Polarity determinants in synaptic stability and plasticity

突触稳定性和可塑性的极性决定因素

基本信息

批准号：
9102286
负责人：
Huaye Zhang
金额：
$ 34.34万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102286
关键词：
Address Affect Animals Autistic Disorder Axon Binding Biochemical Bipolar Disorder Brain Cells Characteristics Complex Data Dendrites Dendritic Spines Electrophysiology (science)Ensure Epithelial Cells Epithelium Equilibrium Fluorescence Resonance Energy Transfer Glutamates Health Human Human body Image Imaging Techniques Knockout Mice Learning Life Light Major Depressive Disorder Mediating Membrane Memory Modeling Molecular Molecular Conformation Morphogenesis Motor Mus Mutation N-Methyl-D-Aspartate Receptors Neurons Occupations Pattern Phosphorylation Play Postdoctoral Fellow Process Proteins Research Personnel Role Schizophrenia Specificity Synapses Synaptic Transmission Synaptic plasticity Testing Time Training Vertebral column Work cell type cognitive function in vivo imaging insight interdisciplinary approach long term memory molecular imaging neuropsychiatric disorder protein degradation scaffold skills two-photon zygote

项目摘要

DESCRIPTION (provided by applicant): The stability and plasticity of synapses are both important for cognitive functions. Plasticity is necessary for learning, while stably formed synapses are believed to encode for long term memory. Yet it is unclear how neurons can maintain this delicate balance and achieve both stability and plasticity in synapses just a few microns apart. Clearly, a high level of compartmentalization is required, which makes polarity proteins ideal candidates to function in this capacity, as they serve to separate and maintain distinct membrane domains. Indeed, we previously showed that a class of polarity proteins called Par (partitioning defective) proteins plays a key role in dendritic spine morphogenesis, with Par1, Par3 and Par6 important for this process. Interestingly, our preliminary studies show that most of the spines in mature neurons are dominated by Par3 and Par6, whereas a smaller fraction of spines are dominated by Par1. This distribution pattern resembles that of Par proteins in developing zygotes and epithelial cells, where Par1 and the Par3/6 complex show opposite localization by mutually excluding each other from their respective domains. Furthermore, our previous studies suggest that Par3 and Par6, which form a complex with atypical PKC (aPKC), promote spine stability and maturation, whereas our preliminary results suggest that Par1 promotes spine plasticity. These data raise the exciting possibility that the Par3/6 complex and Par1 regulate the balance between stability and plasticity of spines, with Par3/6-dominant spines being more stable and Par1-dominant spines being more plastic. We plan to test this overarching hypothesis through two aims. In aim1, we will test the hypothesis that Par1 promotes synaptic plasticity and that plasticity is maintained by increasing the dynamics of the PSD scaffold and by excluding the Par3/6 complex. In aim 2, we will test the hypothesis that the Par3/Par6/aPKC complex promotes synaptic stability and that stability is maintained in part by excluding Par1 from the spines. We will utilize advanced molecular imaging techniques, including FRET, FRAP, fluorescent light-inducible proteins (FLIPs) and 2-photon glutamate uncaging. In addition, we will use 2-photon imaging in live mice to directly test our hypothesis in behaving animals. We will combine these imaging approaches with biochemical analysis as well as electrophysiology. This interdisciplinary approach will allow us to gain fundamental insight into the cellular and molecular mechanisms of synaptic stability and plasticity. Moreover, multiple lines of evidence are pointing to an important role for Par polarity proteins in neuropsychiatric disorders, including schizophrenia, autism, major depressive disorder and bipolar disorder. Thus, our studies will provide mechanistic insight into synaptic plasticity and stability and may shed light on several devastating abnormalities that affect the human brain.

描述（由申请人提供）：突触的稳定性和可塑性对于认知功能都很重要，而稳定形成的突触被认为可以编码长期记忆，但目前尚不清楚神经元如何维持这种微妙的平衡。显然，需要高水平的区隔化，这使得极性蛋白成为发挥这种功能的理想候选者，因为它们用于分离和维持不同的膜。事实上，我们之前表明，一类称为 Par（分配缺陷）蛋白的极性蛋白在树突棘形态发生中起着关键作用，其中 Par1、Par3 和 Par6 对此过程很重要，我们的初步研究表明，大多数极性蛋白都在树突棘形态发生中发挥着重要作用。成熟神经元中的棘以 Par3 和 Par6 为主，而一小部分棘以 Par1 为主，这种分布模式类似于发育中的受精卵和上皮细胞中的 Par 蛋白，其中 Par1 和 Par1。 Par3/6 复合物通过在各自的域中相互排斥而表现出相反的定位。此外，我们之前的研究表明，Par3 和 Par6 与非典型 PKC (aPKC) 形成复合物，可促进脊柱稳定性和成熟，而我们的初步结果表明。这些数据提出了令人兴奋的可能性，即 Par3/6 复合体和 Par1 调节脊柱的稳定性和可塑性之间的平衡，其中 Par3/6 主导的脊柱更稳定，而 Par1 主导的脊柱更稳定。我们计划通过两个目标来测试这一总体假设，即 Par1 促进突触可塑性，以及通过增加 PSD 支架的动态性和排除 Par3/6 复合物来维持可塑性。我们将测试 Par3/Par6/aPKC 复合物促进突触稳定性的假设，并且通过从棘中排除 Par1 来部分维持稳定性。我们将利用先进的分子成像技术，包括 FRET、 FRAP、荧光光诱导蛋白 (FLIP) 和 2 光子谷氨酸解笼锁此外，我们将在活体小鼠中使用 2 光子成像来直接检验我们的假设。我们将这些成像方法与生化分析以及电生理学相结合，这种跨学科方法将使我们能够深入了解突触稳定性和可塑性的细胞和分子机制。 Par 极性蛋白在神经精神疾病（包括精神分裂症、自闭症、重度抑郁症和双相情感障碍）中的作用因此，我们的研究将为突触可塑性和稳定性提供机制见解，并可能揭示一些破坏性的疾病。影响人类大脑的异常。