Excitotoxicity in Huntington disease

摘要

Activation of ionotropic glutamate receptors mediates most fast excitatory synaptic transmission in the brain. Overstimulation of these receptors due to their enhanced responsiveness, or else increased release or decreased uptake of glutamate, can result in neuronal stress or even death via the excessive influx of water and ions - especially calcium. Previous studies have shown that direct injection of glutamate receptor agonists, particularly those that activate the calcium-permeable N -methyl-d-aspartate (NMDA)-type receptors, into the striatum of rodents or non-human primates produces neurochemical, neuropathological, and behavioral changes characteristic of Huntington disease (HD). Identification of the gene associated with HD, encoding the protein huntingtin with an expanded glutamine repeat >35 near its N-terminus, has facilitated testing the hypothesis that excitotoxicity plays a role in the pathogenesis of HD. Recent data reviewed here support this hypothesis. NMDA receptor-mediated current andcell death are enhanced in non-neuronal cell lines expressing mutant huntingtin and in striatal neurons from transgenic mice models of HD. The specificity of these effects for the NR2B-subtype of NMDA receptors may, in part, explain selective degeneration of certain neuronal populations in HD. An increased understanding of the pathways downstream of NMDA receptor overactivation that mediate neuronal stress and death in these model systems will enhance development of new therapies to slow or delay onset of HD. < copyright > 2003 Elsevier B.V. All rights reserved.