Monoacylglycerol lipase limits the duration of endocannabinoid-mediated depolarization-induced suppression of excitation in autaptic hippocampal neurons

Alex Straiker, Shu-Jung Hu, Jonathan Z. Long, Andy Arnold, Jim Wager-Miller, Benjamin F. Cravatt, Ken Mackie

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Depolarization-induced suppression of excitation (DSE) is a major form of cannabinoid-mediated short-term retrograde neuronal plasticity and is found in numerous brain regions. Autaptically cultured murine hippocampal neurons are an architecturally simple model for the study of cannabinoid signaling, including DSE. The transient nature of DSE-tens of seconds-is probably determined by the regulated hydrolysis of the endocannabinoid 2-arachidonoyl glycerol (2-AG). No less than five candidate enzymes have been considered to serve this role: fatty acid amide hydrolase (FAAH), cyclooxygenase-2 (COX-2), monoacylglycerol lipase (MGL), and α/β-hydrolase domain (ABHD) 6 and 12. We previously found that FAAH and COX-2 do not have a role in determining the duration of autaptic DSE. In the current study, we found that two structurally distinct inhibitors of MGL [N-arachidonoyl maleimide and 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5- yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184)] prolong DSE in autaptic hippocampal neurons, whereas inhibition of ABHD6 by N-methyl-N-[[3-(4-pyridinyl) phenyl]methyl]-4́-(aminocarbonyl)[1,1́-biphenyl]-4-yl ester, carbamic acid (WWL70) had no effect. In addition, we developed antibodies against MGL and ABHD6 and determined their expression in autaptic cultures. MGL is chiefly expressed at presynaptic terminals, optimally positioned to break down 2-AG that has engaged presynaptic CB 1 receptors. ABHD6 is expressed in two distinct locations on autaptic islands, including a prominent localization in some dendrites. In summary, we provide strong pharmacological and anatomical evidence that MGL regulates DSE in autaptic hippocampal neurons and, taken together with other studies, emphasizes that endocannabinoid signaling is terminated in temporally diverse ways.

Original languageEnglish
Pages (from-to)1220-1227
Number of pages8
JournalMolecular Pharmacology
Volume76
Issue number6
DOIs
Publication statusPublished - 2009 Dec 1

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Monoacylglycerol Lipases
Endocannabinoids
Neurons
Cannabinoids
Cyclooxygenase 2
Neuronal Plasticity
Presynaptic Terminals
Hydrolases
Dendrites
Islands
Esters
Hydrolysis
Pharmacology
Antibodies
Brain
Enzymes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine

Cite this

Straiker, Alex ; Hu, Shu-Jung ; Long, Jonathan Z. ; Arnold, Andy ; Wager-Miller, Jim ; Cravatt, Benjamin F. ; Mackie, Ken. / Monoacylglycerol lipase limits the duration of endocannabinoid-mediated depolarization-induced suppression of excitation in autaptic hippocampal neurons. In: Molecular Pharmacology. 2009 ; Vol. 76, No. 6. pp. 1220-1227.
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Monoacylglycerol lipase limits the duration of endocannabinoid-mediated depolarization-induced suppression of excitation in autaptic hippocampal neurons. / Straiker, Alex; Hu, Shu-Jung; Long, Jonathan Z.; Arnold, Andy; Wager-Miller, Jim; Cravatt, Benjamin F.; Mackie, Ken.

In: Molecular Pharmacology, Vol. 76, No. 6, 01.12.2009, p. 1220-1227.

Research output: Contribution to journalArticle

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