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.

总结 相当多的美国人工作非传统的时间表，并遭受不利的健康影响， 扰乱了昼夜节律系统主哺乳动物生物钟，位于视交叉上 细胞核（SCN）在整个过程中维持位于组织中的生物钟之间的适当相位关系。 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， 节奏我们研究的长期目标是了解细胞间信号传导机制， SCN神经元转化为产生昼夜节律的神经网络。GABA能神经传递是一种 SCN神经网络的基本组成部分，并改变突触后神经元的强度和极性。 GABA反应改变SCN的活性，并最终改变昼夜节律。GABA作为一种 平衡条件下的去噪声信号和SCN神经网络 已经被环境光改变了GABA作用于突触GABA（A）受体以介导快速信号传导 SCN神经元之间和突触外GABA（A）受体上的信号传导，以激活紧张性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SCN神经元。 突触我们假设两个膜转运蛋白家族在调节细胞膜的功能中起着关键作用。 SCN中GABA神经传递的昼夜活动。GABA转运蛋白GAT-1和GAT-3调节 突触外间隙中神经递质GABA的量和持续时间以及强直的幅度 电流在SCN中，GABA转运体仅在星形胶质细胞中表达，这表明星形胶质细胞在SCN中起着重要作用。 重要的，但尚未确定的作用，在调节生理活动的GABA在SCN网络。在 在成年SCN中，GABA既作为抑制性神经递质又作为兴奋性神经递质，尽管生理上 GABA神经传递极性的这种变化的意义仍然未知。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幅度。我们 提出生物钟使用细胞内第二信使系统WNK-SPAK激酶，Ca2 +- 激活的激酶和环AMP激活的激酶来调节Cl-转运蛋白的活性。的目标 本申请是为了更好地理解调节GABA能信号传导的机制以及GABA- 介导的信号传导有助于SCN中昼夜节律定时信号的产生。为了实现这一 目的：利用单细胞电生理和成像技术， 模型来研究已鉴定的SCN神经元中的GABA能神经传递。加强对 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。