Functional plasticity of astrocyte syncytial network

星形胶质细胞是调节神经元兴奋性和神经传递的关键角色。我们最近展示了 星形胶质细胞通过“团队合作”参与大脑功能。具体地说，强烈的间隙结耦合， 星形胶质细胞在整个大脑中达到合体等电势状态，这对钾的动态平衡至关重要。 现在，我们的新研究进一步表明，合体细胞等电性的急性破坏会损害神经元的兴奋性。 NAD突触传递。然而，关于合胞体是如何形成的，我们的理解还处于起步阶段。 等电势是通过与神经元信号的串扰来建立和动态调节的。开始，开始 为了深入了解星形胶质细胞网络的这一系统范围的电特征，本提案的目标将是 主要集中在神经元信号如何调节合胞等电势。 我们的新研究表明，细胞内钙是星形胶质细胞电耦合的关键调节因子 合胞体。谷氨酸也通过调节[Ca~(2+)]i增强星形胶质细胞合胞体的电耦合 耦合。在基础生理水平，去甲肾上腺素信号被认为是双向调节 星形胶质细胞通过GQ偶联的α1肾上腺素能受体(α1 AR)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体细胞耦合的设定点，而 谷氨酸能信号诱导一种新的形式的胶质可塑性，以增强星形胶质细胞合胞偶联。 我们的第一个具体目标是确定[Ca~(2+)]i在双向调节神经细胞的电偶联中的作用 星形细胞合胞体。星形细胞表达GQ-DREADD Will的电生理和化学发生 在这些研究中使用。第二个目标将确定谷氨酸能信号的机制- 合胞体偶联的诱导增强。海马区CA3、→、CA1谷氨酸能传递 在野生型和条件性Cx43基因敲除(hGfap-Cre：Cx43Flox/Flox)小鼠中激活，以验证这种胶质细胞 网络可塑性是通过Cx43以[Ca~(2+)]i依赖的方式调节的。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 假说将通过对星形细胞α1-AR的药理学和遗传操作来检验。 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 具有神经信号的功能系统。我们希望揭开这一现象背后的分子机制。 星形胶质细胞合胞偶联的基础性和可塑性调节。最终，预计这些结果将 揭示了一个新的研究方向，在这个方向上，星形胶质细胞的神秘功能可以在 生物学上更高的等级，合体系统的水平。这项在健康中枢神经系统中的工作为 探讨星形胶质细胞合胞体的改变在致病和脑损伤中的作用。

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.