OptoNMDA · Optical strategies to investigate NMDA receptor functional diversity and its therapeutic potential

Optical strategies to investigate NMDA receptor functional diversity and its therapeutic potential

The function of the human brain and its capacity for experience-dependent changes hinge on the dynamics of chemical synapses. At these specialized neuronal sites, chemical transmitters released from presynaptic terminals diffuse across the synaptic cleft and activate receptors localized primarily on the postsynaptic cells, thereby transmitting the flow of information from one neuron to another. Among these receptors, NMDA receptors (NMDARs) form a class activated by glutamate, the major neurotransmitter in the mammalian brain. These receptors play fundamental roles in synaptic transmission and plasticity (the cellular basis of memory). They are also involved in numerous pathologies including stroke, mental retardation or schizophrenia. NMDARs are thus targets of strong therapeutic interest. NMDARs are tetramers usually composed of two GluN1 and two GluN2 subunits encoded by four different genes (GluN2A-D), resulting in a large number of receptor subtypes having distinct anatomical, biophysical, pharmacological and signalling properties. Understanding the functional role of these individual subtypes in the brain is of great importance to develop new strategies to counteract the deleterious effects of NMDAR dysregulation. However, tools allowing targeting of a specific population of NMDARs in a given neuronal circuit are currently lacking. The OptoNMDA research programme proposes the development of an innovative optical approach to selectively enhance the activity of NMDARs containing the GluN2B subunit (GluN2B-NMDARs). This approach consists in developing photo-convertible polyamine (PP) derivatives that can reversibly isomerize between an inactive and active configuration with light to act on the GluN2B-NMDAR polyamine allosteric modulating site in a precise spatio-temporal manner (opto-allostery). By tethering these PPs in the polyamine putative binding site, we managed to create photo-enhanced GluN2B-NMDARs. This project should thus provide critical novel information on NMDARs, and more generally, on the physiology and pathology of excitatory synapses.

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