The functions of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid found in the brain, remain largely unknown. Here we show that two previously unknown inhibitors of monoacylglycerol lipase, a presynaptic enzyme that hydrolyzes 2-AG, increase 2-AG levels and enhance retrograde signaling from pyramidal neurons to GABAergic terminals in the hippocampus. These results establish a role for 2-AG in synaptic plasticity and point to monoacylglycerol lipase as a possible drug target.
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We thank N. Hájos for valuable comments and J. Kim for help with cultures. This research was supported by grants from the US National Institute on Drug Abuse and the University of California Discovery Program (D.P.); from Ministero Istruzione Università e Ricerca and University of Urbino 'Carlo Bo' and University of Parma (G.T. and M.M.); and from the Howard Hughes Medical Institute, US National Institutes of Health, European Union Framework Programme 6 and Országos Tudományos Kutatási Alapprogramok (T.F.F).
The authors declare competing financial interests: a patent was filed on behalf of D.P., A.D., A.T., M.M. and G.T. by the University of California, Irvine; the University of Urbino and the University of Parma.
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Makara, J., Mor, M., Fegley, D. et al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci 8, 1139–1141 (2005). https://doi.org/10.1038/nn1521
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