Maintenance of synapses and formation of memory in the adult brain : new mechanisms regulated by the delta2 glutamate receptor

离子型谷氨酸受体在哺乳动物脑内不仅在神经传递、突触可塑性和神经毒性等方面发挥着重要作用。它们被细分为四个亚家族：alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸(AMPA)受体、红藻氨酸受体、N-甲基-D-天冬氨酸受体和β-谷氨酸受体。Delta2谷氨酸受体(GluRd2)主要表达在Purkinje细胞中，在小脑功能中起着至关重要的作用：GluRd2基因缺失的突变小鼠(Delta2缺失小鼠)表现出突触形成障碍和长期抑郁(LTD)，这是一种突触基础运动学习的形式。尽管Delta2很重要，但它调节小脑功能的机制仍然不清楚。一些基本的问题，如谷氨酸是否激活GluRd2，以及GluRd2是否形成离子通道，在很大程度上仍然难以捉摸，这主要是因为没有特定的药物工具来操纵…为了克服缺乏药理工具带来的问题，我们利用GluRd2的几个重要区域，如可能的配体结合区域和通道孔区，与AMPA受体有相当大的相似性，从而采用了“转基因拯救”的方法。我们通过病毒载体或转基因小鼠将突变的GluRd2转基因基因引入到GluRd2缺失的Purkinje细胞中，其中假定的配体结合或通道孔区的保守残基被破坏。令人惊讶的是，突变的GluRd2转基因基因在拯救GluRd2缺失的小鼠方面与野生型GluRd2基因一样有效。因此，我们认为GluRd2可能不被谷氨酸激活，也可能不作为离子通道发挥作用，尽管它属于“离子型谷氨酸受体”家族。相反，在GluRd2缺失的Purkinje细胞中，通过转导缺乏C-末端结构域的突变的GluRd2转基因，并没有恢复被取消的LTD。因此，GluRd2可能通过其C端胞内结构域调节细胞内信号通路发挥作用，几个接头蛋白与该结构域结合。较少

The ionotropic glutamate receptors play important roles in not only neurotransmission, but also synaptic plasticity and neurotoxicity in the mammalian brain. They are subdivided into four subfamilies: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainate receptors, N-methyl-D-aspartate receptors, and delta glutamate receptors. The delta2 glutamate receptor (GluRd2), which is predominantly expressed in Purkinje cells, plays a crucial role in cerebellar functions : mutant mice with a disrupted GluRd2 gene (delta2-null mice) display impaired synapse formation and abrogated long-term depression (LTD), a form of synaptic underlying motor learning. Despite its importance, the mechanisms by which delta2 regulates cerebellar functions have remained elusive. Several fundamental questions, such as whether GluRd2 is activated by glutamate and whether GluRd2 forms ion channels, have remained elusive largely because there were no specific pharmacologic tools to manipula … More te the function of GluRd2.To circumvent the problem caused by the lack of pharmacologic tools, we employed a "transgenic rescue" approach by exploiting the fact that the several important regions, such as the putative ligand-binding and the channel pore domains, of GluRd2 shares considerable similarity with those of AMPA receptors. We introduced a mutant GluRd2 transgene, in which the conserved residues in the putative ligand-binding or channel pore domains were disrupted, into GluRd2-null Purkinje cells by either virus vectors or transgenic mice. Surprisingly, the mutant GluRd2 transgenes were as effective as the wild-type GluRd2 in rescuing the GluRd2-null mice. Thus, we propose that GluRd2 may not be activated by glutamate and may not function as an ion channel although it belongs to the "ionotropic glutamate receptor" family. In contrast, abrogated LTD was not restored in GluRd2-null Purkinje cells by the transduction of a mutant GluRd2 transgene lacking the C-terminal domain. Therefore, GluRd2 may function by modulating an intracellular signalling pathway through its C-terminal intracellular domain, to which several adaptor proteins bind. Less