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The Journal of Neuroscience, January 31, 2007, 27(5):1211-1219; doi:10.1523/JNEUROSCI.4159-06.2007

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Cellular/Molecular
Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

Yuki Hashimotodani,¹ Takako Ohno-Shosaku,³ and Masanobu Kano²

¹Departments of Neurophysiology and ²Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan, and ³Department of Impairment Study, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-0942, Japan

Correspondence should be addressed to Masanobu Kano, Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan. Email: mkano{at}cns.med.osaka-u.ac.jp

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.

Key words: 2-arachidonoylglycerol; monoacylglycerol lipase; diacylglycerol lipase; CB1 cannabinoid receptor; depolarization-induced suppression of inhibition; hippocampus

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Received Sept. 22, 2006; revised Dec. 5, 2006; accepted Dec. 15, 2006.

Correspondence should be addressed to Masanobu Kano, Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan. Email: mkano{at}cns.med.osaka-u.ac.jp

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