Mechanisms of GABAergic Signaling in the Suprachiasmatic Nucleus Network

视交叉上核网络中 GABA 信号传导的机制

• 批准号: 9920789
• 负责人: Charles N Allen
• 金额: $ 48.02万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920789
• 关键词: 5' -AMP-activated protein kinase; Adult; American; Astrocytes; Biological; Brain; Cells; Characteristics; Chlorides; Circadian Dysregulation; Circadian Rhythms; Communication; Coupled; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diffuse; Disease; Dorsal; Electrophysiology (science); Environment; Equilibrium; Family; GABA Transporter 1; GABA transporter; GABA-A Receptor; GAT3 transporter; Generations; Genes; Goals; Health; Human; Hypothalamic structure; Imaging Techniques; Individual; Interneurons; Knowledge; Light; Link; Mediating; Membrane Transport Proteins; Methods; Neurologic; Neurons; Neurotransmitters; Outcome; Output; Patients; Periodicity; Pharmacology; Phase; Phosphotransferases; Physiological; Play; Population; Potassium Chloride; Property; Protein Kinase C; Receptor Activation; Regulation; Research; Role; Schedule; Schools; Second Messenger Systems; Signal Pathway; Signal Transduction; Sleep; Societies; Sodium-Potassium-Chloride Symporters; Structure; Synapses; Synaptic Cleft; System; Testing; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Work; base; cell type; circadian; circadian pacemaker; circadian regulation; designer receptors exclusively activated by designer drugs; experience; fluorescence imaging; gamma-Aminobutyric Acid; intercellular communication; interstitial; millisecond; mouse model; neural network; neurotransmission; postsynaptic; postsynaptic neurons; presynaptic neurons; receptor; reduce symptoms; response; sleep onset; social; suprachiasmatic nucleus; targeted treatment; tool; uptake

Summary A significant number of Americans work non-traditional schedules and suffer the adverse health effects of a disrupted circadian timing system. The master mammalian circadian clock, located in the suprachiasmatic nucleus (SCN) maintains the proper phase relationship between circadian clocks located in tissues throughout the body and entrains the circadian system to the environment. The SCN is composed of individual neuronal oscillators coupled by intercellular communication into a neural network that generates a robust and precise rhythm. The long-term goal of our research is to understand the intercellular signaling mechanisms that couple SCN neurons into a neural network that generates circadian rhythms. GABAergic neurotransmission is a fundamental component of the SCN neural network and changing the strength and polarity of postsynaptic GABA responses modifies the activity of the SCN, and ultimately circadian rhythmicity. GABA serves as a desynchronizing signal under equilibrium conditions and a synchronizing signal when the SCN neural network has been modified by environmental light. GABA acts on synaptic GABA(A) receptors to mediate fast signaling between SCN neurons and on extrasynaptic GABA(A) receptors to activate a tonic GABA(A) current that modulates the activity of individual SCN neurons and communicates the level of network activity to adjacent synapses. We hypothesize that two membrane transporter families play critical roles in the regulation of the circadian activity of GABA neurotransmission in the SCN. The GABA transporters GAT-1 and GAT-3 regulate the amount and duration of neurotransmitter GABA in the extrasynaptic space and the magnitude of the tonic current. In the SCN, the GABA transporters are only expressed in astrocytes suggesting that astrocytes play a vital, but as of yet undetermined role in regulating the physiological actions of GABA in the SCN network. In the adult SCN, GABA serves as both an inhibitory and excitatory neurotransmitter although the physiological significance of this change in the polarity of GABA neurotransmission remains unknown. The chloride cotransporters of the sodium-potassium-chloride (NKCC) and potassium-chloride (KCC) families control the intracellular Cl- concentration and the polarity and magnitude of the GABA(A) receptor-mediated currents. We propose that the circadian clock uses the intracellular second messenger systems WNK-SPAK kinases, Ca2+- activated kinases, and cyclic AMP-activated kinases to regulate the activity of the Cl- transporters. The goal of this application is to understand better the mechanisms regulating GABAergic signaling and how GABA- mediated signaling contributes to the generation of circadian timing signals in the SCN. To accomplish this goal, we will use single cell electrophysiological and imaging techniques together with transgenic mouse models to study GABAergic neurotransmission in identified SCN neurons. Enhanced knowledge of the intercellular signaling mechanisms mediated by GABA will increase our ability to manipulate the circadian clock and reduce the symptoms experienced by patients with circadian-based disorders.

概括 大量美国人的工作时间是非传统的时间表，并遭受了健康的不利影响 破坏的昼夜节律定时系统。哺乳动物大师昼夜节律钟，位于肩部 核（SCN）保持了整个组织中的昼夜节律之间的适当相位关系 身体并将昼夜节律纳入环境。 SCN由单个神经元组成 振荡器通过细胞间通信加入神经网络，产生坚固而精确的 韵律。我们研究的长期目标是了解夫妇的细胞间信号传导机制 SCN神经元进入产生昼夜节律的神经网络。 GABA能神经传递是 SCN神经网络的基本组成部分，改变突触后的力量和极性 GABA响应改变了SCN的活性，最终改变了昼夜节律的节奏。 GABA用作 SCN神经网络时，在平衡条件下和同步信号下的异步信号 已通过环境光修改。 GABA作用于突触GABA（a）受体以介导快速信号传导 在SCN神经元和外鼻外GABA（a）受体之间激活补品GABA（a）电流 调节单个SCN神经元的活动，并将网络活动的水平传达给相邻 突触。我们假设两个膜转运蛋白家族在调节中起关键作用 SCN中GABA神经传递的昼夜活动。 GABA转运蛋白GAT-1和GAT-3调节 神经递质GABA在外部空间中的数量和持续时间和补品的大小 当前的。在SCN中，GABA转运蛋白仅在星形胶质细胞中表达，表明星形胶质细胞发挥作用 至关重要的，但截至尚未确定在调节SCN网络中GABA的生理作用中的作用。在 成人SCN，GABA既是抑制性和兴奋性神经递质，尽管生理 这种变化在GABA神经传递极性上的重要性仍然未知。氯化物 氯化钠 - 氯化钠（NKCC）和氯化钾（KCC）家族的共转运蛋白控制 细胞内CL浓度以及GABA（A）受体介导的电流的极性和大小。我们 提出昼夜节律时钟使用细胞内的第二通信系统WNK-Spak激酶，Ca2+ - 活化的激酶和环状AMP激活的激酶调节Cl-转运蛋白的活性。目标 该应用是为了更好地了解调节GABA能信号的机制以及GABA-如何 介导的信号传导有助于SCN中昼夜节律信号的产生。实现这一目标 目标，我们将与转基因小鼠一起使用单细胞电生理和成像技术 在已鉴定的SCN神经元中研究GABA能神经传递的模型。增强对 GABA介导的细胞间信号传导机制将增加我们操纵昼夜节律的能力 并减少基于昼夜节律疾病的患者的症状。