Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice

Bin Pan, Wei Wang, Peng Zhong, Jacqueline L. Blankman, Benjamin F. Cravatt, Qing Song Liu

Research output: Contribution to journalArticlepeer-review

129 Scopus citations


Endocannabinoid (eCB) signaling is tightly regulated by eCB biosynthetic and degradative enzymes. The eCB 2-arachidonoylglycerol (2-AG) is hydrolyzed primarily by monoacylglycerol lipase (MAGL). Here, we investigated whether eCB signaling, synaptic function, and learning behavior were altered in MAGL knock-out mice. We report that MAGL -/-mice exhibited prolonged depolarization-induced suppression of inhibition (DSI) in hippocampal CA1 pyramidal neurons, providing genetic evidence that the inactivation of 2-AG by MAGL determines the time course of the eCB-mediated retrograde synaptic depression. CB 1 receptor antagonists enhanced basal IPSCs in CA1 pyramidal neurons in MAGL -/-mice, while the magnitude of DSI or CB 1 receptor agonist-induced depression of IPSCs was decreased in MAGL -/-mice. These results suggest that 2-AG elevations in MAGL -/-mice cause tonic activation and partial desensitization of CB 1 receptors. Genetic deletion of MAGL selectively enhanced theta burst stimulation (TBS)-induced long-term potentiation (LTP) in the CA1 region of hippocampal slices but had no significant effect on LTP induced by high-frequency stimulation or long-term depression induced by low-frequency stimulation. The enhancement of TBS-LTP in MAGL -/-mice appears to be mediated by 2-AGinduced suppression of GABA A receptor-mediated inhibition. MAGL -/-mice exhibited enhanced learning as shown by improved performance in novel object recognition and Morris water maze. These results indicate that genetic deletion of MAGL causes profound changes in eCB signaling, long-term synaptic plasticity, and learning behavior.

Original languageEnglish (US)
Pages (from-to)13420-13430
Number of pages11
JournalJournal of Neuroscience
Issue number38
StatePublished - Sep 21 2011
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience


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