Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action
Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action
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DOI：
10.1016/j.celrep.2015.06.075
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发表时间：
2015-08-04
期刊：
影响因子：
8.8
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Viader, Andreu;Blankman, Jacqueline L.;Cravatt, Benjamin F.
内源性大麻素2-花生四烯酰甘油（2-AG）是一种逆行脂质信使，调节突触功能，神经生理学和行为。2-AG信号传导通过酶促水解终止，酶促水解是主要由单酰基甘油脂肪酶（MAGL）进行的反应。MAGL在整个神经系统中广泛表达，并且不同脑细胞类型对体内2-AG活性调节的贡献仍然知之甚少。在这里，我们从遗传学角度剖析了大脑中MAGL介导的2-AG代谢的细胞解剖学，并表明神经元和星形胶质细胞协调调节2-AG含量和内源性大麻素依赖形式的突触可塑性和行为。我们还发现星形胶质细胞MAGL主要负责通过可能涉及脂质底物跨细胞穿梭的机制将2-AG转化为神经炎症前列腺素。因此，星形胶质细胞-神经元相互作用提供了2-AG代谢和功能的分布式监督，并通过这样做，保护神经系统免受过度CB 1受体激活，并促进内源性大麻素与其他脂质递质系统的串扰。
The endocannabinoid 2-arachidonoylglycerol (2-AG) is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis-a reaction that is principally performed by monoacylglycerol lipase (MAGL). MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to the regulation of 2-AG activity in vivo remain poorly understood. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytes coordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible for converting 2-AG to neuroinflammatory prostaglandins via a mechanism that may involve transcellular shuttling of lipid substrates. Astrocytic-neuronal interplay thus provides distributed oversight of 2-AG metabolism and function and, through doing so, protects the nervous system from excessive CB1 receptor activation and promotes endocannabinoid crosstalk with other lipid transmitter systems.