Investigating the role of diazepam binding inhibitor (DBI) in astrocytes and neural circuit maturation

研究地西泮结合抑制剂 (DBI) 在星形胶质细胞和神经回路成熟中的作用

基本信息

批准号：
10567723
负责人：
Dongeun Heo
金额：
$ 6.91万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567723
关键词：
Address Affinity Anxiety Disorders Astrocytes Autophagocytosis Behavioral Assay Benzodiazepines Binding Binding Sites Biological Assay Brain Buffers Cells Central Nervous System Cholesterol Complex Cytoskeleton Data Development Diazepam Diazepam Binding Inhibitor Drosophila genus Epilepsy Equilibrium Exhibits Functional disorder Growth Homeostasis Human Image Investigation Larva Ligands Maintenance Mammals Mediating Mitochondria Molecular Molecular Genetics Morphogenesis Morphology Mus Names Nervous System Neurodevelopmental Disorder Neuroglia Neurons Neuropeptides Neurophysiology - biologic function Neurotransmitters Outer Mitochondrial Membrane Physiology Play Process Proteins RNA Interference Receptor Signaling Recycling Rodent Role Seizures Signal Transduction Signaling Protein Site Synapses Work Zebrafish density extracellular genetic approach genome editing in vivo in vivo imaging insight ionic balance loss of function mitochondrial permeability transition pore model organism mutant nervous system development neural circuit neuronal circuitry neurotransmission novel positive allosteric modulator receptor response synaptic pruning synaptogenesis tool treatment of anxiety disorders

项目摘要

PROJECT SUMMARY Astrocytes are evolutionarily conserved glial cells in the central nervous system (CNS) that play a crucial role in neuronal circuit development and function. Mature astrocytes exhibit remarkably ramified and complex morphology and closely associate with neuronal synapses throughout the brain. Diazepam binding inhibitor (DBI) is a protein that has been shown to be highly enriched in glial cells, including astrocytes, in mouse and human brains. We recently discovered that it is also highly expressed by Drosophila astrocytes, suggesting its crucial and evolutionarily conserved role in astrocyte function. DBI and its proteolytic neuropeptide, Octadecaneuropeptide (ODN), have been shown to bind to the benzodiazepine (BZD) binding site on GABAA receptors and modulate the strength of inhibitory signaling, acting as endogenous ligands of BZD (endozepines). As BZDs are among the most widely prescribed treatments for anxiety disorders and seizures, understanding the astrocytic endozepine signaling will provide insights into how astrocytes can regulate the proper maturation and function of neuronal circuitry, and how the brain responds to BDZs. Another proteolytic fragment of DBI, triakontatetraneuropeptide (TTN), binds to translocator protein (TSPO) receptor on the outer mitochondrial membrane and is involved in mitochondrial cholesterol transport, cytoskeletal dynamics, and Ca2+ homeostasis, all of which are critical for astrocyte morphogenesis and function. Employing a synergistic combination of molecular-genetic tools available in Drosophila and zebrafish, this proposal aims to: determine whether DBI signaling is required for normal astrocyte development (Aim 1); define cell-intrinsic function of TTN-TSPO signaling in astrocyte mitochondrial and Ca2+ dynamics (Aim 2); and investigate the role of astrocytic DBI signaling in neuronal circuit maturation in the context of the excitatory- inhibitory (E/I) balance. This work will elucidate evolutionarily conserved function of DBI signaling in astrocyte development and astrocyte-neuron interactions in vivo and could provide novel insights into the role of astrocytes in anxiety disorders and epilepsy.

项目概要星形胶质细胞是中枢神经系统 (CNS) 中进化上保守的神经胶质细胞，在中枢神经系统 (CNS) 中发挥着至关重要的作用。在神经元回路发育和功能中的作用。成熟的星形胶质细胞表现出明显的分支和复杂性形态并与整个大脑的神经元突触密切相关。地西泮结合抑制剂 (DBI) 是一种蛋白质，已被证明在小鼠和小鼠的神经胶质细胞（包括星形胶质细胞）中高度富集。人类的大脑。我们最近发现果蝇星形胶质细胞也高度表达它，这表明它在星形胶质细胞功能中发挥着至关重要且进化上保守的作用。 DBI及其蛋白水解神经肽，十八神经肽 (ODN) 已被证明可与 GABAA 上的苯二氮卓 (BZD) 结合位点结合受体并调节抑制信号的强度，作为 BZD 的内源性配体（内氮平）。由于 BZD 是最广泛用于治疗焦虑症和癫痫发作的药物之一，了解星形胶质细胞内氮平信号传导将有助于了解星形胶质细胞如何调节神经元回路的正常成熟和功能，以及大脑如何对 BDZ 做出反应。另一种蛋白水解物 DBI 片段，三康酸四神经肽 (TTN)，与外部的易位蛋白 (TSPO) 受体结合线粒体膜，参与线粒体胆固醇转运、细胞骨架动力学和 Ca2+ 稳态，所有这些对于星形胶质细胞的形态发生和功能都至关重要。采用果蝇和斑马鱼中可用的分子遗传工具的协同组合，提案旨在：确定正常星形胶质细胞发育是否需要 DBI 信号传导（目标 1）；定义 TTN-TSPO 信号在星形胶质细胞线粒体和 Ca2+ 动力学中的细胞内在功能（目标 2）；和研究星形胶质细胞 DBI 信号在兴奋性神经回路成熟中的作用抑制 (E/I) 平衡。这项工作将阐明星形胶质细胞中 DBI 信号传导的进化保守功能体内发育和星形胶质细胞-神经元相互作用，可以为了解星形胶质细胞的作用提供新的见解星形胶质细胞在焦虑症和癫痫中的作用。