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中起重要作用，而且在突触可塑性和神经毒性中也起重要作用。它们被细分为四个亚家族：α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体、红藻氨酸受体、N-甲基-D-天冬氨酸受体和δ谷氨酸受体。主要在浦肯野细胞中表达的delta 2谷氨酸受体（GluRd 2）在小脑功能中起着至关重要的作用：具有破坏的GluRd 2基因的突变小鼠（delta 2缺失小鼠）显示出受损的突触形成和废除的长期抑制（LTD），这是一种突触基础运动学习的形式。尽管它的重要性，delta 2调节小脑功能的机制仍然难以捉摸。几个基本问题，如GluRd 2是否被谷氨酸激活以及GluRd 2是否形成离子通道，在很大程度上仍然是难以捉摸的，因为没有特定的药理学工具来操纵。 关于我们 为了克服缺乏药理学工具所带来的问题，我们利用GluRd 2的几个重要区域，如假定的配体结合和通道孔结构域，与AMPA受体具有相当大的相似性这一事实，采用了“转基因拯救”的方法。我们引入了突变型GluRd 2转基因，其中在假定的配体结合或通道孔结构域的保守残基被破坏，到GluRd 2空浦肯野细胞的病毒载体或转基因小鼠。令人惊讶的是，突变型GluRd 2转基因在拯救GluRd 2缺失小鼠方面与野生型GluRd 2一样有效。因此，我们建议，GluRd 2可能不会被谷氨酸激活，可能不会作为一个离子通道，虽然它属于“离子型谷氨酸受体”的家庭。相反，废除LTD没有恢复GluRd 2-null浦肯野细胞的突变GluRd 2转基因缺乏C-末端结构域的转导。因此，GluRd 2可能通过其C-末端细胞内结构域调节细胞内信号传导途径发挥作用，其中几种衔接蛋白结合。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