Schematic of mechanisms implicated in ischemia-induced neuronal death (in red) and the development of ischemic tolerance (in blue) in the brain. During ischemia, glutamate is released into the synaptic cleft and activates NMDA receptors, increasing calcium entry. Calcium activates multiple pathways, promoting cellular injury via the generation of oxygen and NO radicals and the activation of catabolic enzymes. Sublethal insults may induce cytoprotective tolerance, in large part through similar NMDA receptor– and calcium-mediated pathways. Contributing prominently to the development of ischemic tolerance may be alterations in nerve terminals that increase release of GABA and reduce release of glutamate. GABA likely acts both presynaptically through GABA_B receptors (and G-proteins) to decrease glutamate release and postsynaptically through GABA_A receptors (and the gating of Cl^– channels to counter membrane depolarization and to limit calcium entry).