Active endocannabinoids are secreted on extracellular membrane vesicles

Martina Gabrielli, Natalia Battista, Loredana Riganti, Ilaria Prada, Flavia Antonucci, Laura Cantone, Michela Matteoli, Mauro Maccarrone, Claudia Verderio

Research output: Contribution to journalArticle

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. Synopsis Microvesicles (MVs) are identified as new vehicles for the transfer of endocannabinoids from microglia to neurons. By activating presynaptic CB1 receptors on interneurons, these endocannabinoids inhibit spontaneous GABA release. Microglia-derived MVs are enriched in the endocannabinoid AEA and transport it across the extracellular space. AEA-storing MVs activate presynaptic CB1 and downstream signaling to inhibit GABAergic transmission. MV-induced inhibition of neurotransmitter release occurs at GABAergic but not glutamatergic terminals. Microvesicles (MVs) are identified as new vehicles for the transfer of endocannabinoids from microglia to neurons. By activating presynaptic CB1 receptors on interneurons, these endocannabinoids inhibit spontaneous GABA release.

Original languageEnglish
Pages (from-to)213-220
Number of pages8
JournalEMBO Reports
Volume16
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

Keywords

  • anandamide
  • CB receptor
  • extracellular vesicle
  • GABA release
  • microglia-neuron signaling

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biochemistry

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