Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB1 cannabinoid receptors on neurons and CB2 cannabinoid receptors on microglia. Enzymes that hydrolyze 2-AG, such as monoacylglycerol lipase, regulate the accumulation and efficacy of 2-AG at cannabinoid receptors. We found that the recently described serine hydrolase α-β-hydrolase domain 6 (ABHD6) also controls the accumulation and efficacy of 2-AG at cannabinoid receptors. In cells from the BV-2 microglia cell line, ABHD6 knockdown reduced hydrolysis of 2-AG and increased the efficacy with which 2-AG can stimulate CB2-mediated cell migration. ABHD6 was expressed by neurons in primary culture and its inhibition led to activity-dependent accumulation of 2-AG. In adult mouse cortex, ABHD6 was located postsynaptically and its selective inhibition allowed the induction of CB1-dependent long-term depression by otherwise subthreshold stimulation. Our results indicate that ABHD6 is a rate-limiting step of 2-AG signaling and is therefore a bona fide member of the endocannabinoid signaling system.

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Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse (DA14486 and DA26430 to N.S., DA017259, DA009789 and DA025285 to B.F.C. and DA026161 to J.L.B.) and from the National Institute of General Medical Sciences (PHS NRSA 2T32 GM007270 to W.R.M.).

Author information

Author notes

    • Jacqueline L Blankman
    •  & Eric A Horne

    These authors contributed equally to this work.

Affiliations

  1. Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, USA.

    • William R Marrs
    •  & Susan Fung
  2. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.

    • Jacqueline L Blankman
    • , Jessica P Alexander
    • , Jonathan Z Long
    • , Weiwei Li
    •  & Benjamin F Cravatt
  3. Department of Pharmacology, University of Washington, Seattle, Washington, USA.

    • Eric A Horne
    • , Yi Hsing Lin
    • , Jonathan Coy
    • , Cong Xu
    •  & Nephi Stella
  4. INSERM U862, Equipe Physiopathologie de la plasticité synaptique, Bordeaux, France.

    • Aurore Thomazeau
    • , Mathieu Lafourcade
    •  & Olivier J Manzoni
  5. Department of Otolaryngology, University of Washington, Seattle, Washington, USA.

    • Agnes L Bodor
  6. Bioanalysis and Pharmacology of Bioactive Lipids Laboratory, CHAM7230, Louvain Drug Research Institute, Université catholique de Louvain, Bruxelles, Belgium.

    • Giulio G Muccioli
  7. Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, USA.

    • Sherry Shu-Jung Hu
    •  & Ken Mackie
  8. Neurobiology Undergraduate Program, University of Washington, Seattle, Washington, USA.

    • Grace Woodruff
  9. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • Thomas Möller
  10. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.

    • Nephi Stella

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Contributions

W.R.M. prepared the cell cultures, performed the hydrolysis experiments, conducted the data analysis and wrote the manuscript. J.L.B. performed the ABPP experiments and contributed to the data analysis. E.A.H. performed the GC-MS and immunofluoresence experiments and contributed to the electron microscopy experiments and data analysis. A.T. and M.L. performed the electrophysiology experiments. Y.H.L. prepared the cell culture transfections and the shRNA constructs, and performed the qPCR experiments. J.C. contributed to the immunofluorescence experiments. A.L.B. performed the electron microscopy experiments. G.G.M. contributed to the hydrolysis experiments. S.S.-J.H. contributed to antibody production. G.W. and S.F. performed the cell migration experiments. J.P.A. contributed to the ABPP experiments. J.Z.L. and W.L. produced the hydrolase inhibitors. C.X. contributed to the cell culture experiments. T.M. provided the transgenic mice. K.M. provided antibodies. O.J.M. supervised the electrophysiology experiments. B.F.C. supervised the ABPP experiments and the development of hydrolase inhibitors. N.S. supervised the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nephi Stella.

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DOI

https://doi.org/10.1038/nn.2601

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