NMDA Receptor Co-agonism: New Roles and Mechanisms in Synaptic Plasticity and Circuit Dynamics – DynamicCoSite

N-methyl-D-aspartate receptors(NMDARs) are essential ionotropic glutamate receptors that play a key role in fast synaptic transmission in the brain and are vital for processes such as synaptic plasticity, learning, and memory. These receptors are unique in requiring a co-agonist in addition to glutamate to gate. Yet, despite significant advances in our knowledge of NMDAR structure and function, the physiological relevance of co-agonist modulation in the brain remains enigmatic. The prevailing view suggests that the activity dependent release of D-serine is a major contributor to NMDAR-mediated synaptic plasticity in the central nervous system. In the consortium, using new genetic tools allowing to discriminate between glycine and D-serine effects on NMDARs, we now observed that glycine binding to GluN1 subunits is essential for LTP in the Hippocampus. Furthermore, preliminary findings reveal that, unexpectedly, GluN3A subunits, which are preferentially activated by glycine and predominantly locate extrasynaptically regulate the sensitivity of classical synaptic GluN1/GluN2 NMDARs to coagonists. This observation calls for a reevaluation of the role of glycine as a co-agonist in regulating synaptic plasticity and influencing neuronal circuits. In this proposal, motivated by the development of new tools – including a KI mice harboring NMDARs that discriminate between the co-agonists glycine and D-serine - and original, unexpected preliminary results, we aim to investigate with improved molecular and cellular resolution how co-agonist modulation of NMDARs controls synaptic plasticity and circuit operation in both neocortex and hippocampus. Dysregulation of NMDAR function is linked to various neuropsychiatric disorders, including depression and schizophrenia. By uncovering novel mechanisms that regulate NMDAR function, our project could reveal novel pathways contributing to brain dysfunction while identifying potential new therapeutic targets to correct NMDAR activity