Endocannabinoids and GABAergic Control of Plasticity

描述(申请人提供)：大麻素，其中的生物活性成分 大麻和大麻，通过作用于特定的膜结合而影响大脑。 G蛋白偶联受体(CB1s)。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不揭示 内源性大麻素系统的详细工作原理，即释放的细胞 内源性大麻素和对它们有反应的细胞。在细胞水平上 对内源性大麻素的释放及其功能作用几乎一无所知。 海马CA1区锥体神经元去极化释放内源性大麻素， 它们与亚类中间神经元突触前终末上的Cb1s结合 在它们身上进行突触。CB1s的激活导致GABA的一过性下降 放手。这个过程被称为DSI(去极化诱导抑制 抑制)，代表了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 正常大鼠和小鼠海马脑片的记录技术 基因改变的小鼠，我们将测试神经细胞 兴奋性由内源性大麻素系统控制。详细信息： 内源性大麻样物质在Cal DSI中的功能作用尚不清楚。此外， 内源性大麻素受体存在于大脑的其他部位，但并不存在 知道它们是否在任何地方执行相同的功能。齿状回(DG) 在许多方面不同于CA1，包括神经元电路和机制 可塑性，如长时程增强(LTP)。DG中的CB 1是 与Cal中的同一类中间神经元有关。DG是一个理想的选择 检验内源性大麻素假说普适性的模型。副秘书长是一名 从海马区到海马区的通道以及如何理解 可塑性得到控制将显得尤为重要。最后，一个主要的 科学和临床问题是对外源药物应用的耐受性 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。我们的具体目标是检验假设：1. 内源性大麻素是介导DSI的必要条件和充分条件。2.该条 内源性大麻素释放促进NMDAR依赖的LTP在CAL的诱导。3. DSI的调节作用是齿状回中内源性大麻素的作用。4. 这种内源性大麻素的释放促进了齿状回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。

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.