COX-2 oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity
Introduction
Endocannabinoids (eCBs) are endogenous lipid mediators that play an important role in modulating cannabinoid CB1 receptor-mediated inhibitory and excitatory synaptic transmission and plasticity in the brain (Alger, 2005, Chevaleyre et al., 2006, Freund et al., 2003, Mackie, 2006, Piomelli, 2003, Sugiura et al., 2006). The most studied eCBs are 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA). The production and degradation of 2-AG and AEA occur through different pathways (Piomelli, 2003, Freund et al., 2003, Sugiura et al., 2004, Stella, 2004, Mackie, 2006). 2-AG is mainly produced from diacylglycerol (DAG) by diacylglycerol lipase (DGL) and hydrolyzed to arachidonic acid (AA) by monoacylglycerol lipase (MGL), whereas AEA is largely synthesized from N-arachidonoylphosphatidylethanolamine (NAPE) by phospholipase D (PLD) and degraded to AA by fatty acid amide hydrolase (FAAH, Freund et al., 2003, Piomelli, 2003, Sugiura et al., 2004). Recent studies show that 2-AG and AEA are substrates for cyclooxygenase-2 (COX-2), an inducible enzyme that converts AA to classic prostaglandins. 2-AG and AEA can also be oxygenated by COX-2 to novel prostaglandin isoforms: prostaglandin glyceryl esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs, Kozak et al., 2000, Kozak et al., 2002, Kozak et al., 2004, Sang and Chen, 2006, Yu et al., 1997). Interestingly, 2-AG and AEA are poor substrates for COX-1, suggesting that the COX-2 oxidative metabolism is an important pathway in degrading eCBs (Kozak et al., 2004, Sang and Chen, 2006). This means that up- or down-regulation of COX-2 expression and activity will significantly influence eCB signaling in synaptic activity. This prediction has been confirmed by recent studies where the COX-2 inhibition augments hippocampal DSI (Kim and Alger, 2004, Sang et al., 2006) and elicits a CB1-mediated decrease of excitatory transmission and LTP in rat CA1 hippocampus (Slanina and Schweitzer, 2005, Slanina et al., 2005).
COX-2 has been demonstrated to participate in synaptic transmission and plasticity (Chen et al., 2002, Murray and O'Connor, 2003, Chen and Bazan, 2005, Sang et al., 2005, Akaneya and Tsumoto, 2006). COX-2 effects on synaptic transmission are dependent on increased production of AA-derived prostaglandins, mainly PGE2. Since eCBs are important mediators involved in synaptic transmission and plasticity, COX-2 oxidative metabolism of eCBs likely alters eCB signaling. In this study, we determined effects of the COX-2 elevation and inhibition, and COX-2 oxidative metabolites of eCBs on hippocampal synaptic plasticity. We observed that increased COX-2 expression increases hippocampal basal synaptic transmission, augments LTP, and abolishes depolarization-induced suppression of inhibition (DSI), while inhibition of COX-2 reduces LTP and potentiates DSI. Moreover, we demonstrate that COX-2 oxidative metabolites of eCBs enhance LTP, an effect that is opposite to that of their parent molecules 2-AG and AEA. In addition, we provide evidence that ERK, p38 MAPK and IP3 pathways mediate PGE2-G-, a major COX-2 oxidative metabolite of 2-AG, induced elevation of LTP. Our results suggest that COX-2 oxidative metabolism of eCBs is an important mechanism in regulation of eCB signaling in synaptic plasticity.
Section snippets
Elevation of COX-2 expression enhances basal synaptic transmission and augments LTP
Pharmacologic or genetic inhibition of COX-2 decreases LTP and LTD (Akaneya and Tsumoto, 2006, Chen et al., 2002, Murray and O'Connor, 2003, Slanina et al., 2005). However, it is not known whether elevated COX-2 activity influences synaptic efficacy. To determine whether increased COX-2 expression produces an effect on long-term synaptic plasticity, we first examined the time course of COX-2 expression following the injection of lipopolysaccharide (LPS), a commonly used inducer of COX-2
Discussion
We demonstrate here that hippocampal synaptic transmission is strengthened when COX-2 activity is elevated. The COX-2 mediated enhancement of synaptic plasticity is likely to be a result of increased production of AA-derived PGE2 and eCB-derived PG-Gs and PG-EAs, and reduced eCBs. This is evidenced by (1) enhanced LTP and diminished DSI when COX-2 expression is induced by LPS or over-expressed in a transgenic COX-2 model, (2) by enhanced DSI when COX-2 is pharmacologically or genetically
Animals
C57BL/6 mice (Charles River), COX-2 −/− (Ptgs2tm1Jed Jackson Laboratory) and human Thy-1-COX-2 transgenic mice (Andreasson et al., 2001) weighing 20–25 g were used according to the guidelines approved by the Institutional Animal Care and Use Committee of Louisiana State University Health Sciences Center. Mice were intraperitoneally (i.p.) injected with vehicle, LPS (3 mg/kg), NS398 (10 mg/kg), AH 6809 (10 mg/kg) or SR141716 (5 mg/kg), and killed 4, 12 and 24 h after injection.
Hippocampal slice preparation
Hippocampal slices
Acknowledgments
This work was supported by National Institutes of Health grants R01NS054886 and P20RR16816, and the Alzheimer’s Association grant IIRG-05-13580 (to CC).
References (38)
- et al.
Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glycerol prostaglandins by COX-2
J. Biol. Chem.
(2000) - et al.
Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides
J. Biol. Chem.
(2002) - et al.
A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro
Neuropharmacology
(2003) - et al.
Inhibition of cyclooxygenase-2 elicits a CB1-mediated decrease of excitatory transmission in rat CA1 hippocampus
Neuropharmacology
(2005) - et al.
Endocannabinoids restrict hippocampal long-term potentiation via CB1
Neuropharmacology
(2005) - et al.
Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand
Prog. Lipid Res.
(2006) - et al.
Lipopolysaccharide inhibits long term potentiation in the rat dentate gyrus by activating caspase-1
J. Biol. Chem.
(2000) - et al.
Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids
Neuron
(1993) - et al.
Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2
J. Biol. Chem.
(1997) - et al.
Bidirectional trafficking of prostaglandin E2 receptors involved in long-term potentiation in visual cortex
J. Neurosci.
(2006)