Dynamic Control of Local Synaptic-Membrane Protein Composition by the Dendritic Secretory Pathway

树突分泌途径动态控制局部突触膜蛋白组成

• 批准号: 9270091
• 负责人: Aaron Bowen
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270091
• 关键词: AMPA Receptors; Address; Alzheimer' s Disease; Area; Autistic Disorder; Cell Adhesion Molecules; Cell membrane; Cell surface; Characteristics; Cognition; Complement; Data; Dendrites; Development; Developmental Delay Disorders; Diffusion; Dimensions; Disease; Endoplasmic Reticulum; Foundations; Future; Glutamate Receptor; Glutamates; Golgi Apparatus; Huntington Disease; Impaired cognition; Integral Membrane Protein; Ion Channel; Kinetics; Lead; Learning; Ligands; Location; Mediator of activation protein; Membrane; Membrane Proteins; Memory; Microscopy; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitter Receptor; Organelles; Pathway interactions; Pharmacology; Plasma; Play; Process; Property; Protein Biosynthesis; Proteins; Resolution; Role; Schizophrenia; Signal Transduction; Site; Spatial Distribution; Stimulus; Surface; Synapses; Synaptic Membranes; Synaptic plasticity; System; Testing; Translating; Translations; Variant; addiction; autism spectrum disorder; base; cognitive function; experience; experimental study; membrane synthesis; neural patterning; neuroligin 1; neuronal cell body; neuropsychiatric disorder; protein transport; public health relevance; receptor; response; small molecule; targeted delivery; trafficking

 DESCRIPTION (provided by applicant): During learning and memory formation, synaptic connections between neurons are selectively reorganized based on patterns of neural activity in a process called "synaptic plasticity". Underlying this phenomenon is the precise, regulated delivery of synaptic proteins, such as neurotransmitter receptors, adhesion molecules and ion channels that modify synaptic strength and cellular excitability in response to activity. Local translation has emerged as an important mechanism that facilitates protein delivery to dendritic locations long-distances from the neuronal soma. A diverse array of soluble and integral-membrane proteins are locally synthesized, including glutamate receptor subunits and neuroligins that are important for certain forms of synaptic plasticity. However, the delivery of integral-membrane proteins is complicated by the fact that they require not just the machinery for protein synthesis, but also trafficking through the entire complement of secretory organelles to reach the cell surface. Studies characterizing the dendritic secretory organelles have revealed that many of the post-endoplasmic reticulum (ER) organelles, such as Golgi Complex, are scarce within the dendrite and their functional significance unclear. Consequently, it is unknown whether locally translated proteins undergo delivery to nearby areas of the dendritic membrane, or if there are specific signals that control their delivery. This proposal addresses the hypothesis that the distribution of synaptic cargo within the dendritic early secretory pathway spatially defines its delivery to the dendritic plasma membrane and that synaptic activity is a key regulatory of this process. I will investigate thhis hypothesis by tracking synaptic proteins as they traffic from the dendritic ER (the site of local synthesis for membrane proteins) to the plasma membrane to determine the range and kinetics of their delivery. The results will reveal whether the secretory pathway exerts spatial and temporal control of trafficking in order to direct cargo to specific dendritic locations, thus selectively modifying certain synapses. Overall, the findings will provide a foundation to understand the contribution of the secretory pathway to fundamental aspects of normal cognition, as well as how perturbed secretory trafficking may lead to cognitive dysfunction in a wide variety of diseases and disorders, including Alzheimer's disease, developmental delay, Huntington's disease, and autistic disorders.