Endocannabinoids and GABAergic Control of Plasticity

内源性大麻素和可塑性的 GABA 能控制

• 批准号: 6424886
• 负责人: BRADLEY E ALGER
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6424886
• 关键词: biological transport; calcium flux; calcium indicator; cannabinoid receptor; cannabinoids; cell cell interaction; cell population study; chemical structure function; cytology; dentate gyrus; drug tolerance; electrophysiology; fluorescence microscopy; gamma aminobutyrate; genetically modified animals; hippocampus; laboratory mouse; laboratory rat; neural inhibition; neural plasticity; neural transmission; neurons; neuroregulation; voltage /patch clamp

DESCRIPTION (provided by applicant): Cannabinoids, the bioactive ingredients in marijuana and hashish, affect the brain by acting at specific, membrane bound. G-protein-coupled receptors (CB1s). Endogenous ligands for CB1 exist (endocannabinoids), but information on receptors, receptor localization, endogenous agonists and associated second-messenger systems does not reveal the detailed workings of the endocannabinoid system, i.e., the cells that release endocannabinoids and the cells that respond to them. At the cellular level almost nothing is known about endocannabinoid release or its functional roles. Depolarization of hippocampal CA 1 pyramidal neurons releases endocannabinoids, which bind to CB 1s on presynaptic terminals of a sub-class of interneurons synapsing on them. Activation of CB1s causes a transient decrease in GABA release. This process, called DSI (depolarization-induced suppression of inhibition), represents a unique means for detecting the release and studying the actions of endocannabinoids. Using electrophysiological and optical recording techniques on hippocampal slices from normal rats and mice, and from genetically altered mice, we will test the hypothesis that neuronal excitability is governed by the endocannabinoid system. Details of the functional roles of endocannabmoids in CAl DSI remain unclear. Moreover, endocannabinoid receptors exist in other parts of the brain, and it is not known if they perform the same functions everywhere. The dentate gyrus (DG) differs from CA 1 in many ways, including neuronal circuitry and mechanisms of plasticity, such as long-term potentiation (LTP). CB 1s in the DG are associated with the same class of interneurons as in CAl. The DG is an ideal model for testing the generality of the endocannabinoid hypothesis. The DG is a gateway to the hippocampus from extrahippocampal areas and so understanding how plasticity is controlled there will be especially important. Finally, a major scientific and clinical problem is "tolerance" to the application of exogenous cannabinoids. It is not known if tolerance to exogenous cannabinoids affects the endocannabinoid system. Our Specific Aims are to test the hypotheses: 1. That endocannabinoids are necessary and sufficient to mediate DSI. 2. That endocannabinoid release facilitates NMDAR-dependent LTP induction in CAl. 3. That mediation of DSI is a function of endocannabinoids in dentate gyrus. 4. That endocannabinoid release facilitates induction of LTP in dentate gyrus. 5. That the development of tolerance to exogenous cannabinoids affects the endocannabinoid system.

描述（由申请人提供）：大麻素，生物活性成分 大麻和大麻，通过在特定的膜结合处作用会影响大脑。 G蛋白偶联受体（CB1）。 CB1的内源配体 （内源性大麻素），但有关受体，受体定位的信息， 内源性激动剂和相关的第二童年系统并未揭示 内源性大麻素系统的详细工作，即释放的单元 内源性大麻素和对它们反应的细胞。在细胞水平 关于内源性大麻素的释放或其功能作用几乎一无所知。 海马Ca 1的去极化1锥体神经元释放内源性大麻素， 在子类中间神经元的突触前终端上与CB 1S结合 在它们上突触。 CB1的激活导致GABA的短暂下降 发布。此过程称为DSI（去极化引起的抑制 抑制），代表一种检测释放和研究的独特手段 内源性大麻素的作用。使用电生理和光学 在正常大鼠和小鼠的海马切片上记录技术，以及 遗传改变的小鼠，我们将检验神经元的假设 兴奋性受内源性大麻素系统的控制。细节 内源性大麻瘤在CAL DSI中的功能作用尚不清楚。而且， 内源性大麻素受体存在于大脑的其他部位，而不是 知道他们是否到处执行相同的功能。齿状回（DG） 在许多方面与CA 1不同，包括神经元电路和机制 可塑性，例如长期增强（LTP）。 DG中的CB 1是 与Cal中的同一类中间神经元相关。 DG是理想的 测试内源性大麻素假设的一般性的模型。 DG是 从外公寓地区到达海马的门户，因此了解如何 可控制可塑性将特别重要。最后，一个少校 科学和临床问题是对外源的应用“耐受性” 大麻素。尚不知道对外源大麻素的耐受性是否会影响 内源性大麻素系统。我们的具体目的是检验假设：1。 内源性大麻素是必要的，足以介导DSI。 2。那 内源性大麻素释放促进CAL中NMDAR依赖性LTP诱导。 3。 DSI的介导是齿状回中内源性大麻素的函数。 4。 内源性大麻素的释放促进了LTP在齿状回中的诱导。 5。 对外源性大麻素的耐受性的发展会影响 内源性大麻素系统。