Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters such as glutamate or GABA, yet they act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical, and physiological characteristics of endocannabinoid signaling has revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then, we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes, thereby differentially governing homeostatic, short-term, and long-term synaptic plasticity throughout the brain. Finally, we discuss how cell type- and synapse-specific refinement of endocannabinoid signaling may explain the characteristic behavioral effects of cannabinoids.

中文翻译：

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大脑中内源性大麻素信号传导的多种功能。


尽管几十年来大麻素研究一直被视为嬉皮科学，但它终于在主流神经科学中找到了应有的地位。一系列突破性的发现表明，内源性大麻素分子与谷氨酸或 GABA 等传统神经递质一样广泛和重要，但它们的作用方式却非常非传统。我们的目的是说明揭示内源性大麻素信号传导的分子、解剖和生理特征如何揭示突触生理学中几种基本现象的新机制见解。首先，我们总结了两种内源性大麻素（anandamide 和 2-arachidonoylglycerol）的生物发生和失活的分子复杂性方面的意外进展。然后，我们展示了这些新的代谢途径如何整合到众所周知的细胞内信号通路中。这些产生内源性大麻素的信号体以阶段性和强直性模式运作，从而差异性地控制整个大脑的稳态、短期和长期突触可塑性。最后，我们讨论了内源性大麻素信号传导的细胞类型和突触特异性细化如何解释大麻素的特征行为效应。