Control of NMDA receptor activity via D-serine : role of the astrocytic EphB3 and CB1 receptors
Defended on December 13, 2016
PhD supervisor: Stéphane Oliet – Research Team: Glia-neuron relations
Abstract : Astrocytes are key partners of neurons. In the hippocampus, and more particularly at CA3-CA1 synapses, by releasing D-serine, these glial cells regulate the activity of synaptic N-methyl-D-aspartate (NMDA) receptors and thus synaptic memory, also known as long-term synaptic plasticity. Yet, the synaptic signal inducing D-serine release by astrocytes is still unknown. Based on interesting data from the literature we have investigated the role of the astrocytic receptors for ephrinB3 (EphB3) and endocannabinoids (CB1).
To this end we used electrophysiological approaches on acute hippocampal slices of adult mice. In a first study, our data indicate on one hand that the activation of EphB3 receptors increases synaptic D-serine availability and in consequences the activity of synaptic NMDA receptor activity. On the other hand, inhibition of EphB3 receptors induces a decrease of synaptic NMDA receptor activity as well as the induction of the long-term potentiation (LTP; a form of long-term plasticity). Thus, EphB3-ephrinB3 interaction controls LTP induction through the availability of synaptic D-serine. In a second study, we used a transgenic model allowing the inhibition of CB1 receptors expression in astrocytes (GFAP-CB1-KO mice).
We discovered that their deletion reduced synaptic D-serine availability. Our work shows that astrocytic CB1 receptors are necessary for LTP induction via this D-serine. All together, this PhD work reveals that astrocytic EphB3 and CB1 receptors regulate synaptic NMDA receptor functions through the control of D-serine availability.
Keywords : ephrin, endocannabinoid system, hippocampus, LTP
Publications : Langlais, V.C., Benazzouz, I., Jourdes, A., Belluomo, I., Matias, I., Oliet, S.H.R. #, and Panatier, A. # (2016). Astrocytic EphB3 receptors control NMDA receptor activity. In preparation. # : A.P & S.H.R.O share senior autorship
Robin, L.M.*, Oliveira da Cruz, J.F. *, Langlais, V.C. *, Metna-Laurent, M., Busquets-Garcia, A., Bellocchio, L., Soria-Gomez, E., Papouin, T., Bosier, B., Drago, F., Van Eeckhaut, A., Smolders, I., Georges, F., Panatier, A., Oliet, S.H.R. #, Marsicano, G. # (2016). Astroglial CB1 receptors control memory via D-serine. In revision (Nature Communications). * : L.M.R., J.F.O & V.C.L share first autorship. # : G.M. & S.H.R.O share senior authorship
Président DR IINS, CNRS, UMR 5297, Bordeaux
Rapporteur DR CIRB, Collège de France, INSERM U1050, Paris
Rapporteur CR Institut NeuroMyoGène, INSERM U1217, Lyon Federico Massa
Examinateur CR Neurocentre Magendie, INSERM U1215, Bordeaux Vincent Prévot
Examinateur DR Centre de Recherche Jean Pierre Aubert,
INSERM U1172, Lille
Directeur de thèse DR Neurocentre Magendie, INSERM U1215, Bordeaux
CR CNRS Invitée