N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease.
Many lines of evidence support a role for neuronal damage arising as a result of excessive activation of glutamate receptors by excitatory amino acids in the pathogenesis of Huntington disease. The N-methyl-d-aspartate subclass of ionotropic glutamate receptors (NMDARs) is more selective and effective than the other subclasses in mediating this damage. As well, neurons expressing high levels of NMDARs are lost early from the striatum of individuals affected with Huntington's disease (HD), and injection of NMDAR agonists into the striatum of rodents or non-human primates recapitulates the pattern of neuronal damage observed in HD. Altered NMDAR function has been reported in corticostriatal synapses in one mouse model of HD, and NMDAR-mediated current and/or toxicity have been found to be potentiated in striatal neurons from several HD mouse models as well as heterologous cells expressing the mutant huntingtin protein. Changes in NMDAR activity have been correlated with altered calcium homeostasis, mitochondrial membrane depolarization and caspase activation. NMDAR stimulation is also closely linked to mitochondrial activity, as treatment with mitochondrial toxins has been demonstrated to produce striatal damage that can be reversed by the addition of NMDAR antagonists. Recent efforts have focused on the elucidation of molecular pathways linking huntingtin to NMDARs, as well as the mechanisms which underlie the enhancement of NMDAR activity by mutant huntingtin. Here, we review the literature to date and recent findings concerning the role of NMDARs in HD pathogenesis.
Fan
Mannie M Y
MM
Department of Psychiatry/Kinsmen Laboratories of Neurological Research, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.
Raymond
Lynn A
LA
D000818:Animals; D004195:Disease Models, Animal; D018846:Excitatory Amino Acids / Q000633:toxicity*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D018846:Excitatory Amino Acids; D016194:Receptors, N-Methyl-D-Aspartate