Excessive stimulation of glutamate receptors is believed to contribute substantially in determining neuronal vulnerability to ischemia. However, how this pathological event predisposes neurons to excitotoxic insults is still largely unknown. By using electrophysiological recordings from single striatal neurons, we demonstrate in a corticostriatal brain-slice preparation that in vitro ischemia (glucose and oxygen deprivation) activates a complex chain of intracellular events responsible for a dramatic and irreversible increase in the sensitivity of striatal neurons to synaptically released glutamate. This process follows the stimulation of both N-methyl-D-aspartate and metabotropic glutamate receptors and involves the activation of the mitogen-activated protein kinase ERK via protein kinase C. This pathological form of synaptic plasticity might play a role in the cell type-specific neuronal vulnerability in the striatum, because it is selectively expressed in neuronal subtypes that are highly sensitive to both acute and chronic disorders involving this brain area.