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.

我们最近证明，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。 星形胶质细胞通过“团队合作”参与大脑功能，具体来说，是强大的间隙连接耦合， 星形胶质细胞在大脑中实现合胞体等电位状态，这对于钾稳态至关重要。 现在我们新的进一步研究表明，合胞体等电位的急性破坏会损害神经元的兴奋性 然而，我们对合胞体如何传递的理解仍处于起步阶段。 等电位通过与神经信号的串扰建立并动态调节。 深入了解星形胶质细胞网络的全系统电气特征，该提案的目标将 主要关注神经信号如何调节合胞体等电位。 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因子 谷氨酸还通过调节 [Ca2+]i 增强星形胶质细胞合胞体的电耦合。 在基础生理水平上，去甲肾上腺素信号传导可以双向调节。 通过 Gq 偶联 α1 肾上腺素受体 (α1-AR) 进行星形胶质细胞偶联的设定点强度 因此，我们。 率先提出神经元去甲肾上腺素信号传导建立合胞体耦合的设定点，而 谷氨酸信号传导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确定 [Ca2+]i 在双向调节电耦合中的作用 星形胶质细胞合胞体的电生理学和化学遗传学与 Gq-DREADD 的星形胶质细胞表达有关。 用于这些研究的第二个目标是确定谷氨酸信号传导的机制。 海马CA3→CA1谷氨酸能传递 在野生型和条件性 Cx43 敲除 (hGfap-Cre:Cx43flox/flox) 小鼠中激活，以验证该神经胶质细胞 网络可塑性通过 Cx43 以 [Ca2+]i 依赖性方式介导。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体耦合设定点强度中的作用。 该假设将通过星形胶质细胞 α1-AR 的药理学和基因操作得到检验。 该项目的完成预计将验证星形胶质细胞合胞体确实作为一种相互作用的观点。 我们期望揭示具有神经信号传导的功能系统。 最终，这些结果有望实现星形胶质细胞合胞体耦合的基础性和可塑性的调节。 揭示了一个新的研究方向，可以在其中探索星形胶质细胞的神秘功能 生物学上更高的层次，合胞体系统的水平，为健康中枢神经系统的这项工作奠定了基础。 探索星形胶质细胞合胞体的改变如何在病因学上导致大脑患病和受伤。