Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum.
Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum.
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DOI：
10.1523/eneuro.0048-16.2016
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发表时间：
2016-05
期刊：
影响因子：
3.4
通讯作者：
Liu QS
中科院分区：
文献类型：
--
作者：
Chen Y;Liu X;Vickstrom CR;Liu MJ;Zhao L;Viader A;Cravatt BF;Liu QS
内源性大麻素是可扩散的亲脂性分子，可以扩散到邻近的突触。单酰甘油脂肪酶 (MAGL) 是降解内源性大麻素 2-花生四烯酰甘油 (2-AG) 的主要酶。使用神经元和星形胶质细胞中 MAGL 被全局或选择性删除的敲除小鼠，我们研究了神经元和星形胶质细胞 MAGL 在多大程度上限制小脑切片中 2-AG 介导的逆行突触抑制的扩散。对分子层中平行纤维的短暂强直刺激会诱导浦肯野细胞中的突触诱发兴奋抑制 (SSE)，并且神经元和星形细胞 MAGL 都有助于终止这种形式的内源性大麻素介导的突触抑制。 SSE 在浦肯野细胞中的传播仅在 MAGL 整体敲除或 MAGL 或谷氨酸摄取的药理学阻断后发生，但在神经元或星形胶质细胞特异性删除 MAGL 后未检测到传播。内源性大麻素信号传导的传播也受到突触刺激的空间模式的影响，因为它不会发生在刺激颗粒层诱导的空间分散的平行纤维突触处。即使在 MAGL 和谷氨酸摄取被破坏后，平行纤维的强直刺激也不会诱导高尔基细胞中内源性大麻素介导的突触抑制，这表明浦肯野细胞释放 2-AG 的增加不会将逆行信号传播到支配高尔基细胞的平行纤维。这些结果表明神经元和星形细胞 MAGL 限制 2-AG 的空间扩散并赋予内源性大麻素信号传导的突触特异性。
Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knock-out of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation, because it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.