Unconventional NMDA Receptor Signaling

Abstract

In the classical view, NMDA receptors (NMDARs) are stably expressed at the postsynaptic membrane, where they act via Ca²⁺ to signal coincidence detection in Hebbian plasticity. More recently, it has been established that NMDAR-mediated transmission can be dynamically regulated by neural activity. In addition, NMDARs have been found presynaptically, where they cannot act as conventional coincidence detectors. Unexpectedly, NMDARs have also been shown to signal metabotropically, without the need for Ca²⁺ This review highlights novel findings concerning these unconventional modes of NMDAR action.

Keywords: Alzheimer's disease; LTD; LTP; metabotropic NMDA receptor; presynaptic NMDA receptor; short-term plasticity.

Figure 1.

Recent discoveries of novel unconventional NMDAR signaling modes indicate that our view of this receptor type may need to be expanded. Mg²⁺-blocked presynaptic NMDARs (preNMDAR) rely on RIM1 to control, in a frequency-dependent manner, the replenishment rate of the readily releasable pool of vesicles. Control of spontaneous release by preNMDARs, however, is not sensitive to Mg²⁺ or Ca²⁺ and relies on JNK2. Postsynaptic NMDARs can act as coincidence detectors for Hebbian plasticity of AMPARs, but plasticity of NMDARs can also be coinduced and likely plays important roles. Moreover, several studies suggest that, if ion flux is blocked through postsynaptic NMDARs, they can still signal metabotropically. Upon glutamate binding, movement in the NMDAR cytoplasmic domain may permit PP1 catalytic access to phospho-CaMKII-T286 and, in parallel, activation of p38 MAPK. These (and other) signaling molecules can eventually lead to LTD: AMPAR removal and spine shrinkage. Furthermore, elevated amyloid-β can depress synaptic transmission and cause spine elimination in a manner that is dependent on glutamate binding to, but not ion flux through, NMDARs. All signaling modes need not coexist at the same synapse type.