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: 10550252
• 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/10550252
• 关键词: Acute; Adrenergic Receptor; Astrocytes; Biological; Brain; Brain Injuries; Chemosensitization; Clozapine; Connexin 43; Coupled; Coupling; Data; Data Set; Dependence; Disease; Dissociation; Dose; Electrophysiology (science); Etiology; Foundations; Gap Junctions; Giant Cells; Glutamate Transporter; Glutamates; Hippocampus; Homeostasis; Impairment; In Situ; Knock-out; Link; LoxP-flanked allele; Mediating; Mediator; Methods; Molecular; Mus; Mutant Strains Mice; Neurons; Norepinephrine; Physiological; Potassium; Potassium Channel; Proteins; Regulation; Research; Role; Series; Signal Induction; Signal Pathway; Signal Transduction; Slice; 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; pharmacologic; 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.

星形胶质细胞是调节神经元兴奋性和神经传递的关键参与者。我们最近的研究表明 星形胶质细胞通过“团队合作”参与大脑功能。具体地说，强间隙连接耦合， 星形胶质细胞在整个大脑中达到对钾稳态至关重要的合胞体等电位状态。 现在我们的新研究进一步表明，合胞体等电位的急性破坏损害神经元的兴奋性 和突触传递然而，我们对合胞体是如何 通过与神经元信号的串扰建立并动态调节等电位性。开始 为了深入了解星形胶质细胞网络的这种系统范围的电特征，本提案的目的将 主要集中在神经元信号如何调节合胞体等电位性。 我们的新研究表明，细胞内Ca 2+（[Ca 2 +]i）是星形胶质细胞电耦合的关键调节因子 合胞体谷氨酸还通过调节[Ca 2 +]i，增强星形胶质细胞合胞体的电偶联， 偶合器.在基础生理水平上，去甲肾上腺素信号传导被指示双向调节神经元的功能。 通过Gq偶联α1-肾上腺素能受体（α1-AR）的星形胶质细胞偶联的设定点强度。因此我们 假设神经元去甲肾上腺素信号建立了合胞体偶联的设定点，而 神经元能信号诱导一种新形式的胶质细胞形成，以增强星形胶质细胞合胞体偶联。 我们的第一个具体目标是建立[Ca 2 +]i在双向调节细胞电偶联中的作用。 星形胶质细胞合胞体。星形胶质细胞表达Gq-DREADD的电生理学和化学发生学将 用于这些研究。第二个目标将确定潜在的代谢能信号传导机制- 合胞体偶联的诱导增强。海马CA 3 → CA 1介导的传递将是 在野生型和条件性Cx43敲除（hGfap-Cre：Cx43 flox/flox）小鼠中激活，以验证这种神经胶质细胞 网络可塑性通过Cx43以[Ca 2 +] i依赖的方式介导。第三个目标将决定 去甲肾上腺素信号在建立星形胶质细胞合胞偶联的设定点强度中的作用。这 将通过药理学和遗传操作星形胶质细胞α1-AR来检验这一假说。 该项目的完成有望验证星形胶质细胞合胞体确实作为一种细胞因子相互作用的观点。 神经元信号传导的功能系统。我们希望能够揭示这些疾病背后的分子机制。 调节星形胶质细胞合胞体偶联的基础和可塑性。最终，这些结果预计将 揭示了一个新的研究方向，其中星形胶质细胞的神秘功能可以在一个 生物学上更高的层次，合胞体系统的水平。这项在健康中枢神经系统中的工作为以下方面奠定了基础： 探索星形胶质细胞合胞体的改变如何在病因学上导致患病和受伤的大脑。