Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism
Open accessAbstract
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.
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Microglia-derived MVs affect the presynaptic compartment causing an excitation-inhibition unbalance.
“Our previous studies have shown that microglia-derived MVs affect the presynaptic compartment causing an excitation–inhibition unbalance.”
From Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations (2018) · cites this paper as [1]
The Discussion reports that microglia-derived MVs mainly act at presynaptic excitatory synapses, increasing vesicle release probability. It says the observed change in visual-cortex receptive fields can typically be explained by altered excitation–inhibition balance, but does not establish that MVs caused such an imbalance. (LLM, conf=0.83)
Experimental — accuracy not yet measuredActivated microglia can shed MVs in response to several signals, including cytokines; these MVs contain bioactive molecules (IL-1β, proteases, and MHC-II) which modulate the activity of neuronal and non-neuronal cells.
“Activated microglia can shed MVs in response to several signals, including cytokines. These MVs contain bioactive molecules (i.e., IL-1β, proteases, and MHC-II) which modulate the activity of neuronal and non-neuronal cells (Antonucci et al., 2012).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Antonucci et al., 2012
Presynaptic changes caused by microglial MVs are independent of the phenotype of donor microglia (unstimulated, pro-inflammatory or pro-regenerative cells).
“Importantly, presynaptic changes caused by microglial MVs are independent of the phenotype of donor microglia (unstimulated, pro-inflammatory or pro-regenerative cells) [1], suggesting that bioactive lipids secreted in association with MVs may contribute to homeostatic regulation of neurotransmission, in the absence of inflammation and microglia reaction.”
From Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations (2018) · cites this paper as [1]
The action of MVs on glutamate release and spontaneous GABA transmission is due to the lipid components of MVs.
“MVs acutely enhance glutamate release while suppress spontaneous GABA transmission in both hippocampal cultures [62] and in the visual cortex [1] and their action is due to the lipid components of MVs.”
From Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations (2018) · cites this paper as [1]
MVs acutely enhance glutamate release while suppress spontaneous GABA transmission in both hippocampal cultures and in the visual cortex.
“MVs acutely enhance glutamate release while suppress spontaneous GABA transmission in both hippocampal cultures [62] and in the visual cortex [1] and their action is due to the lipid components of MVs.”
From Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations (2018) · cites this paper as [1]
EV fusion also occurs along neuronal processes, where synaptic activity is influenced by EVs.
“Importantly, EV fusion also occurs along neuronal processes, where synaptic activity is influenced by EVs [1, 62].”
From Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations (2018) · cites this paper as [1]
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References 56 · Cited by 328
- Authors
- Antonucci, F., Turola, E., Riganti, L., Caleo, M., Gabrielli, M., Perrotta, C., Novellino, L., Clementi, E., Giussani, P., Viani, P., Matteoli, M., & Verderio, C.
- Affiliations
- University of Milan (IT)
- Neuroscience Institute (IT)
- Corresponding author
- Verderio, Claudia
- ORCID
- Venue
- The EMBO Journal
- Published
- 2012-01-13
- Volume
- 31
- Issue
- 5
- Pages
- 1231-1240
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC3297996
- OpenAlex
- W1892074666
- Cited by
- 328
- References
- 56
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 31 · 2023: 20 · 2022: 39 · 2021: 46 · 2020: 28 · 2019: 36 · 2018: 17 · 2017: 18 · 2016: 22 · 2015: 13 · 2014: 13 · 2013: 9 · 2012: 6
- FWCI
- 5.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- Compagnia di San Paolo
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microvesicles, microglia, sphingolipid metabolism, sphingosine, ceramide, glutamate release, miniature excitatory postsynaptic currents, release probability, excitatory neurotransmission, visual cortex
- MeSH terms
- Animals, Cerebral Cortex, Neurons, Sphingolipids, Synapses, Microglia, Secretory Vesicles, Rats
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