Synaptic and extra-synaptic NMDA receptors in the CNS

The N-methyl d-aspartate receptor (NMDAR) is a ligand-gated ion channel that binds the neurotransmitter glutamate. It was pharmacologically identified and differentiated from other ionotropic amino-acid receptors at excitatory synapses in the late 70s for it is activated by NMDA and not kainate. Due to its large calcium conductance, it is involved in many physiological and pathological phenomena, the most notorious of which is synaptic plasticity, considered to be the molecular substrate of learning and memory. During the 40 years that followed their discovery, and owing to other unique properties such as their magnesium-block that makes them key “coincidence detectors”, NMDARs have been mostly studied at synapses. Yet, NMDARs exhibit a great number of other fundamental features that have remained unknown, underappreciated or challenging to study, and that have only become the focus of intense investigation over the past decade. These properties, such as the co-agonist-gating or the subcellular compartmentalization, greatly contribute to the functional diversity of NMDARs and will be the focus of this chapter as they are greatly relevant in the context of their physiological and pathological impact on the central nervous system.