Astrocytes role in lipid mediated synaptic activity

星形胶质细胞在脂质介导的突触活动中的作用

• 批准号: 8205170
• 负责人: Nathan A Smith
• 金额: $ 4.18万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205170
• 关键词: Address; Adenosine; Affect; Arachidonic Acids; Astrocytes; Biological Assay; Brain; Calcium; Calcium Signaling; Cells; Central Nervous System Diseases; Chemicals; Complex; Data; Dependency; Dinoprostone; Disease; Docosahexaenoic Acids; Epilepsy; Event; Glutamates; Hippocampus (Brain); Investigation; Kinetics; Lead; Lipids; Mediating; Mental Depression; Modeling; Modification; Neuraxis; Neurons; Pathway interactions; Pharmacology; Phospholipase A2; Physiological; Play; Process; Production; Radioactive; Rattus; Regulation; Role; Signal Pathway; Signal Transduction; Supporting Cell; Synapses; Synaptic Transmission; Testing; Time; Tissues; Transgenic Animals; Vasodilation; base; extracellular; information processing; insight; interest; millisecond; nervous system disorder; neurotransmission; novel; receptor; research study; response; synaptic function; uptake

DESCRIPTION (provided by applicant): Observations in our lab have demonstrated that vasodilation is seemingly dissociable from astrocytic calcium dynamics in many cases, thus prompting us to test whether astrocytes through lipid release can signal on a faster signaling scale in a calcium-independent manner. Thus far, virtually all studies looking at astrocytic signaling mechanisms focus on intracellular Ca2+, which is on a signaling time scale of seconds. However, astrocytes are capable of Ca2+ independent signaling that is potentially on a time scale one to two orders of magnitude faster (msec). In line with this, astrocytes possess Ca2+ -independent PLA2 that can lead to the production of AA in the absence of calcium. However, further investigation is needed to reveal the existence of Ca2+-independent signaling from astrocytes and whether this can influence physiological function. To that end, I will in Aim 1 study the hypothesis that astrocytes can release AA and/or its metabolites in a Ca2+ independent manner. Specifically, I will use cultured rat astrocytes to assess receptor stimulated release of lipids in the absence of increases in cytosolic calcium. In Aim 2, I will use a model of Transient Heterosynaptic Depression (tHSD) to study astrocyte-neuronal signaling in intact hippocampal tissue. I will first assess the role of lipid signaling in tHSD focusing on rapid events occurring on the time-scale of msec. Combined, the proposed studies will provide novel insight into the controversial role of astrocytes in synaptic regulation and thereby in higher information processing. More specifically, because the role of astrocytes in lipid signaling is poorly understood, this proposal will address the mechanism and kinetics of release, as well as it putative function in tHSD. PUBLIC HEALTH RELEVANCE: The proposed studies will explore a novel mechanism of calcium independent astrocytic lipid signaling modulation of synaptic activity. Furthermore, since lipids are known to play an important role in many pathophysiological disorders such as epilepsy, these studies may also give new insight into the role that astrocytes play in neurological disease. Illuminating the importance of this novel lipid signaling mechanism may reveal pathways suitable for pharmacological manipulation to treat diseases of the central nervous system.

描述（由申请人提供）：在我们实验室中的观察结果表明，在许多情况下，血管舒张似乎与星形细胞钙动力学可以分离，从而促使我们测试通过脂质释放的星形胶质细胞是否可以以钙独立的方式在更快的信号量表上发出信号。到目前为止，几乎所有研究星形胶质性信号传导机制的研究都集中在细胞内CA2+上，这是信号传导时间尺度的秒数。但是，星形胶质细胞具有CA2+独立信号的能力，该信号可能在时间尺度上更快地尺度（MSEC）。与此相一致，星形胶质细胞具有Ca2+非依赖性PLA2，可以在没有钙的情况下导致AA产生。但是，需要进一步研究以揭示星形胶质细胞中Ca2+非依赖性信号的存在，以及这是否会影响生理功能。为此，我将在AIM 1中研究星形胶质细胞可以以Ca2+独立方式释放AA和/或其代谢物的假设。具体而言，在没有胞质钙的增加的情况下，我将使用培养的大鼠星形胶质细胞评估受体刺激的脂质释放。在AIM 2中，我将使用瞬时异质抑郁症（THSD）模型来研究完整的海马组织中的星形胶质 - 神经元信号。我将首先评估脂质信号在THSD中的作用，重点是在MSEC的时间尺度上发生的快速事件。拟议的研究结合在一起，将为星形胶质细胞在突触调节中的有争议的作用以及在更高信息处理中的有争议作用提供新的见解。更具体地说，由于星形胶质细胞在脂质信号传导中的作用知之甚少，因此该建议将解决释放的机制和动力学，以及在THSD中的推定功能。 公共卫生相关性：拟议的研究将探索突触活动的独立星形胶质细胞脂质信号调节的新型机制。此外，由于已知脂质在许多病理生理疾病（例如癫痫病）中起着重要作用，因此这些研究也可能给星形胶质细胞在神经系统疾病中起的作用提供新的见解。阐明这种新型脂质信号传导机制的重要性可能揭示了适合治疗中枢神经系统疾病的药理操作的途径。