MOLECULAR CHARACTERIZATION OF GLUTAMATE RECEPTOR EXPRESSION IN BRAIN

发育中和成人活动依赖的神经可塑性 在很大程度上由N-甲基-D-天冬氨酸受体(NR)激活介导； 这种兴奋性氨基酸受体的天然配体是谷氨酸。这个 NMDA受体激活对神经可塑性的影响很大 由钙内流调节，这需要调节，因为 过量的钙离子进入会杀死神经元。出于这个原因，监管 NR通道动力学特性对信号有重要影响 由这些受体转导。在此期间，NR功能发生了变化 因应活动而发展。我们发现，这个表达方式 NR2B抑制和NR2C激活的模式与 颗粒细胞神经支配的时空模式。下调监管 NR2BmRNAs，发生在颗粒细胞迁移到 他们接受传入输入的IGL可能是突触引起的 活动。因此，不同的NR亚基不仅可以发挥明显的作用 调节突触连接以响应活动，但它们的 表达模式也可能对表观遗传因素做出反应。 转录调控是指导细胞类型的一种常见机制 基因在发育和成体中的特定表达。在……里面 才能开始了解指挥 NR基因在神经发生和发育过程中的区域特异性转录 调节它们的水平以响应突触的活动，我们已经开始 研究控制NR2亚基表达的机制 在转录水平上。我们已经发现NR2B的转录 转录从不同的位置开始，尽管差异很大 启动子的使用不能解释NR2B在 小脑自启动以来的发育模式是相同的 和前脑。转基因小鼠的调控区分析揭示 不同的DNA调控序列是需要的 该基因的神经特异性和发育调节。我们有 确定了一个800bp的上游区域，该区域指导神经特异性 在转基因小鼠中转录，但未能传递适当的 小脑中该基因的发育下调。其他内容 位于主要起始点下游的顺式作用序列， 可能位于第一内含子内，被证明是必要的 抑制小脑发育过程中NR2B的表达。

Activity-dependent neural plasticity during development and in the adult is largely mediated by N-methyl-D-aspartate receptor (NR) activation; the natural ligand for this excitatory amino acid receptor is glutamate. The effects of NMDA receptor activation on neural plasticity are largely mediated by the calcium influx, which needs to be regulated since excessive Ca2+ entry kills neurons. For this reason, the regulation of NR channel kinetic properties has important consequences on the signals transduced by these receptors. There are changes in NR function during development in response to activity. We have found that the expression patterns of NR 2B repression and NR 2C activation closely follow the spatial-temporal pattern of granule cell innervation. The down-regulation of NR 2B mRNAs, which occurs after granule cells have migrated into the IGL where they receive afferent inputs, may result from synaptic activity. Thus, different NR subunits may not only function to distinctly modulate synaptic connections in response to activity, but their expression patterns may also be responsive to epigenetic factors. Transcriptional control is a common mechanism directing cell-type specific expression of genes during development and in the adult. In order to begin understanding the complex mechanisms that direct regional-specific transcription of NR genes during neurogenesis and modulate their levels in response to synaptic activity, we have begun to investigate the mechanisms that control expression of the NR2 subunits at the transcriptional level. We have found that transcription of NR 2B transcripts is initiated from different sites, however differential promoter use cannot account for the patterns of NR 2B expression during development since the patterns of initiation were the same in cerebellum and forebrain. Analysis of regulatory regions in transgenic mice reveal that distinct DNA regulatory sequences are required for the neural-specific and developmental regulation of the gene. We have identified an 800bp upstream region that directs neural-specific transcription in transgenic mice but fails to impart the proper developmental down-regulation of the gene in cerebellum. Additional cis-acting sequences residing downstream of the major initiation sites, possibly located within the first intron, were shown to be necessary to repress NR 2B expression during cerebellar development.