The role of glutamate receptor mediated excititoxicity in neurodegeneration and Huntington's disease

谷氨酸是大脑中主要的兴奋性神经递质，作用于三种类型的嗜离子性谷氨酸受体（iGluRs）， AMPA， kainate和NMDA受体。有证据表明，异常的NMDA受体介导的钙流入神经元可导致兴奋性毒性细胞死亡。通过AMPA和盐酸盐受体的钙内流也与兴奋性毒性神经变性有关。人们普遍认为，兴奋性毒性与慢性神经退行性疾病有关。我们将通过研究突变小鼠的退行性变来验证这一假设，突变小鼠仅具有改变的iGluR介导的钙通量，并结合已知引起亨廷顿氏病的突变基因：在小鼠的选定脑区域中敲除NMDA受体，并确定是否保护这些脑区域免受神经退行性病理。产生带有kainate或AMPA-Rs的突变小鼠，这些突变小鼠的钙通量异常高，并确定这是否使小鼠的大脑容易发生神经退行性病理。这些实验将提供有价值的动物模型，使我们能够更深入地了解神经退行性过程。这些模型还将为开发预防神经变性的治疗方法提供宝贵的资源。

Glutamate, the principal excitatory neurotransmitter in the brain, acts on three subtypes of ionotropic glutamate receptors (iGluRs), AMPA, kainate and NMDA receptors. Evidence suggests that aberrant NMDA receptor mediated calcium influx into neurons leads to excitotoxic cell death. Calcium influx through AMPA and kainate receptors has also been implicated in excitotoxic neurodegeneration. It is widely thought that excitotoxicity contributes to chronic neurodegenerative disease. We will test this hypothesis by investigating degeneration in mutant mice with altered iGluR mediated calcium flux alone and combined with mutant genes known to cause Huntington s disease by: knocking-out the NMDA receptor in select brain regions of mice and determining if that protects against neurodegenerative pathology in those brain regions. generating mutant mice with kainate or AMPA-Rs that flux abnormally high amounts of calcium and determine if that predisposes the mouse brains to neurodegenerative pathology. These experiments will provide valuable animal models enabling a deeper understanding of neurodegenerative processes. The models will also provide invaluable resources for developing therapies to protect against neurodegeneration.