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

谷氨酸是脑中主要的兴奋性神经递质，作用于离子型谷氨酸受体（iGluRs）的三种亚型，AMPA、红藻氨酸和NMDA受体。有证据表明，异常的NMDA受体介导的钙内流进入神经元导致兴奋毒性细胞死亡。通过AMPA和红藻氨酸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导致慢性神经退行性疾病。我们将通过单独研究iGluR介导的钙流改变的突变小鼠的变性以及与已知引起亨廷顿病的突变基因的组合来验证这一假设：敲除小鼠选定脑区域中的NMDA受体，并确定这是否保护这些脑区域免受神经变性病理学的影响。产生具有红藻氨酸盐或AMPA-R的突变小鼠，这些突变小鼠流动异常高的钙量，并确定这是否使小鼠大脑易于发生神经退行性病变。这些实验将提供有价值的动物模型，使人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疗法提供宝贵的资源。

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.