Biomedical Sciences Research Seminar

Glia-to neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations

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Seminars

As part of the School of Science and Technology Biomedical Sciences Research Centre Seminar Series, Dr Ilaria Prada, CNR Institute of Neuroscience presents: Glia-to neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations.

  • From: Wednesday 6 June 2018, 1.10 pm
  • To: Wednesday 6 June 2018, 2 pm
  • Location: 282, Erasmus Darwin, Nottingham Trent University, Clifton Campus, Clifton Lane, Nottingham, NG11 8NS

Past event

Event details

As part of the School of Science and Technology Biomedical Sciences Research Centre Seminar Series, Dr Ilaria Prada, CNR Institute of Neuroscience presents: Glia-to neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations.

Abstract

Recent evidence indicates synaptic dysfunction as an early mechanism affected in neuroinflammatory diseases, such as multiple sclerosis, which are characterized by chronic microglia activation. However, the mode(s) of action of reactive microglia in causing synaptic defects are not fully understood. In this study we show that inflammatory microglia produce extracellular vesicles (EVs) which are enriched in a set of miRNAs that regulate the expression of key synaptic proteins. Among them, miR-146a-5p, a microglia-specific miRNA not present in hippocampal neurons, controls the expression of presynaptic synaptotagmin1 (Syt1) and postsynaptic neuroligin1 (Nlg1), an adhesion protein which play a crucial role in dendritic spine formation and synaptic stability. By the use of a Renilla-based sensor we provide formal proof that inflammatory EVs transfer their miR-146a-5p cargo to neuron. By western blot and immunofluorescence analysis we show that vesicular miR-146a-5p suppresses Syt 1 and Nlg1 expression in receiving neurons. Notably, microglia-to-neuron miR-146a-5p transfer and down-regulation of neuronal Syt1 and Nlg1 do not occur when EV-neuron contact is inhibited by cloaking crucial vesicular phosphatidylserine residues, and when neurons are exposed to EVs either depleted of miR-146a-5p, produced by pro-regenerative microglia, or storing inactive miR-146a-5p, produced by cells transfected with an anti-miR-146a-5p. Moreover, morphological analysis reveals that prolonged exposure to inflammatory EVs leads to significant decrease in dendritic spine density in hippocampal neurons in vivo and in primary culture, which is rescued in vitro by transfection of a miR-146-insensitive Nlg1 form. Finally, dendritic spine loss is accompanied by a decrease in the density and strength of excitatory synapses, as indicated by reduced mEPSC frequency and amplitude. These findings link inflammatory microglia and enhanced EV production to loss of excitatory synapses, uncovering a previously unrecognized role for microglia-enriched miRNAs, released in association to EVs, in silencing of key synaptic genes.

This seminar is hosted by Dr Elisabetta Verderio-Edwards

All welcome.

For any enquiries please contact Dr Amanda Coutts

Location details

Room/Building:

282, Erasmus Darwin

Address:

Nottingham Trent University
Clifton Campus
Clifton Lane
Nottingham
NG11 8NS

Past event

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