Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, The Netherlands.
J Neurosci. 2010 Feb 17;30(7):2710-5. doi: 10.1523/JNEUROSCI.BC-3622-09.2010.
Endocannabinoids control hippocampal inhibitory synaptic transmission through activation of presynaptic CB(1) receptors. During depolarization-induced suppression of inhibition (DSI), endocannabinoids are synthesized upon postsynaptic depolarization. The endocannabinoid 2-arachidonoylglycerol (2-AG) may mediate hippocampal DSI. Currently, the best studied pathway for biosynthesis of 2-AG involves the enzyme diacylglycerol lipase (DAGL). However, whether DAGL is necessary for hippocampal DSI is controversial and was not systematically addressed. Here, we investigate DSI at unitary connections between CB(1) receptor-containing interneurons and pyramidal neurons in CA1. We found that the novel DAGL inhibitor OMDM-188, as well as the established inhibitor RHC-80267, did not affect DSI. As reported previously, effects of the DAGL inhibitor tetrahydrolipstatin depended on the application method: postsynaptic intracellular application left DSI intact, while incubation blocked DSI. We show that all DAGL inhibitors tested block slow self-inhibition in neocortical interneurons, which involves DAGL. We conclude that DAGL is not involved in DSI at unitary connections in hippocampus.
内源性大麻素通过激活突触前 CB1 受体来控制海马抑制性突触传递。在去极化诱导的抑制性抑制 (DSI) 期间，内源性大麻素在后突触去极化时合成。内源性大麻素 2-花生四烯酸甘油 (2-AG) 可能介导海马 DSI。目前，2-AG 生物合成的研究最多的途径涉及酶二酰基甘油脂肪酶 (DAGL)。然而，DAGL 是否对海马 DSI 是必需的存在争议，且尚未系统解决。在这里，我们在 CA1 中含有 CB1 受体的中间神经元和锥体细胞之间的单位连接上研究 DSI。我们发现，新型 DAGL 抑制剂 OMDM-188 以及已建立的抑制剂 RHC-80267 均不影响 DSI。如前所述，DAGL 抑制剂四氢脂抑素的作用取决于应用方法：突触后细胞内应用使 DSI 保持完整，而孵育则阻断 DSI。我们表明，所有测试的 DAGL 抑制剂都阻断了新皮层中间神经元中的慢自身抑制，其中涉及 DAGL。我们的结论是，DAGL 不参与海马体单位连接中的 DSI。
