title: Active endocannabinoids are secreted on extracellular membrane vesicles.
abstract: Endocannabinoids primarily influence neuronal synaptic communication within the nervous system. To exert their function, endocannabinoids need to travel across the intercellular space. However, how hydrophobic endocannabinoids cross cell membranes and move extracellularly remains an unresolved problem. Here, we show that endocannabinoids are secreted through extracellular membrane vesicles produced by microglial cells. We demonstrate that microglial extracellular vesicles carry on their surface N-arachidonoylethanolamine (AEA), which is able to stimulate type-1 cannabinoid receptors (CB1), and inhibit presynaptic transmission, in target GABAergic neurons. This is the first demonstration of a functional role of extracellular vesicular transport of endocannabinoids.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Gabrielli
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Battista
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Riganti
authors.affiliation: CNR Institute of Neuroscience, Milano, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Prada
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Antonucci
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milano, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cantone
authors.affiliation: CNR Institute of Neuroscience, Milano, Italy IRCCS Humanitas, Rozzano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.affiliation: European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy m.maccarrone@unicampus.it c.verderio@in.cnr.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: CNR Institute of Neuroscience, Milano, Italy IRCCS Humanitas, Rozzano, Italy m.maccarrone@unicampus.it c.verderio@in.cnr.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
mesh_terms: D000818:Animals; D001095:Arachidonic Acids; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism; D017628:Microglia / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D043882:Receptors, Cannabinoid / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; C078814:anandamide
keywords: CB1 receptor; GABA release; anandamide; extracellular vesicle; microglia‐neuron signaling