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: 10088474
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088474
• 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; MeCP2 Duplication Syndrome; 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; 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.

项目总结

项目成果

Ketamine: Neuroprotective or Neurotoxic?

• DOI: 10.3389/fnins.2021.672526
• 发表时间: 2021
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Choudhury D;Autry AE;Tolias KF;Krishnan V
• 通讯作者: Krishnan V

RhoGTPases Spread the Word for Synaptic Crosstalk.

• DOI: 10.1016/j.devcel.2016.10.007
• 发表时间: 2016-10
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: J. G. Duman;K. Tolias

The Adhesion-GPCR BAI1 Promotes Excitatory Synaptogenesis by Coordinating Bidirectional Trans-synaptic Signaling.

Adhesion-GPCR BAI1 通过协调双向跨突触信号传导促进兴奋性突触发生。

• DOI: 10.1523/jneurosci.3461-17.2018
• 发表时间: 2018
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Tu,Yen-Kuei;Duman,JosephG;Tolias,KimberleyF
• 通讯作者: Tolias,KimberleyF

The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors.

• DOI: 10.1111/nyas.14094
• 发表时间: 2019-11
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Morgan RK;Anderson GR;Araç D;Aust G;Balenga N;Boucard A;Bridges JP;Engel FB;Formstone CJ;Glitsch MD;Gray RS;Hall RA;Hsiao CC;Kim HY;Knierim AB;Kusuluri DK;Leon K;Liebscher I;Piao X;Prömel S;Scholz N;Srivastava S;Thor D;Tolias KF;Ushkaryov YA;Vallon M;Van Meir EG;Vanhollebeke B;Wolfrum U;Wright KM;Monk KR;Mogha A
• 通讯作者: Mogha A

Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses.

• DOI: 10.1080/21541248.2021.1885264
• 发表时间: 2022-01
• 期刊: Small GTPases