Roles of unconventional GluN3A-containing NMDA receptors in adult brain function – GluBrain3A

In this project we propose to explore, using a multilevel approach, the role of unconventional NMDA receptors (NMDARs) in specific regions of the adult brain involved in higher cognitive functions.
Much is indeed known about the central role of the family of conventional GluN1/GluN2 NMDARs in glutamatergic transmission during brain function and dysfunction. In contrast, there exists a largely underappreciated group of glycine-binding NMDAR subunits, GluN3A and GluN3B, which have been so far uniquely associated with synaptic maturation and plasticity at early developmental stages. Our project lies its foundations upon exciting preliminary results showing that there are specific regions of the adult brain- the epithalamus (medial habenula, MHb) and the thalamus (intralaminar and midline nuclei, IL/MDL) - where GluN3A is expressed at high levels, and where it participates to several subtypes of NMDARs including a completely novel type of neuronal excitatory glycine-activated receptors.
The MHb participates to the expression of a large variety of aversive physiological states, whereas the IL/MDL nuclei are likely at the heart of the generation and the maintenance of attentional vigil states. The intimate association of GluN3A subunits with these brain territories raises important questions about the rules and roles of GluN3A receptors in adult brain function. By unveiling a novel receptor target, it also bears potential from a therapeutic perspective. We will investigate how and when GluN3A receptors are activated and what is their impact on local circuit function and on higher cognitive functions linked to behavioral tasks. To do so, we will combine a broad spectrum of different technical approaches ranging from ion channel sequence engineering to optogenetic-based mapping, in-vitro electrophysiology and behavioral tests associated with EEG and optical recordings in freely moving animals. In particular, we will use available genetic tools (KO, shRNA, genetically-modified mice) and innovative molecular tools including GluN3A-containing receptors whose function can be reversibly and specifically manipulated by light. These instruments will allow us to achieve a molecular level control of GluN3A-NMDARs that is subunit-specific, reversible within a time scale compatible with fast neuronal communication, and usable both in vitro and in vivo in behaving animals. We aim at providing key insights of GluN3A function at the biophysical, cellular and behavioral level.
At the cross roads of neuroscience and protein engineering, this multi-scale project aims at providing key insights into an underexplored class of receptors with important implications both for adult brain physiology and pathology. Furthermore by implementing original light-controllable receptor tools, our project should boost the emerging field of molecular optopharmacology in vivo. This project involves four internationally-recognized neuroscience groups, including three French groups (Diana, Paoletti, Dieudonné) and one Canadian lab (Kieffer) with a solid experience in collaborative networks. The synergism between the involved teams creates a strong research environment for successful implementation of GluBrain3A.
At the outcome of the GluBrain3A project, we envisage unmasking the functional importance of a neglected receptor class and unveiling the functional benefit of the association of this receptor family with specific forebrain relay nuclei critically involved in the regulation of motivational states.