Synapse formation in the C. elegans nervous system

描述（由申请人提供）：神经元通过调节突触的突触后表面的分化来调节突触活性，包括到达突触后表面的谷氨酸受体的量。谷氨酸受体运输的变化是完整动物行为可塑性、学习和记忆的基础吗？调节谷氨酸受体定位的信号分子需要完全阐明，以解决这个问题。C.线虫是研究体内谷氨酸受体的一个很好的模型系统。谷氨酸受体亚单位GLR-1是谷氨酸能信号传导所必需的，并且定位于C. elegans神经元在mechanosensory电路。使用正向遗传筛选，我们已经确定了多个基因，调节GLR-1的运输和从突触。其中一个基因编码PDZ结构域蛋白，在哺乳动物中具有直系同源物，该基因的突变导致突触不能从习惯化中恢复。这些基因中的另一个编码泛素连接酶，该基因的突变导致GLR-1受体无法从突触中移除。我们提出了三个目标，了解这些基因在调节神经元突触的作用，以响应行为。首先，我们将描述GLR-1贩运的机械感觉回路的习惯化和恢复过程中的变化。其次，我们将表征泛素连接酶在适应后下调GLR-1的作用方面的分子和细胞生物学功能。第三，我们将表征我们的PDZ结构域蛋白的分子和细胞生物学功能，关于其在从习惯化恢复后上调GLR-1中的作用。这些新基因的分子和细胞生物学功能将为谷氨酸受体的调节机制提供线索。

DESCRIPTION (provided by applicant): Neurons regulate synaptic activity by regulating the differentiation of the postsynaptic face of the synapse, including the amount of glutamate receptors that reach the postsynaptic surface. Do changes in glutamate receptor trafficking underlie behavioral plasticity, learning, and memory in the intact animal? The signaling molecules that regulate glutamate receptor localization need to be completely elucidated to address this question. C. elegans has been an excellent model system for studying glutamate receptors in vivo. The glutamate receptor subunit GLR-1 is required for glutamatergic signaling, and is localized to postsynaptic clusters between C. elegans neurons in a mechanosensory circuit. Using forward genetic screens, we have identified multiple genes that regulate the trafficking of GLR-1 to and from the synapse. One of these genes encodes a PDZ domain protein with orthologs in mammals, and mutations in this gene result in the failure of glutamatergic synapses to recover from habituation. Another of these genes encodes an ubiquitin ligase, and mutations in this gene result in the failure of GLR-1 receptors to be removed from the synapse. We propose three aims for understanding the role of these genes in regulating glutamatergic synapses in response to behavior. First, we will characterize changes in GLR-1 trafficking during habituation and recovery of the mechanosensory circuit. Second, we will characterize the molecular and cell biological function of the ubiquitin ligase with regard to its role in downregulating GLR-1 after habituation. Third, we will characterize the molecular and cell biological function of our PDZ domain protein with regard to its role in upregulating GLR-1 after recovery from habituation. The molecular and cell biological function of these new genes will provide clues to the mechanisms by which glutamate receptors are regulated.