Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus
Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus
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DOI：
10.1523/jneurosci.4159-06.2007
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发表时间：
2007-01-31
影响因子：
5.3
通讯作者：
Kano, Masanobu
中科院分区：
文献类型：
--
作者：
Hashimotodani, Yuki;Ohno-Shosaku, Takako;Kano, Masanobu
内源性大麻素作为逆行信使，通过突触前大麻素CB 1受体调节突触传递。内源性大麻素信号传导的幅度和时间过程被认为取决于内源性大麻素的产生和降解之间的平衡。主要的内源性大麻素2-花生四烯酰甘油（2-AG）被单酰基甘油脂肪酶（MGL）水解，这被证明是位于轴突末端。在本研究中，我们研究了MGL如何调节内源性大麻素信号传导和影响海马中的突触传递。我们发现，MGL抑制剂，甲基花生四烯酰氟膦酸酯和花生四烯酰三氟甲基酮，引起培养的海马神经元中大麻素敏感的IPSC的逐渐抑制。这种抑制作用可通过阻断CB 1受体而逆转，并通过抑制2-AG合成而减弱，表明MGL清除组成性释放的2-AG。我们还发现，MGL抑制剂显着延长抑制IPSC和EPSC诱导的外源性2-AG和去极化诱导的抑制/兴奋，一种现象，已知是由逆行内源性大麻素信号转导介导的抑制。相反，其他内源性大麻素水解酶，脂肪酸酰胺水解酶和环氧合酶-2的抑制剂，对2-AG诱导的IPSC抑制没有影响。这些结果强烈地表明，突触前MGL不仅水解从激活的突触后神经元释放的2-AG，而且有助于降解组成性产生的2-AG和防止其在突触前末梢周围的积聚。因此，MGL活性决定基础内源性大麻素张力并终止海马中的逆行内源性大麻素信号传导。
Endocannabinoids function as retrograde messengers and modulate synaptic transmission through presynaptic cannabinoid CB1 receptors. The magnitude and time course of endocannabinoid signaling are thought to depend on the balance between the production and degradation of endocannabinoids. The major endocannabinoid 2-arachidonoylglycerol (2-AG) is hydrolyzed by monoacylglycerol lipase (MGL), which is shown to be localized at axon terminals. In the present study, we investigated how MGL regulates endocannabinoid signaling and influences synaptic transmission in the hippocampus. We found that MGL inhibitors, methyl arachidonoyl fluorophosphonate and arachidonoyl trifluoromethylketone, caused a gradual suppression of cannabinoid-sensitive IPSCs in cultured hippocampal neurons. This suppression was reversed by blocking CB1 receptors and was attenuated by inhibiting 2-AG synthesis, indicating that MGL scavenges constitutively released 2-AG. We also found that the MGL inhibitors significantly prolonged the suppression of both IPSCs and EPSCs induced by exogenous 2-AG and depolarization-induced suppression of inhibition/excitation, a phenomenon known to be mediated by retrograde endocannabinoid signaling. In contrast, inhibitors of other endocannabinoid hydrolyzing enzymes, fatty acid amide hydrolase and cyclooxygenase-2, had no effect on the 2-AG-induced IPSC suppression. These results strongly suggest that presynaptic MGL not only hydrolyzes 2-AG released from activated postsynaptic neurons but also contributes to degradation of constitutively produced 2-AG and prevention of its accumulation around presynaptic terminals. Thus, the MGL activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus.