Key questions of endocannabinoid signalling in the CNS: which, where and when?
Key questions of endocannabinoid signalling in the CNS: which, where and when?
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中枢神经系统内源性大麻素信号传导的关键问题：哪个、在哪里、何时？
DOI：
10.1113/jphysiol.2011.219493
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Frazier,CharlesJ
中科院分区：
文献类型：
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作者：
Frazier,CharlesJ
在2001年，内源性大麻素（EC）被确定为逆行信使的一种形式的短期突触可塑性称为去极化诱导抑制（DSI）。在这种形式的可塑性中，突触后细胞中的活性依赖性钙内流促进EC的合成和释放，EC向后穿过突触间隙以激活代谢性突触前1型大麻素受体（CB 1 R）。这些受体的激活导致动作电位诱导的GABA释放到突触后神经元的短期抑制。因此，DSI代表了一种机制，通过这种机制，单个神经元可以瞬时但有效地调节其自身输入的释放概率。在海马和小脑的最初发现的主要动机，在过去的十年中的工作已经产生了巨大的增加，我们的理解EC介导的和CB 1 R依赖形式的突触可塑性。现在清楚的是，EC介导的逆行传递发生在CNS的许多区域，EC可以通过各种特定机制动员，并且EC信号传导的多样性支持各种各样的抑制性和兴奋性突触的短期、长期甚至化生现象。然而，尽管取得了广泛的进展，但该领域一直难以明确地将特定的EC与特定形式的CB 1 R依赖性突触可塑性联系起来。在多种类型的EC依赖性现象中，两个主要候选物显然是2-花生四烯酰甘油（2-AG）和N-花生四烯酰乙醇酰胺（花生四烯酰胺）。这些化合物中的每一种都是在CNS中广泛可用的脂肪酸衍生物，并且每一种都是有效的CB 1 R配体。此外，这些化合物的合成和分解的各种分子机制已经变得越来越好地described.Initial努力，以确定是否2-AG或anandamide是DSI所需的逆行信使依赖于使用酶抑制剂，以延长故障或防止EC的合成。在几项研究中，2-AG的长期分解增加了DSI的持续时间，而花生四烯酸的长期分解没有。另一方面，大量的研究，试图破坏EC介导的信号通过抑制二酰基甘油脂肪酶（DAGL），从二酰基甘油合成2-AG所必需的酶，产生高度不一致的结果。此外，很明显，这些研究中使用的药理学药物不足以区分DAGL的两种亚型（DAGLα和DAGLβ），这两种亚型可能具有不同的发育和功能作用。
In 2001, endogenous cannabinoids (ECs) were identified as retrograde messengers in a form of short-term synaptic plasticity known as depolarization-induced suppression of inhibition (DSI). In this form of plasticity, activity-dependent calcium influx in a postsynaptic cell promotes synthesis and release of ECs that travel backward across the synaptic cleft to activate metabotropic presynaptic type1 cannabinoid receptors (CB1Rs). Activation of these receptors leads to short-term inhibition of action potential-induced GABA release onto the postsynaptic neuron. As such, DSI represents a mechanism whereby an individual neuron may transiently, but effectively, regulate the release probability of its own inputs. Motivated largely by initial discoveries in hippocampus and cerebellum, work over the last decade has produced an enormous increase in our understanding of EC-mediated and CB1R-dependent forms of synaptic plasticity. It is now clear that EC-mediated retrograde transmission occurs in many areas of the CNS, that ECs can be mobilized by a variety of specific mechanisms, and that diversity of EC signalling supports a wide range of short-term, long-term, and even metaplastic phenomena at a wide variety of both inhibitory and excitatory synapses. However, despite extensive progress, it has been persistently difficult for the field to definitively associate specific ECs with specific forms of CB1R-dependent synaptic plasticity. The two primary candidates in multiple types of EC-dependent phenomena are clearly 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamide(anandamide). Each of these compounds is a fatty acid derivative that is widely available in the CNS, and each is an effective CB1R ligand. Further, a variety of molecular mechanisms for synthesis and breakdown of each of these compounds has become increasingly well described.Initial efforts to determine whether 2-AG or anandamide is the retrograde messenger specifically required for DSI relied on the use of enzyme inhibitors to prolong breakdown or prevent synthesis of ECs. In several studies prolonged breakdown of 2-AG increased the duration of DSI, while prolonged breakdown of anandamide did not. On the other hand, a large number of studies that attempted to disrupt EC-mediated signalling by inhibition of diacylglycerol lipase (DAGL), an enzyme necessary to synthesize 2-AG from diacylglycerol, produced highly inconsistent results. Further, it became clear that the pharmacological agents used in these studies were insufficient to distinguish between two isoforms of DAGL (DAGLα and DAGLβ) that have potential for distinct developmental and functional roles.