Synapse formation in the C. elegans nervous system

描述(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的活动，包括到达突触后表面的谷氨酸受体的数量。谷氨酸受体转运的变化是否是完整动物行为可塑性、学习和记忆的基础？为了解决这个问题，需要完全阐明调节谷氨酸受体定位的信号分子。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是谷氨酸能信号转导所必需的，定位于机械感觉回路中线虫神经元之间的突触后簇。使用正向基因筛查，我们已经确定了多个基因，这些基因调控GLR-1进出突触的运输。其中一个基因编码一个PDZ结构域蛋白，与哺乳动物中的同源基因，该基因的突变导致谷氨酸能突触无法从习惯性中恢复。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。为了了解这些基因在调节谷氨酸能突触对行为的反应中的作用，我们提出了三个目标。首先，我们将描述机械感觉回路习惯化和恢复过程中GLR-1转运的变化。其次，我们将描述泛素连接酶在习服后下调GLR-1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，关于它在习惯性恢复后上调GLR-1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控机制提供线索。

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.