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

• 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
• 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

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.

项目摘要 星形胶质细胞是中枢神经系统（CNS）中进化上保守的胶质细胞，在中枢神经系统（CNS）中起关键作用。 在神经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， 形态学和密切相关的神经元突触在整个大脑。地西泮结合抑制因子 (DBI)是一种蛋白质，已显示在小鼠中的神经胶质细胞（包括星形胶质细胞）中高度富集， 人类的大脑我们最近发现它在果蝇星形胶质细胞中也有高表达，这表明它的 在星形胶质细胞功能中至关重要且在进化上保守的作用。DBI及其蛋白水解神经肽， 十八碳神经肽（ODN）可与GABAA上的苯二氮卓类（BZD）结合位点结合 受体和调节抑制信号的强度，作为BZD的内源性配体 （endozepines）。由于BZD是治疗焦虑症和癫痫发作最广泛的处方药之一， 了解星形胶质细胞内分泌信号将有助于深入了解星形胶质细胞如何调节细胞内分泌， 神经元回路的适当成熟和功能，以及大脑如何对BDZ做出反应。另一种蛋白水解 DBI的片段，三链四神经肽（TTN），与外膜上的转运蛋白（TSPO）受体结合， 线粒体膜，并参与线粒体胆固醇转运，细胞骨架动力学， Ca 2+稳态，所有这些都是星形胶质细胞形态发生和功能的关键。 利用果蝇和斑马鱼中可用的分子遗传工具的协同组合， 该提案旨在：确定DBI信号传导是否是正常星形胶质细胞发育所必需的（目标1）; 定义星形胶质细胞线粒体和Ca 2+动力学中TTN-TSPO信号传导的细胞内在功能（Aim 2）;以及 研究星形胶质细胞DBI信号传导在兴奋性- 抑制（E/I）平衡。这项工作将阐明DBI信号在星形胶质细胞中的进化保守功能 发育和星形胶质细胞-神经元的相互作用，并可以提供新的见解的作用， 星形胶质细胞在焦虑症和癫痫中的作用