NMDA receptors in axons: there's no coincidence

• Published in: The Journal of physiology Vol. 599; no. 2; pp. 367 - 387
• Main Authors: Wong, Hovy Ho‐Wai, Rannio, Sabine, Jones, Victoria, Thomazeau, Aurore, Sjöström, P. Jesper
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2021; Wiley
• Subjects: axon; Axons; Calcium; Glutamic acid receptors (ionotropic); Life Sciences; long‐term plasticity; Magnesium; Metabotropic receptors; metabotropic signalling; N-Methyl-D-aspartic acid receptors; Neuralgia; Neurons and Cognition; neuropathic pain; neurotransmitter release; NMDA receptor; presynaptic terminal; Receptors, N-Methyl-D-Aspartate; short‐term plasticity; Subunit structure; Synapses; Therapeutic targets; neuropathic pain; long-term plasticity; presynaptic terminal; axon; NMDA receptor; neurotransmitter release; metabotropic signalling; short-term plasticity
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP280059

In the textbook view, N‐methyl‐d‐aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short‐term and long‐term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse‐type‐specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident. figure legend Presynaptic NMDARs (preNMDARs) are present in axons of specific synapses to regulate different forms of neurotransmission and synaptic plasticity. PreNMDARs can signal through both ionotropic mode by fluxing calcium and metabotropic mode without calcium influx.