COX-2 oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity

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Abstract

Endocannabinoids (eCBs) are important endogenous lipid mediators in synaptic transmission and plasticity and are oxygenated by cyclooxygenase-2 (COX-2) to form new types of prostaglandins. However, little is known about whether COX-2 oxidative metabolism of eCBs and their metabolites alter synaptic signaling. Here we demonstrate that increased COX-2 expression significantly enhances basal synaptic transmission and augments long-term potentiation (LTP) in the mouse hippocampus. This augmentation was inhibited in the presence of a selective COX-2 inhibitor or with deletion of the COX-2 gene. The CB1 receptor-mediated depolarization-induced suppression of inhibition (DSI) was diminished when COX-2 expression was increased either with lipopolysaccharide (LPS) stimulation or transgenic neuronal over-expression of COX-2. Conversely, DSI was potentiated when COX-2 activity was pharmacologically or genetically inhibited. Interestingly, COX-2 oxidative metabolites of eCBs elevated LTP, an effect opposite to that of their parent molecules 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA). In addition, the ERK/MAPK and IP3 pathways were found to mediate PGE2-G-induced enhancement of LTP. Our results indicate that COX-2 oxidative metabolism of eCBs is an important signaling pathway in modulation of synaptic transmission and 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).

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