Thesis defense – Dorian Arnouil

Venue: Neurocentre Magendie (Salle de conférence)

Defense in french

Title

Study of the regulation of synaptic transmission and long-term synaptic plasticity by the astrocyte in adult hippocampus.

Abstract

The functioning of the brain relies on communication between neurons at the level of specialized structures: the synapses. Information processing at synapses is plastic and finely modulated over time. In the hippocampus, this cellular plasticity is proposed as the cellular basis of learning and memory. It is important to note that neurons are not alone in the brain, glial cells perform many functions essential to its functioning. Among them, astrocytes, ideally positioned in between blood vessels and synapses, play a key role in modulating transmission and long-term synaptic plasticity. Indeed, works done in recent years have shown that astrocytes are able to detect neurotransmitters released in the synaptic cleft and in turn to regulate the efficiency with which neurons communicate. To do this, astrocytes, like neurons, release gliotransmitters at the synapse, as purines and D-serine. In the hippocampus, it has been shown in juvenile rats that astrocytes are able to regulate the efficiency of synaptic transmission at the level of a single synapse. In addition, each astrocyte occupies an exclusive territory allowing it to be in close apposition with more than 100,000 neighbouring synapses belonging to several neurons. Functionally, this may allow them to coordinate the regulation of transmission at the scale of 100,000 synapses.

The main goal of my thesis was to better understand how information is transmitted and regulated in the hippocampus in adulthood. To this end, I studied the role of astrocytes in regulating the efficiency of synaptic transmission at the single synapse and domain levels. Using electrophysiological techniques, combining pharmacological and viral approaches, the work I performed during my thesis revealed that:

(1) The astrocyte, in adulthood is still able to regulate the efficiency of basic synaptic transmission at the single synapse level. To do so, the astrocyte detects glutamate released in the synaptic cleft via the metabotropic glutamatergic receptor type 5 (mGluR5) and in return releases purines allowing it to increase the efficiency of synaptic transmission via their action on presynaptic adenosine receptors type A2A. Interestingly, this regulation seems to be activity-dependent since it is no longer present when the number of activated synapses increases.

(2) The mGluR5, even in the adult hippocampus, is a key receptor for the astrocyte since it is necessary for the mechanism of regulation of transmission by purines that I studied. Indeed, to better understand this regulatory loop, I used a new viral vector developed in collaboration with Dr. Carole Escartin’s team. This vector allows to functionally block mGluR5 pathway specifically in astrocytes by the expression of a dominant negative peptide. This technique allowed me to demonstrate the importance of this astrocytic receptor in the regulation of basal synaptic transmission and long-term synaptic plasticity.

(3) In collaboration with Dr. Jean-Michel Revest’s team, I study long-term synaptic plasticity and its alteration in the context of Down syndrome (DS). DS or trisomy 21, is the most common genetic cause of intellectual disability. In this study, I demonstrated that the mouse model of DS studied showed a deficit in long-term synaptic plasticity that was dependent on endocannabinoid receptor signalling (CB1) and correlated with a memory deficit. As CB1 signalling is important for the production of gliotransmitters necessary for the induction of plasticity, these results open new perspectives to understand the involvement of astrocytes in cognitive deficits of DS.

Keywords : Astrocytes ; Gliotransmission ; synaptic plasticity ; Electrophysiology ; mGluR5 ; Purines ; Down syndrome.

Jury

– Etienne AUDINAT (Rapporteur)

– Micaela GALANTE (Rapportrice)

– Eric BOUE-GRABOT (Examinateur)

– Aude PANATIER (Directrice de Thèse)