis for the development of innovative treatments.