Towards resolving the presynaptic NMDA receptor debate

Curr Opin Neurobiol. 2018 Aug;51:1-7. doi: 10.1016/j.conb.2017.12.020. Epub 2018 Jan 30.


In the classical view, postsynaptic NMDA receptors (NMDARs) trigger Hebbian plasticity via Ca2+ influx. However, unconventional presynaptic NMDARs (preNMDARs) which regulate both long-term and short-term plasticity at several synapse types have also been found. A lack of sufficiently specific experimental manipulations and a poor understanding of how preNMDARs signal have contributed to long-standing controversy surrounding these receptors. Although several prior studies linked preNMDARs to neocortical timing-dependent long-term depression (tLTD), a recent study argues that the NMDARs are actually postsynaptic and signal metabotropically, that is, without Ca2+. Other recent work indicates that, whereas ionotropic preNMDARs signaling controls evoked release, spontaneous release is regulated by metabotropic NMDAR signaling. We argue that elucidating unconventional NMDAR signaling modes-both presynaptically and metabotropically-is key to resolving the preNMDAR debate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Neuronal Plasticity / physiology*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Receptors, Presynaptic / metabolism*
  • Receptors, Presynaptic / physiology
  • Synapses / physiology*


  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Presynaptic