Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action

Abstract

Summary The endocannabinoid 2-arachidonoylglycerol (2-AG) is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis—a reaction that is principally performed by monoacylglycerol lipase (MAGL). MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to regulating 2-AG activity have remained unclear. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytes coordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible for converting 2-AG to neuroinflammatory prostaglandins via a mechanism that may involve transcellular shuttling of lipid substrates. Astrocytic-neuronal interplay thus provides distributed oversight of 2-AG metabolism and function, and, through doing so, protects the nervous system from excessive CB1 receptor activation and promotes endocannabinoid crosstalk with other lipid transmitter systems.

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

“…5E). These results, when combined with previous findings (36,39,41), indicate that blockade of the principal 2-AG biosynthetic and degradation enzymes in the brain, DAGLα and MAGL, respectively, produces overlapping (reductions in brain prostaglandins and cytokines), but distinct (suppression versus enhancement of anapyrexia) effects on LPS-induced neuroinflammation.…”

“…Monoacylglycerol lipase (MAGL or MGLL)-mediated hydrolysis of 2-AG provides a major source of AA substrate for prostaglandin synthesis in the nervous system under basal and neuroinflammatory states (36)(37)(38)(39). Having discovered that acute, pharmacological inhibition of DAGLs coordinately lowers 2-AG and prostaglandin content of the brain (Fig.…”

“…High-dose lipopolysaccharide (LPS) treatment induces brain prostaglandin and cytokine production (36,39) and leads to profound anapyrexia in rodents (40,41), an effect that is thought to be mediated, at least in part, by centrally produced prostaglandins and endocannabinoids (40). MAGL blockade has been shown to suppress LPS-induced prostaglandin and cytokine production in the CNS (36,39), but also exacerbates the anapyrexia observed in this paradigm through a CB 1 R-dependent mechanism (41). Building on these observations, we examined the effects of pharmacological and genetic inactivation of DAGL activity on neuroinflammatory responses induced by LPS.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Biosynthetic enzymes as well as FAAH and MAGL are expressed in astrocytes (827,861). A recent study genetically dissected the cellular anatomy of MAGLmediated 2-AG metabolism in the brain and showed that neurons and astrocytes coordinately regulate 2-AG levels and CB1-mediated synaptic plasticity and behavior, and that astrocytic MAGL converts 2-AG to neuroinflammatory prostaglandins (882).…”

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

“…The MAGL enzyme is present in postsynaptic astro-glial compartments [56][57][58] and it hydrolyzes 2-AG to form ARA and glycerol. There is some redundancy in degradation enzymes for 2-AG because ABHD6 (Abhydrolase domain containe protein 6) and ABHD12 can also hydrolyze 2-AG [48,56].…”