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 microgliato-neuron signalling pathway.

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

“…In our study, we also observed that the MVs derived from microglia enhanced the frequency and amplitude of sEPSC within 1 min after treatment with MVs (Fig. 8), as seen in a previous study [50]. However, mechanical and thermal hypersensitivities were induced by MVs from 1 h but not MVs on the amplitude of sEPSC in sham rats (b) or SNL 7-day rats (e).…”

Sphingosine-1-Phosphate (S1P) Impacts Presynaptic Functions by Regulating Synapsin I Localization in the Presynaptic Compartment

“…Primary neuronal cultures were obtained from the hippocampi of 18-d -old fetal Sprague Dawley rats of either sex (Charles River), A-SMase KO or wild-type (WT) C57BL/6 mice (of either sex) as described previously (Banker and Groslin, 1998;Antonucci et al, 2012). Briefly, dissociated cells were plated onto poly-L-lysine (Sigma-Aldrich) treated coverslips and maintained in Neurobasal with 2% B27 supplement (Invitrogen), antibiotics, glutamine, and glutamate.…”

“…Externally added Sph and S1P stimulate depolarization-induced glutamate release from synaptosomes Darios et al, 2009) and increase the rate of spontaneous glutamate transmission in hippocampal slices or in cultures (Darios et al, 2009;Kanno et al, 2010). Endogenous production of Sph or S1P, triggered by sphingomyelinase activity, also activates exocytosis (Darios et al, 2009;Okada et al, 2009;Kanno and Nishizaki, 2011;Antonucci et al, 2012). Furthermore, knock-out of SphK-1, which is recruited to presynaptic terminals in response to neuronal activity (Chan and Sieburth, 2012), results in reduction of evoked transmitter and impairment of long term-potentiation, spatial learning, and memory Chan and Sieburth, 2012), confirming that endogenous S1P crucially regulates synaptic activity.…”

Extracellular-vesicle type of volume transmission and tunnelling-nanotube type of wiring transmission add a new dimension to brain neuro-glial networks

“…A large number of possibly different extracellular vesicles were described, but it proved difficult to subdivide them into well-defined classes [24,25]. The socalled exosomes (endosome-derived), however, appear to be the major vesicular carrier for intercellular communication (table 2) [31,45] but microvesicles (shedding vesicles from the plasma membrane) also play a significant role (table 2) [46][47][48][49]. Exosomes are endosome-derived vesicles (diameter 40-100 nm) produced during the formation of MVBs.…”