Adhesion-GPCRs: Regulators of dendritic development, synaptogenesis and mental health

粘附-GPCR：树突发育、突触发生和心理健康的调节因子

• 批准号: 9311432
• 负责人: Kimberly R Tolias
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-08 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311432
• 关键词: Adhesions; Affect; Alzheimer' s Disease; Angiogenesis Inhibitors; BAI1 gene; BAI2 gene; BAI3 gene; Biochemistry; Biological Assay; Biology; Bipolar Disorder; Bipolar I; Brain; Brain Diseases; Cell Surface Receptors; Characteristics; Chromosome Mapping; Cognition Disorders; Complex; Copy Number Polymorphism; Coupling; Data; Dendrites; Dendritic Spines; Development; Disease; Electrophysiology (science); Equilibrium; Excitatory Synapse; Exhibits; Family; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic Models; Germ-Line Mutation; Goals; Growth; Heterogeneity; Hippocampus (Brain); Hot Spot; Human; Image; Intellectual functioning disability; Knowledge; Lead; Ligand Binding; Link; Measures; Mediating; Mental Depression; Mental Health; Microtubules; Modality; Modeling; Molecular; Molecular Conformation; Monomeric GTP-Binding Proteins; Mood Disorders; Neurons; Pathway interactions; Patients; Phase; Physiological; Play; Process; Property; Proteins; Psyche structure; Publishing; Regulation; Reporter; Research; Resistance; Rett Syndrome; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Single Nucleotide Polymorphism; Structure; Synapses; Syndrome; Testing; Time; Translating; Validation; Vertebral column; age related; autism spectrum disorder; base; extracellular; growth promoting activity; human disease; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; neural circuit; neurodevelopment; neuroligin 1; neuron development; new therapeutic target; novel; response; rho; rho GTP-Binding Proteins; spatiotemporal; success; synaptic function; synaptogenesis

PROJECT SUMMARY Dendrites exhibit immense diversity in their macrostructure (arbors), which stipulates the availability of a neuron to circuits and its computational properties, and microstructure (dendritic spines), which dynamically support and shape synaptic function. Arbor and spine/synapse development must be coordinated to form functional dendrites. Though synaptic activity plays a crucial role, the heterogeneity of developmental responses to activity indicates that other mechanisms are required. In this proposal, we will test the hypothesis that the adhesion G-protein coupled receptor (A-GPCR) brain-specific angiogenesis inhibitor 1 (BAI1/ ADGRB1) coordinates dendritic arbor and spine development through differential activation of multiple signaling pathways. This hypothesis is based on our published and preliminary data showing: (i) that BAI1 mediates growth arrest of dendritic arbors via a novel pathway coupling to the Rho-family small GTPase RhoA; (ii) that BAI1 promotes excitatory synaptogenesis in cortical and hippocampal neurons via the Rho-family small GTPase Rac1 and trans-synaptic signaling; and (iii) that BAI1 differentially affects dendrite development in an age-dependent manner and that altering BAI1 configuration has age-dependent effects on downstream signaling pathways. We propose a multidisciplinary approach to define the roles of BAI A-GPCRs in regulating and coordinating dendritic arbor and spine/synapse development utilizing in vivo and cultured neurons, genetic models, molecular replacement, live imaging with fluorescent reporters, mixed culture assays, biochemistry and electrophysiology. The pathways that we are defining include proteins implicated in treatment-resistant bipolar disorder (Bcr), autism spectrum disorder (neuroligin-1 and IRSp53), and schizophrenia (BAI3). Thus, success of this proposal will not only provide material advances in the study of dendrite development and synaptogenesis, but also test a novel and powerful hypothesis regarding the coordination of these processes and provide new therapeutic targets against widespread human mental diseases.

项目概要 树突在其宏观结构（乔木）中表现出巨大的多样性，这规定了树突的可用性 神经元到电路及其计算特性，以及动态的微观结构（树突棘） 支持和塑造突触功能。乔木和脊柱/突触的发育必须协调才能形成 功能性树突。尽管突触活动起着至关重要的作用，但发育的异质性 对活动的反应表明需要其他机制。在这个提案中，我们将测试假设 粘附 G 蛋白偶联受体 (A-GPCR) 脑特异性血管生成抑制剂 1 (BAI1/ ADGRB1）通过多个差异激活来协调树突乔木和脊柱发育 信号通路。该假设基于我们已发布的初步数据，显示：(i) BAI1 通过与 Rho 家族小 GTPase RhoA 偶联的新途径介导树突状乔木的生长停滞； (ii) BAI1 通过 Rho 家族小分子促进皮质和海马神经元的兴奋性突触发生 GTPase Rac1 和跨突触信号传导； (iii) BAI1 对树突发育有不同的影响 年龄依赖性方式，并且改变 BAI1 配置对下游具有年龄依赖性影响 信号通路。我们提出了一种多学科方法来定义 BAI A-GPCR 在调节中的作用 并利用体内和培养的神经元协调树突乔木和脊柱/突触发育，遗传 模型、分子替代、荧光报告基因实时成像、混合培养测定、生物化学 和电生理学。我们正在定义的途径包括与治疗耐药相关的蛋白质 双相情感障碍 (Bcr)、自闭症谱系障碍（neuroligin-1 和 IRSp53）和精神分裂症 (BAI3)。因此， 该提案的成功不仅将为枝晶发育的研究提供实质​​性进展， 突触发生，还测试了关于这些过程协调的新颖而有力的假设 并为人类普遍存在的精神疾病提供新的治疗靶点。