Pierre Paoletti, CNRS, Institut de Biologie de l'École Normale Supérieure, Paris
Excitatory glycine receptors: new actors in the brain
Since their discovery over three decades ago, NMDA receptors (NMDARs) have kept drawing attention of neuroscientists because of their central roles in CNS development and function. These glutamate-gated ion channels are essential mediators of brain plasticity converting specific patterns of neuronal activity into long-term changes in synapse structure and function that are thought to underlie higher cognitive functions. The well characterized conventional NMDARs are hetero-tetramers composed of two GluN1 and two GluN2 subunits, and require two different agonists, glutamate and glycine (or D-serine) for their activation. They are highly Ca2+ permeable, exhibit strong voltage-dependency due to Mg2+ pore block, and cluster at excitatory synapses where they control synaptic strength by acting as coincident detectors. Far less is known regarding NMDARs incorporating the glycine-binding GluN3 subunits (GluN3A-B), which decrease Ca2+ permeability and confer resistance to Mg2+ block. Remarkably, in heterologous expression systems, GluN1 and GluN3 subunits can co-assemble to form ‘unconventional’ NMDARs that lack glutamate-binding sites and are gated by glycine only, thus forming GluN1/GluN3 excitatory glycine receptors (eGlyRs). However, the physiological relevance of such excitatory glycine NMDARs has sparked intense controversy since until recently their activity was barely detectable in native neuronal tissues, pointing to potential artifacts of expression systems. Based on the discovery of a pharmacological agent (CGP-78608) that uniquely and massively potentiates GluN1/GluN3 receptors, we and colleagues recently discovered that GluN1/GluN3A receptors are functionally expressed at high levels in specific regions and neuronal types of the adult mouse brain. In these regions, eGlyRs define a novel signaling modality by which extracellular glycine tunes neuronal excitability, circuit function and behavior. The unique molecular, anatomical and functional attributes of GluN1/Glu3A excitatory glycine receptors open new vistas on the diversity of NMDAR signaling and glycinergic neurotransmission.
Pierre Paoletti is a researcher at INSERM and the current director of the Institute of Biology of the Ecole Normale Supérieure (IBENS, Paris), a joined ENS-CNRS-INSERM unit which gathers 30 research groups and >300 staff members in Genomics, Cell & Developmental Biology, Ecology & Evolution, and Neuroscience. After a PhD in Neuroscience and Molecular Pharmacology at the ENS & University Paris 6, Pierre Paoletti underwent postdoctoral training in ion channel biophysics at Columbia University in New York. In 2005, he established his own lab at the ENS working on various aspects of ionotropic glutamate receptors and excitatory neurotransmission. Key contributions include the identification of essential regions of NMDAR subunits controlling the receptor functional properties and allosteric mechanisms, uncovering novel binding sites for neuro-active compounds and discovery that endogenous zinc, which is highly enriched in the brain, is a potent and widespread modulator of neurocircuits and synaptic plasticity through its action on GluN2A-NMDARs. Together with colleagues in Paris, he also discovered that GluN3A-NMDARs form a novel type of excitatory glycine receptors in the brain, thus reshaping our understanding of NMDAR diversity and glycinergic neurotransmission. Pierre Paoletti and his team recently developed innovative approaches of molecular engineering to reprogram brain receptors to artificially respond to light, opening new avenues for interrogating their structure and function with unprecedented resolution. Pierre Paoletti received the FENS Young Investigator Award in 2010, an ERC Advanced Award in 2016, the Grand Prix Lamonica de Neurologie – Académie des Sciences in 2017, and is a member of the Academia Europaea.