Receptor and post-receptor mechanisms of ischemic long-term potentiation in the striatum.

On the basis of a large body of experimental data showing that pharmacological modulation of glutamate receptors has a great impact on ischemia-induced neuronal death, excessive activation of glutamate receptors is widely accepted as one of the most important determinants in the development of tissue damage produced by cerebral ischemia (1). In spite of this evidence, howe v e r, how energy deprivation predisposes to excitotoxic insults is still largely unclear. Energ y supply failure causes both preand postsynaptic alteration of excitatory transmission, which mainly involves abnormal release of glutamate into the extracellular space, impairment of glutamate reuptake processes, and increased postsynaptic sensitivity of glutamate receptors (2,3). This latter pathological event is commonly attributed to anoxic cell membrane depolarization and, consequently, to the relief of the voltage-dependent block of glutamate NMDA receptors. NMDA receptors, in fact, are accredited as the most important source of free cytosolic calcium, recognized as a critical component of the intracellular events leading to neuronal death (1,4). Stimulation of other glutamate receptors, howeve r, also favors excitotoxic damage in the ischemic brain. It has been shown, in fact, that both AMPA/kainate antagonists and group I metabotropic glutamate receptor (mGluR) blockers protect hippocampal and cortical neurons after transient global ischemia (5,6). All these observations are convergent with the classical notion that ischemic injury causes neurons to und e rgo acute necrotic death, as a result of a severe perturbation of ionic homeostasis between the internal and external plasma membrane and of the consequent neuronal swelling. Overstimulation of AMPA/kainate and NMDA receptors, in fact,