ABSTRACT
N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity is implicated as a proximate cause of neurodegeneration in Huntington Disease (HD). This hypothesis has not been tested rigorously in vivo. NMDAR-NR2B subunits are a major NR2 subunit expressed by striatal medium spiny neurons that degenerate in HD. To test the excitotoxic hypothesis, we crossed a well validated murine genetic model of HD (Hdh((CAG)150)) with a transgenic line overexpressing NMDAR-NR2B subunits. In the resulting double-mutant line, we show exacerbation of selective striatal neuron degeneration. This is the first direct in vivo evidence of NR2B-NMDAR-mediated excitotoxicity in the context of HD. Our results are consistent with previous suggestions that direct and/or indirect interactions of mutant huntingtin with NMDARs are a proximate cause of neurodegeneration in HD.
Subject(s)
Disease Models, Animal , Huntington Disease/genetics , Huntington Disease/metabolism , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Female , Humans , Huntingtin Protein , Huntington Disease/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Nuclear Proteins/genetics , Nuclear Proteins/physiology , Receptors, N-Methyl-D-Aspartate/geneticsABSTRACT
Considering the great physiological and behavioral similarities with humans, monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the preclinical research and development of novel therapeutics for treating human diseases. Various powerful genetic technologies initially developed for making mouse models are being explored for generating transgenic primate models. We review the latest genetic engineering technologies and discuss the potentials and limitations for systematic production of transgenic primates.