RESUMEN
Previous work suggests N-methyl-D-aspartate receptor (NMDAR) activation may be involved in degeneration of medium-sized spiny striatal neurons in Huntington's disease (HD). Here we show that these neurons are more vulnerable to NMDAR-mediated death in a YAC transgenic FVB/N mouse model of HD expressing full-length mutant huntingtin, compared with wild-type FVB/N mice. Excitotoxic death of these neurons was increased after intrastriatal injection of quinolinate in vivo, and after NMDA but not AMPA exposure in culture. NMDA-induced cell death was abolished by an NR2B subtype-specific antagonist. In contrast, NMDAR-mediated death of cerebellar granule neurons was not enhanced, consistent with cell-type and NMDAR subtype specificity. Moreover, increased NMDA-evoked current amplitude and caspase-3 activity were observed in transgenic striatal neurons. Our data support a role for NR2B-subtype NMDAR activation as a trigger for selective neuronal degeneration in HD.
Asunto(s)
Muerte Celular/fisiología , Enfermedad de Huntington/patología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas Nucleares/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Caspasa 3 , Caspasas/metabolismo , Células Cultivadas , Cuerpo Estriado/citología , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Humanos , Proteína Huntingtina , Enfermedad de Huntington/metabolismo , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Ratones , Ratones Transgénicos , N-Metilaspartato/farmacología , Proteínas del Tejido Nervioso/genética , Neuronas/citología , Neuronas/efectos de los fármacos , Proteínas Nucleares/genética , Técnicas de Placa-ClampRESUMEN
Evidence suggests N-methyl-D-aspartate receptor (NMDAR) activation is involved in the degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). We tested the hypothesis that enhanced NMDAR-mediated excitotoxicity is mediated by the mitochondrial-associated apoptotic pathway in cultured MSNs from YAC transgenic mice expressing full-length huntingtin (htt) with a polyglutamine (polyQ) expansion of 46 or 72 (YAC46 or YAC72). NMDAR-mediated Ca(2+) transients and mitochondrial membrane depolarization were significantly increased in YAC compared to wild-type mice MSNs. Inhibitors of the mitochondrial permeability transition (mPT), cyclosporin A and bongkrekic acid, and coenzyme Q10 (an anti-oxidant involved in bioenergetic metabolism) dramatically diminished NMDA-induced cell death and eliminated genotypic differences. In YAC46 MSNs, NMDA stimulated significantly higher activation of caspase-3 and caspase-9 but not caspase-8, and NMDA-induced caspase-3 and -9 activation was markedly attenuated by cyclosporin A. Agents that improve mitochondrial function or inhibit the permeability transition may eliminate increased caspase activation and cell death associated with enhanced NMDAR activity in HD.