CALCIUM-PERMEABLE AMPA RECEPTORS AND MOTONEURON SURVIVAL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 钙离子通过离子型谷氨酸受体的内流是早期胚胎发育活性依赖性调节所需的钙离子内流的主要来源之一。NMDA受体最初被认为是钙离子通过谷氨酸受体内流的唯一来源；然而，AMPA受体也允许大量的钙离子内流。AMPA受体的钙通透性是通过插入至少一个编辑的GluR2亚基来调节的，这显著地降低了钙通透性。以鸡脊髓为模型，我们证明了AMPA受体在运动神经元发育的早期阶段是钙离子通透性的。然而，AMPA受体在胚胎第11天变得不透钙，此时后肢神经肌肉系统的分化几乎完成，功能性突触和能够产生自发收缩的收缩肌肉。AMPA受体钙通透性的发育转换是由运动神经元中GluR2表达增加触发的。因此，问题出现了，在脊髓发育的早期阶段，瞬时表达的、钙离子渗透性的AMPA受体在发育中的作用是什么。我们假设E8表达GluR2将通过抑制通过AMPA受体的钙内流来促进运动神经元的存活。在这里，我们打算追求以下特定的目标：测试GluR2表达下调是否扰乱了运动神经元在体内的正常存活模式。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ca2+ influx through ionotropic glutamate receptors constitutes one main source of Ca2+ entry required for activity-dependent regulation of early embryonic development. NMDA receptors were originally thought to be the sole source of Ca2+ influx through glutamate receptors; however, AMPA receptors also allow a significant influx of Ca2+ ions. The Ca2+ permeability of AMPA receptors is regulated by the insertion of at least one edited GluR2 subunit, which significantly reduces the Ca2+ permeability. Using the chick spinal cord as a model, we have demonstrated that AMPA receptors are Ca2+ permeable at early stages of motoneuron development. However, AMPA receptors become Ca2+ impermeable by embryonic day 11, when differentiation of the hindlimb neuromuscular system is virtually complete with functional synapses and contractile muscles capable of generating spontaneous contractions. The developmental switch in the Ca2+ permeability of AMPA receptors is triggered by increased GluR2 expression in motoneurons. Thus, the question arises what is the developmental role of transiently expressed, Ca2+-permeable AMPA receptors at early stages of spinal cord development. We hypothesize that GluR2 expression by E8 will promote motoneuron survival by dampening Ca2+ influx through AMPA receptors. Here we propose to pursue the following specific aim: to test whether downregulation of GluR2 expression disrupts the normal pattern of motoneuron survival in vivo.