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

项目总结 星形胶质细胞是中枢神经系统(CNS)中进化保守的胶质细胞，在中枢神经系统(CNS)中起着至关重要的作用 在神经元回路发育和功能中的作用。成熟星形胶质细胞表现出明显的分支和复杂 在形态上，它与整个大脑中的神经元突触密切相关。安定结合抑制剂 (DBI)是一种蛋白质，已被证明在小鼠和小鼠的胶质细胞中高度丰富，包括星形胶质细胞 人类的大脑。我们最近发现，它也在果蝇星形胶质细胞中高表达，这表明它 在星形胶质细胞功能中起关键的和进化上保守的作用。DBI及其蛋白水解神经肽， 研究表明，十八烷神经肽(ODN)可与GABAA上的苯二氮卓类药物(BZD)结合 受体和调节抑制信号强度，作为BZD的内源性配体 (阿司匹林)。由于BZD是治疗焦虑症和癫痫的最广泛的处方之一， 了解星形胶质细胞内皮质素信号将有助于深入了解星形胶质细胞如何调节 神经回路的正常成熟和功能，以及大脑对BDZ的反应。另一种蛋白水解剂 DBI片段，即TTN，与外层的转运蛋白(TSPO)受体结合 线粒体膜，参与线粒体胆固醇的运输、细胞骨架动力学和 钙稳态，所有这些都是星形胶质细胞形态发生和功能的关键。 利用果蝇和斑马鱼可用的分子遗传工具的协同组合，这 该提案旨在：确定DBI信号是否是正常星形胶质细胞发育所必需的(目标1)； 确定星形胶质细胞线粒体和钙动力学中TTN-TSPO信号的细胞内在功能(目标2)；以及 在兴奋性脑损伤的背景下，研究星形细胞DBI信号在神经元回路成熟中的作用 抑制性(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 在体内的发育和星形胶质细胞-神经元的相互作用，并可能提供新的洞察力的作用 焦虑障碍和癫痫中的星形胶质细胞。

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.