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， 大麻和印度大麻，通过作用于特定的膜结合来影响大脑。 G蛋白偶联受体（CB1）。存在CB1的内源性配体 （内源性大麻素），但关于受体的信息，受体定位， 内源性激动剂和相关的第二信使系统并没有揭示 内源性大麻素系统的详细工作原理，即，这些细胞释放 endocannabinoids和对它们有反应的细胞。在细胞水平上 对内源性大麻素释放或其功能作用几乎一无所知。 海马CA1锥体神经元的去极化释放内源性大麻素， 它与中间神经元亚类的突触前末梢上的CB 1结合 与它们形成突触CB1s的激活导致GABA的短暂减少 release.这个过程，称为DSI（去极化诱导的抑制， 抑制），代表了检测释放和研究 内源性大麻素的作用利用电生理学和光学 正常大鼠和小鼠海马脑片的记录技术， 基因改变的小鼠，我们将测试的假设，神经元 兴奋性由内源性大麻素系统控制。细节 内源性大麻素在CA1DSI中的功能作用仍不清楚。此外，委员会认为， 内源性大麻素受体存在于大脑的其他部位，它不是 如果它们在任何地方都执行相同的功能。齿状回（DG） 与CA 1在许多方面不同，包括神经元回路和 可塑性，如长时程增强（LTP）。DG中的CB 1是 与CAl中相同类别的中间神经元相关联。DG是理想的 测试内源性大麻素假设的一般性的模型。DG是一个 从海马体外区域进入海马体， 可塑性的控制就显得尤为重要。最后，一个主要 科学和临床的问题是“耐受性”的应用外源性 大麻素目前尚不清楚对外源性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标是测试假设：1。 内源性大麻素是介导DSI的必要和足够的。2.的 内源性大麻素释放促进CA1中NMDAR依赖性LTP诱导。 DSI的介导是齿状回内源性大麻素的功能。4. 内源性大麻素的释放促进齿状回LTP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