COX-2 and fatty acid amide hydrolase can regulate the time course of depolarization-induced suppression of excitation

A. Straiker, J. Wager-Miller, S. S. Hu, J. L. Blankman, B. F. Cravatt, K. MacKie

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE Depolarization-induced suppression of inhibition (DSI) and excitation (DSE) are two forms of cannabinoid CB 1 receptor-mediated inhibition of synaptic transmission, whose durations are regulated by endocannabinoid (eCB) degradation. We have recently shown that in cultured hippocampal neurons monoacylglycerol lipase (MGL) controls the duration of DSE, while DSI duration is determined by both MGL and COX-2. This latter result suggests that DSE might be attenuated, and excitatory transmission enhanced, during inflammation and in other settings where COX-2 expression is up-regulated. EXPERIMENTAL APPROACH To investigate whether it is possible to control the duration of eCB-mediated synaptic plasticity by varied expression of eCB-degrading enzymes, we transfected excitatory autaptic hippocampal neurons with putative 2-AG metabolizing enzymes: COX-2, fatty acid amide hydrolase (FAAH), α/β hydrolase domain 6 (ABHD6), α/β hydrolase domain 12 (ABHD12) or MGL. KEY RESULTS We found that overexpression of either COX-2 or FAAH shortens the duration of DSE while ABHD6 or ABHD12 do not. In contrast, genetic deletion (MGL -/-) and overexpression of MGL both radically altered eCB-mediated synaptic plasticity. CONCLUSIONS AND IMPLICATIONS We conclude that both FAAH and COX-2 can be trafficked to neuronal sites where they are able to degrade eCBs to modulate DSE duration and, by extension, net endocannabinoid signalling at a given synapse. The results for COX-2, which is often up-regulated under pathological conditions, are of particular note in that they offer a mechanism by which up-regulated COX-2 may promote neuronal excitation by suppressing DSE while enhancing conversion of 2-AG to PGE 2-glycerol ester under pathological conditions.

Original languageEnglish
Pages (from-to)1672-1683
Number of pages12
JournalBritish Journal of Pharmacology
Volume164
Issue number6
DOIs
Publication statusPublished - 2011 Nov

All Science Journal Classification (ASJC) codes

  • Pharmacology

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