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

Abstract

BACKGROUND AND PURPOSEDepolarization-induced suppression of inhibition (DSI) and excitation (DSE) are two forms of cannabinoid CB1 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 APPROACHTo 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), a/b hydrolase domain 6 (ABHD6), a/b hydrolase domain 12 (ABHD12) or MGL. KEY RESULTSWe 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 IMPLICATIONSWe 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 PGE2-glycerol ester under pathological conditions. Abbreviations 2-AG, 2-arachidonylglycerol; ABHD6, a/b hydrolase domain 6; ABHD12, a/b hydrolase domain 12; AEA, arachidonyl ethanolamide; DSE, depolarization-induced suppression of excitation; DSI, depolarization-induced suppression of inhibition; eCB, endocannabinoid; FAAH, fatty acid amide hydrolase; MGL, monoacylglycerol lipase

α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

“…The brain-penetrant ABHD6 inhibitor, WWL123, did not affect DSE in cerebellar slices, whereas genetic inactivation of MAGL resulted in prolonged DSE at Purkinje cell synapses in granule cells or the inferior olivary nucleus (41). WWL123 had no effects on DSI or DSE in autapse preparations (28,42), and overexpression of mouse ABHD6 or ABHD12 in hippocampal autapse preparations had no effects on the kinetics of DSE (43). In layer 5 of prefrontal cortical slices, blocking ABHD6 or MAGL activity with WWL70 or JZL184, respectively, induced endocannabinoid-dependent long-term depression via subthreshold stimulation of layer 2 neurons (29).…”

Mammalian alpha beta hydrolase domain (ABHD) proteins: Lipid metabolizing enzymes at the interface of cell signaling and energy metabolism

“…Furthermore, ABHD6 expression might be linked to the pathogenesis of EBV-related disorders such as: endemic Burkitt's lymphoma, Hodgkin's Lymphoma, and Post-Transplant Lymphoma [46, 47]. The first physiological substrate identified for ABHD6 was 2-arachidonylglycerol (2-AG) [48-50], an endocannabinoid signaling lipid that plays key roles in neurotransmission and metabolic disease. Although monoacylglycerol lipase (MAGL) was long thought to be the only mechanism of 2-AG hydrolysis, recently both ABHD6 and ABHD12 have also been shown to hydrolyze this key signaling lipid [48-52].…”

Stress regulates endocannabinoid-CB1 receptor signaling

“…Available data indicate that glucocorticoids increase 2-AG concentrations; however, it seems that different glucocorticoid receptor sub-types and signaling cascades are employed, allowing for the specific pattern and time-course of eCB mobilization to be matched to the function of the glucocorticoids at a particular synapse. COX2 can oxidize both AEA and 2-AG [46] and its inhibition has been shown to increase ECS in the hippocampus [64, 65] and dorsal raphe [60]. There is evidence that COX2 is negatively regulated by glucocorticoids [66] supporting the possibility that glucocorticoids can regulate concentrations of the eCBs available to signal via alterations in the activity of COX2.…”