Venue: Neurocentre Magendie – salle de conférence
Defense in french
Rebecca Hekking
Oliet’s team, Neurocentre Magendie
Supervisor: Aude Panatier
Title
Identification of the role of astrocyte-derived extracellular vesicles in the regulation of synaptic transmission and synaptic plasticity
Abstract
Brain function relies on the transfer of information between neurons, which occurs at a subcellular structure called the synapse. Interestingly, the efficiency of a synapse can be modified under certain conditions, potentiating or inhibiting information transfer. Over the past 20 years, astrocytes, a type of glial cells, have been identified as key neuronal partners that are able to regulate synaptic transmission. Several pathways allowing astrocytes to regulate synaptic function have already been elucidated. Another interesting but under-investigated pathway would be through the release of extracellular vesicles.
Extracellular vesicles (EVs) are small membrane-bound particles that contain bioactive molecules such as proteins, nucleic acids, and lipids. Most cells release these vesicles which allow them to exchange cellular components with neighbouring -but also sometimes distant- cells. Some studies suggest that astrocytes also release EVs, yet it is still unclear whether these astrocyte-derived vesicles are involved in synaptic functions.
This thesis aims at elucidating whether astrocyte-derived extracellular vesicles play a key role in the regulation of synaptic transmission and plasticity. To address this question, we have designed two complementary studies.
We first isolated astrocyte-derived EVs in vitro in order to investigate their release rate and their content. We have shown on one hand that exposing astrocyte cultures to ATP in vitro leads to an increase in the amount of small EVs released within 30 min of the stimulus. Furthermore, the microRNA content of these vesicles is altered in response to the stimulus. A bioinformatics analysis predicted that the altered EV content could eventually affect signalling pathways involved in synaptic transmission in recipient cells. These changes seem to be induced specifically by ATP, since exposure to the excitatory neurotransmitter glutamate or to the inhibitory neurotransmitter GABA did not modify the amount of small EVs released within 30 min of the stimulation.
We also studied the involvement of astrocyte-derived EVs in vivo. To this end, we developed a virus that specifically targets astrocytes in the adult mouse brain and uses the Cas9 enzyme to invalidate a gene involved in EV biogenesis. Using this tool, our preliminary data suggest that inhibiting the release of small EVs from astrocytes alters a form of synaptic plasticity in the hippocampus of adult male mice.
To conclude, our findings suggest that small astrocyte-derived extracellular vesicles could indeed be involved in the regulation of some forms of synaptic plasticity and will hopefully encourage further studies to understand the underlying mechanisms.
Key words : CRISPR-Cas9 system, Electrophysiology, Astrocyte, Extracellular vesicle, Long-term synaptic plasticity, Synaptic transmission
Jury
– Mme PANATIER, Aude – DR – Université de Bordeaux – Directrice de thèse
– Mme ESCARTIN, Carole – DR – Université Paris Saclay – Rapporteure
– M. LEFEBVRE, Christophe – PR – Université de Lille – Rapporteur
– Mme MALNOU, Cécile – PR – Université de Toulouse – Examinatrice
– M. DELPECH, Jean-Christophe – CR – Université de Bordeaux – Examinateur
– M. FAVEREAUX, Alexandre – DR – Université de Bordeaux – Invité