Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice. J Neurosci 2011 Sep 21;31(38):13420-30
Date
09/24/2011Pubmed ID
21940435Pubmed Central ID
PMC3371386DOI
10.1523/JNEUROSCI.2075-11.2011Scopus ID
2-s2.0-80053024234 (requires institutional sign-in at Scopus site) 129 CitationsAbstract
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. CB₁ receptor antagonists enhanced basal IPSCs in CA1 pyramidal neurons in MAGL⁻/⁻ mice, while the magnitude of DSI or CB₁ 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 CB₁ 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-AG-induced 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.
Author List
Pan B, Wang W, Zhong P, Blankman JL, Cravatt BF, Liu QSAuthor
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCA1 Region, Hippocampal
Cannabinoid Receptor Modulators
Electric Stimulation
Endocannabinoids
Female
Learning
Long-Term Potentiation
Long-Term Synaptic Depression
Male
Maze Learning
Memory
Mice
Mice, Inbred C57BL
Mice, Knockout
Monoacylglycerol Lipases
Neural Inhibition
Neuronal Plasticity
Neurons
Receptor, Cannabinoid, CB1
Signal Transduction
