Meccanismi molecolari e cellulari dell'ischemia sperimentale nello striato

Neurons express extremely different sensitivity to ischemic insults. Striatal spiny neurons are selectively vulnerable during ischemia, whereas striatal large aspiny (LA) cholinergic interneurons are spared in this pathological condition. The reason for this cell-type specific vulnerability is still largely unknown. Excessive stimulation of glutamate receptors is believed to contribute substantially in determining neuronal vulnerability to ischemia. 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 leading to long-term potentiation of the corticostriatal synaptic transmission or ischemic LTP (i-LTP). This process, which selectively affects the striatal spiny neurons but not the large aspiny cholinergic interneurons, involves the stimulation of both N-methyl-D-aspartate and metabotropic glutamate receptors and the activation of the mitogen-activated protein kinase ERK via protein kinase C. Moreover we show the role of endogenous dopamine in the ischemia-induced neuronal damage. In fact, endogenous dopamine, via D1 receptors, selectively facilitates the expression of i-LTP on the AMPA-mediated component of the EPSPs, while it does not alter the expression of this form of synaptic plasticity on the N-methyl-D-aspartate-mediated component of corticostriatal synaptic potentials. Finally we also illustrate the role of nitric oxide during an ischemic insult. We demonstrate that nitric oxide takes part in ischemia-induced neuronal damage through the activation of guanylate cyclase and protein kinase G. In conclusion, 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. Understanding the cellular and molecular mechanisms of ischemia-triggered excitotoxicity offers hope for the development of specific treatments able to interfere with this pathological process