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不符合传统，并遭受着不良健康影响。 扰乱了昼夜节律系统。主要的哺乳动物生物钟，位于视交叉上 细胞核（SCN）在整个组织中维持生物钟之间的适当相位关系 身体并将昼夜节律系统带入环境。 SCN 由单个神经元组成 振荡器通过细胞间通信耦合到神经网络中，生成稳健且精确的信号 韵律。我们研究的长期目标是了解细胞间信号传导机制 SCN 神经元转变为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并改变突触后的强度和极性 GABA 反应会改变 SCN 的活动，并最终改变昼夜节律。 GABA 充当 平衡条件下的去同步信号和SCN神经网络时的同步信号 已被环境光修改。 GABA 作用于突触 GABA(A) 受体，介导快速信号传导 SCN 神经元之间和突触外 GABA(A) 受体上激活强直 GABA(A) 电流 调节单个 SCN 神经元的活动并将网络活动水平传达给相邻的神经元 突触。我们假设两个膜转运蛋白家族在调节 SCN 中 GABA 神经传递的昼夜节律活动。 GABA 转运蛋白 GAT-1 和 GAT-3 调节 突触外空间神经递质 GABA 的数量和持续时间以及强直的强度 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着 在调节 SCN 网络中 GABA 的生理作用方面发挥着重要但尚未确定的作用。在 在成人 SCN 中，GABA 既是抑制性神经递质，又是兴奋性神经递质，尽管生理学 GABA 神经传递极性的这种变化的意义仍不清楚。氯化物 钠钾氯化物 (NKCC) 和钾氯化物 (KCC) 家族的协同转运蛋白控制着 细胞内 Cl- 浓度以及 GABA(A) 受体介导电流的极性和大小。我们 提出生物钟使用细胞内第二信使系统 WNK-SPAK 激酶，Ca2+- 激活激酶和环 AMP 激活激酶来调节 Cl-转运蛋白的活性。目标是 该应用是为了更好地了解调节 GABA 信号传导的机制以及 GABA- 介导的信号传导有助于 SCN 中昼夜节律计时信号的产生。为了实现这一点 目标，我们将使用单细胞电生理和成像技术与转基因小鼠一起 研究已识别的 SCN 神经元中 GABA 能神经传递的模型。增强了相关知识 GABA 介导的细胞间信号传导机制将增强我们操纵生物钟的能力 并减轻昼夜节律紊乱患者的症状。