title: Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism.
abstract: Microvesicles (MVs) released into the brain microenvironment are emerging as a novel way of cell-to-cell communication. We have recently shown that microglia, the immune cells of the brain, shed MVs upon activation but their possible role in microglia-to-neuron communication has never been explored. To investigate whether MVs affect neurotransmission, we analysed spontaneous release of glutamate in neurons exposed to MVs and found a dose-dependent increase in miniature excitatory postsynaptic current (mEPSC) frequency without changes in mEPSC amplitude. Paired-pulse recording analysis of evoked neurotransmission showed that MVs mainly act at the presynaptic site, by increasing release probability. In line with the enhancement of excitatory transmission in vitro, injection of MVs into the rat visual cortex caused an acute increase in the amplitude of field potentials evoked by visual stimuli. Stimulation of synaptic activity occurred via enhanced sphingolipid metabolism. Indeed, MVs promoted ceramide and sphingosine production in neurons, while the increase of excitatory transmission induced by MVs was prevented by pharmacological or genetic inhibition of sphingosine synthesis. These data identify microglia-derived MVs as a new mechanism by which microglia influence synaptic activity and highlight the involvement of neuronal sphingosine in this microglia-to-neuron signalling pathway.
authors.affiliation: Department of Medical Pharmacology, CNR Institute of Neuroscience, Università di Milano, Milano, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Antonucci
authors.forename: Elena
authors.initials: E
authors.lastname: Turola
authors.forename: Loredana
authors.initials: L
authors.lastname: Riganti
authors.forename: Matteo
authors.initials: M
authors.lastname: Caleo
authors.forename: Martina
authors.initials: M
authors.lastname: Gabrielli
authors.forename: Cristiana
authors.initials: C
authors.lastname: Perrotta
authors.forename: Luisa
authors.initials: L
authors.lastname: Novellino
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.forename: Paola
authors.initials: P
authors.lastname: Giussani
authors.forename: Paola
authors.initials: P
authors.lastname: Viani
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D013107:Sphingolipids