Synaptic transport of endocannabinoids in the brain

大脑中内源性大麻素的突触转运

• 批准号: 10377918
• 负责人: SAMIR HAJ-DAHMANE
• 金额: $ 58.36万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377918
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Address; Anabolism; Anxiety; Area; Astrocytes; Behavioral; Biochemical; Biology; Brain; Brain region; CNR1 gene; Carrier Proteins; Cells; Cytosol; Development; Diffusion; Disease; Electrophysiology (science); Endocannabinoids; Engineering; Enzymes; Excitatory Synapse; FABP5 gene; Family; Functional disorder; Future; Genetic; Glutamates; Hippocampus (Brain); Hydrophobicity; Inhibitory Synapse; Knockout Mice; Lead; Lipids; Mediating; Mental Depression; Mental disorders; Mus; Nature; Neurons; Outcome Study; Output; Pathologic; Pharmacology; Physiological; Play; Population; Positioning Attribute; Presynaptic Terminals; Process; Proteins; Psychiatric therapeutic procedure; Receptor Activation; Reporting; Role; Signal Transduction; Signaling Molecule; Solubility; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic plasticity; Testing; Variant; Ventral Tegmental Area; Viral; aqueous; autism spectrum disorder; brain dysfunction; cannabinoid receptor; cognitive reappraisal; dorsal raphe nucleus; emotion regulation; endocannabinoid signaling; endogenous cannabinoid system; fatty acid-binding proteins; gamma-Aminobutyric Acid; genetic approach; improved; lipid transport; lipophilicity; nervous system disorder; neurotransmission; neurotransmitter release; new therapeutic target; novel; novel therapeutic intervention; postsynaptic neurons; presynaptic; synaptic function; therapeutic target; therapy development

Project Summary The endocannabinoid (eCB) system plays a key role in regulating synaptic function in the brain. Dysfunction of eCB signaling contributes to numerous psychiatric and neurological disorders including anxiety, depression, and autism. Consequently, the development of treatments for disorders involving eCB dysfunction requires a thorough understanding of the mechanisms regulating eCB signaling in the brain. It is well-established that physiological and/or pathological activation of postsynaptic neurons leads to the biosynthesis and release of the eCB 2-arachidonoylglycerol (2-AG). Once released, 2-AG traverses the synaptic cleft and activates cannabinoid receptors located on presynaptic axon terminals, which mediate its behavioral and physiological effects. Although considerable progress has been made in elucidating how 2-AG signaling controls synaptic function and behavioral outputs, the mechanism(s) governing synaptic 2-AG transport remains unknown, highlighting a major gap in our fundamental understanding of 2-AG signaling in the brain. The lipophilic nature of 2-AG limits its diffusion across the synapse, suggesting the existence of a carrier(s) that facilitates 2-AG transport to permit cannabinoid receptor activation. Identification of a synaptic 2-AG carrier would not only greatly enhance our basic understanding of 2-AG signaling but could also lead to the discovery of a new therapeutic target(s) to treat disorders involving eCB dysfunction. To that end, our group has recently identified fatty acid binding proteins (FABPs) as intracellular carriers for eCBs. In this application, we will build upon this progress and test the novel hypothesis that FABP5, secreted by astrocytes, functions as a synaptic carrier that is essential for 2-AG signaling in multiple brain areas. In Aim 1, we will employ complementary pharmacological and genetic approaches to test the hypothesis that FABP5 mediates retrograde 2-AG transport at inhibitory and excitatory synapses in the hippocampus and ventral tegmental area, brain areas involved in cognitive and emotional regulation. In Aim 2, we will employ our novel FABP5Flox/Flox mice to delineate the roles of astrocytic and neuronal FABP5 in controlling synaptic 2-AG transport. Aim 3 will characterize the contributions of intracellular and secreted FABP5 in mediating 2-AG transport at hippocampal and ventral tegmental area synapses. Successful completion of this proposal will position FABP5 as a synaptic carrier for 2-AG at central synapses, which will greatly enhance our basic understanding of eCB signaling and may facilitate the development of future therapeutics targeting disorders involving eCB dysfunction.

项目摘要 内源性大麻素(ECB)系统在脑内调节突触功能中起着关键作用。失调症 ECB信号与许多精神和神经疾病有关，包括焦虑、抑郁和 自闭症。因此，开发治疗涉及欧洲央行功能障碍的疾病需要一种 彻底了解大脑中调控ECB信号的机制。众所周知， 突触后神经元的生理和/或病理激活导致生物合成和释放 ECB 2-花生四烯基甘油(2-AG)。一旦释放，2-AG穿过突触裂隙并激活大麻素 受体位于突触前轴突终末，介导其行为和生理效应。 尽管在阐明2-AG信号如何控制突触功能和 行为输出，支配突触2-AG运输的机制(S)仍不清楚，突出了一个主要的 我们对大脑中2-AG信号的基本理解存在差距。2-AG的亲脂性限制了其 跨突触扩散，提示存在促进2-AG转运的载体(S) 大麻素受体激活。鉴定突触2-AG携带者不仅会大大增强我们的 对2-AG信号的基本了解，但也可能导致发现新的治疗靶点(S) 涉及欧洲央行功能障碍的疾病。为此，我们的研究小组最近确定了脂肪酸结合蛋白 (FABP)作为ECB的胞内载体。在这个应用程序中，我们将在这一进展的基础上进一步测试小说 假设FABP5由星形胶质细胞分泌，作为突触载体发挥作用，对2-AG信号是必不可少的 在多个大脑区域。在目标1中，我们将使用互补的药理学和遗传学方法来测试 FABP5通过抑制性和兴奋性突触介导2-AG逆行转运的假说 海马体和腹侧被盖区，大脑中参与认知和情绪调节的区域。在目标2中， 我们将使用我们的新型FABP5Flox/Flox小鼠来描述星形细胞和神经元FABP5在控制 突触2-AG转运。目的3将表征细胞内和分泌的FABP5在 介导2-AG在海马区和腹侧被盖区突触的运输。成功完成这项工作 提案将FABP5定位为2-AG在中央突触的突触载体，这将极大地增强我们的 对ECB信号的基本了解，并可能促进未来靶向治疗的发展 涉及欧洲央行功能障碍的疾病。