Polarity determinants in synaptic stability and plasticity

突触稳定性和可塑性的极性决定因素

• 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
• 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

 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（由适用提供）：突触的稳定性和可塑性对于认知功能都很重要。可塑性对于学习是必要的，而稳定形成的突触被认为是为了长期记忆的编码。然而，目前尚不清楚神经元如何保持这种微妙的平衡并在突触中达到稳定性和可塑性仅几微米。显然，需要高水平的隔室化，这使极性蛋白质理想的候选者可以以这种能力发挥作用，因为它们可以分离和维持不同的膜结构域。确实，我们先前表明，一类称为PAR（分配有缺陷）蛋白的极性蛋白在树突状脊柱形态发生中起关键作用，PAR1，PAR3和PAR6对此过程很重要。有趣的是，我们的初步研究表明，成熟神经元中的大多数棘突都以PAR3和PAR6为主，而较小的棘突则由PAR1主导。这种分布模式类似于开发Zygotes和上皮细胞中PAR蛋白的分布模式，其中PAR1和PAR3/6复合物通过将彼此互相排除在各自的域而相反。此外，我们先前的研究表明，与非典型PKC（APKC）形成复合物的PAR3和PAR6促进了脊柱稳定性和成熟，而我们的初步结果表明PAR1促进了脊柱可塑性。这些数据提出了令人兴奋的可能性，即PAR3/6复合物和PAR1调节棘突的稳定性和可塑性之间的平衡，而Par3/6占主导地位的刺更稳定，而PAR1优势刺是更塑性。我们计划通过两个目标检验这一总体假设。在AIM1中，我们将检验以下假设：PAR1促进突触可塑性，并通过增加PSD支架的动力学并排除PAR3/6复合物来维持可塑性。在AIM 2中，我们将检验以下假设：PAR3/PAR6/APKC复合物促进合成稳定性，并且该稳定性在某种程度上通过将PAR1排除在刺中来维持。我们将利用晚期分子成像技术，包括FRET，FRAP，荧光光诱导蛋白（翻转）和2光片谷氨酸蛋白质。此外，我们将在活小鼠中使用2光子成像直接检验我们的假设 行为动物。我们将将这些成像方法与生化分析以及电生理学结合起来。这种跨学科的方法将使我们能够对突触稳定性和可塑性的细胞和分子机制获得基本洞察力。此外，多种证据表明，在神经精神疾病中，包括精神分裂症，自闭症，主要抑郁症和双相情感障碍在内的神经精神疾病中的重要作用。这是我们的研究将提供对突触可塑性和稳定性的机械洞察力，并可能阐明几种影响人脑的毁灭性异常。