Functional plasticity of astrocyte syncytial network

星形胶质细胞合胞体网络的功能可塑性

• 批准号: 10330472
• 负责人: MIN ZHOU
• 金额: $ 35.74万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330472
• 关键词: Acute; Adrenergic Receptor; Astrocytes; Biological; Brain; Brain Injuries; Chemosensitization; Clozapine; Connexin 43; Coupled; Coupling; Data; Data Set; Dependence; Disease; Dose; Electrophysiology (science); Etiology; Foundations; Gap Junctions; Giant Cells; Glutamate Transporter; Glutamates; Hippocampus (Brain); Homeostasis; Impairment; In Situ; Knock-out; Light; Link; Mediating; Mediator of activation protein; Methods; Molecular; Mus; Mutant Strains Mice; Neurons; Norepinephrine; Pharmacology; Physiological; Potassium; Potassium Channel; Proteins; Regulation; Research; Role; Series; Signal Pathway; Signal Transduction; Slice; Synapses; Synaptic Transmission; System; Testing; Work; designer receptors exclusively activated by designer drugs; dosage; functional plasticity; gap junction channel; genetic manipulation; glutamatergic signaling; infancy; insight; nervous system disorder; neuronal excitability; neurotransmission; novel; operation; patch clamp; response; short-term potentiation; transmission process

Astrocytes are key players in regulating neuronal excitability and neurotransmission. We have recently shown that astrocytes participate in brain functions thrugh “team-work”. Specifically, a strong gap junction coupling, astrocytes achieve a state of syncytial isopotentiality across the brain that is crucial for potassium homeostasis. Now our new studies further show that acute disruption of syncytial isopotentiality impairs neuronal excitability nad synaptic transmision. However, our understanding is still in its infancy with respect to how the syncytial isopotentiality is established and dynamically regulated through crosstalk with neuronal signals. To begin to gain insight into this system-wide electrical feature of the astrocyte network, the objective of this proposal will be mostly focused on how neuronal signalings regulate syncytial isopotentiality. Our new studies show that intracellular Ca2+ ([Ca2+]i) is a key regulator of the electrical coupling of astrocyte syncytium. Also through regulating [Ca2+]i, glutamate potentiates electrical coupling of astrocyte syncytial coupling. At the basal physiological level, norepinephrine signaling is indicated to bidirectionally regulate the set point strength of astrocyte coupling through Gq-coupled α1-adrenergic receptors (α1-AR). Thus, we hypothesize that neuronal norepinephrine signaling establishes the set point of syncytial coupling, whereas glutamatergic signaling induces a novel form of glioplasity for potentiation of astrocyte syncytial coupling. Our first specific aim will establish the role of [Ca2+]i in bidirectionally regulating the electrical coupling of astrocyte syncytium. The electrophysiology and chemogentics with astrocytic expression of Gq-DREADD will be used in these studies. The second aim will determine the mechanism underlying a glutamatergic signaling- induced potentiation of syncytial coupling. Hippocampal CA3→CA1 glutamatergic transmission will be activated in wildtype and conditional Cx43 knockout (hGfap-Cre:Cx43flox/flox) mice to validate that this glial network plasticity is mediated through Cx43 in an [Ca2+]i-dependent fashion. The third aim will determine the role of norepinephrine signaling in establishing a set point strength of astrocyte syncytial coupling. This hypothesis will be examined through pharmacologial and genetic manipulation of astrocytic α1-AR. The completion of this project is expected to validate the view that astrocyte syncytium indeed interacts as a functional system with neuronal signaling. We expect to uncover the molecular mechanisms underlying the regulation of the basic and plasticity of astrocyte syncytial coupling. Ultimately, these results are expected to shed light on a new research direction, in which the mysterious function of astrocytes can be explored at a biologically higher hierarchy, the level of the syncytial system. This work in healthy CNS lays the foundation for exploring how alteration of astrocyte syncytium etiologically contributes to diseased and injured brains.

星形胶质细胞是确定神经元令人兴奋和神经传递的关键参与者。我们最近显示了 星形胶质细胞忠实地参与大脑功能“团队合作”。具体而言，一个强大的间隙连接耦合， 星形胶质细胞在整个大脑中达到了突触性等等状态，这对于钾稳态至关重要。 现在，我们的新研究进一步表明，急性合成等电势会损害神经元令人兴奋 NAD突触传播。但是，我们的理解仍处于启发性方面的起步阶段 等速度是通过与神经元信号的串扰来建立和动态调节的。开始 深入了解星形胶质细胞网络的全系统电气特征，该提案的目的将 主要集中于神经元信号如何调节合胞tiripential性。 我们的新研究表明，细胞内Ca2+（[Ca2+] i）是星形胶质细胞电耦合的关键调节剂 合成。同样通过调节[Ca2+] i，谷氨酸电势的星形胶质细胞合成型电耦合 耦合。在基本的物理层面，去甲肾上腺素信号传导在双向调节 星形胶质细胞耦合通过GQ耦合α1-肾上腺素受体（α1-AR）的设定点强度。 假设神经元肾上腺素信号传导建立了突触耦合的设定点，而 谷氨酸能信号传导诱导了一种新型的胶质质，以增强星形胶质细胞合成耦合。 我们的第一个具体目的将确定[Ca2+] i在双向调节电气耦合中的作用 星形胶质细胞同步。 GQ-DreadD的星形胶质细胞表达的电生理学和化学学将 在这些研究中使用。第二个目标将确定谷氨酸能信号传导的机制 引起的突触耦合的增强。海马CA3→CA1谷氨酸能传输将是 用野生型和有条件的CX43敲除（HGFAP-CRE：CX43FLOX/FLOX）激活 网络可塑性以[Ca2+] i依赖性方式通过CX43介导。第三个目标将决定 去甲肾上腺素信号传导在建立星形胶质细胞合成耦合的设定点强度中的作用。这 假设将通过对星形胶质细胞α1-AR的药物和遗传操纵进行检验。 预计该项目的完成将验证星形胶质细胞合成剂确实作为一个相互作用的观点 具有神经元信号传导的功能系统。我们期望揭示依据的分子机制 星形胶质细胞合成耦合的基本和可塑性的调节。最终，这些结果有望 阐明了一个新的研究方向，在该方向上，可以在一个新的研究方向上探索星形胶质细胞的神秘功能 生物学上更高的层次结构，即突触系统的水平。这项工作在健康中枢神经系统中为 探索星形胶质细胞合成的改变在病因上如何促进患病和受伤的大脑。