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Site co-agoniste des récepteurs NMDA: de la dynamique synaptique à des mécanismes de signalisation nouveaux.

Le projet porté par Stéphane Oliet, réunit trois équipes :

  • Equipe "Relations glie-neurone" dirigée par Stéphane Oliet - Unité : Neurocentre Magendie - Physiopathologie de la plasticité neuronale - Pier Vincenzo Piazza
  • Equipe  "Développement et adaptation des circuits neuronaux"
     dirigée par Laurent Groc - Unité: Institut interdisciplinaire de Neurosciences - Daniel Choquet
  • Equipe Pierre Paoletti à l'ENS à Paris


Consistent with their critical role in physiological processes and the need for precise regulation,  NMDA receptors  contain  numerous  sites for fine-­‐tuning  of receptor  function  by biologically  relevant factors.   These   include   the   glycine-­‐site, which   binds   the   NMDAR   co-­‐agonist   D-­‐serine   or   glycine. Intriguingly, D-­‐serine is abundant in the forebrain and preferentially localize to glutamatergic synapses. We have much information about the actions of D-­‐serine/glycine on recombinant NMDARs but little on receptors embedded in the native synaptic environment. D-­‐serine is proposed to be released by astrocytes that ensheath glutamatergic synapses. However, the  nature  of  receptor  modulation  depends  on  the temporal dynamics and concentration profile of the modulator at the synapse, two parameters that remain poorly defined. Furthermore, for D-­‐serine and glycine, it is still unclear which of the two co-­‐agonists preferentially bind to synaptic NMDARs and how dynamic occupancy of the co-­‐agonist binding site is during neuronal activity. In that context, a major breakthrough was recently made by members of our consortium. We   showed   that   synaptic   and   extrasynaptic   hippocampal   CA1   NMDARs   were   gated   by   different endogenous co-­‐agonists, that such a difference was matching the subunit composition of the receptors and that glycine and D-­‐serine were impacting NMDAR membrane diffusion differentially in a subunit-­‐dependent and activity-­‐independent  manner,  pointing  to  a  possible  non-­‐canonical  signaling pathway for these receptors.

In this project, building on our recent  findings,  we aim to further  study  how NMDAR  activity  is regulated through its glycine-­‐site under native conditions. In particular, we plan to determine the nature of the endogenous co-­‐agonist at different synapses and at different developmental stages to establish the relationship between receptor subunit composition and the identity of this co-­‐agonist. We also aim at characterizing the synaptic profiles of glycine and D-­‐serine in and outside the synaptic cleft under different conditions of neuronal activity and microenvironment. Finally we plan to investigate the molecular process by which co-­‐agonist  binding affects NMDAR signaling and influences the dynamics of receptor membrane trafficking. This project should provide critical novel information on the endogenous modulation of NMDARs, and more generally, on the physiology of the excitatory synapse and its deregulation during pathological events.