Synaptic plasticity of NMDA receptors: mechanisms and functional implications

Abstract

Beyond their well-established role as triggers for LTP and LTD of fast synaptic transmission mediated by AMPA receptors, an expanding body of evidence indicates that NMDA receptors (NMDARs) themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. NMDARs can significantly contribute to information transfer at synapses particularly during periods of repetitive activity. It is also increasingly recognized that NMDARs participate in dendritic synaptic integration and are critical for generating persistent activity of neural assemblies. Here we review recent advances on the mechanisms and functional consequences of NMDAR plasticity. Given the unique biophysical properties of NMDARs, synaptic plasticity of NMDAR-mediated transmission emerges as a particularly powerful mechanism for the fine tuning of information encoding and storage throughout the brain.

Figure 1. Unique biophysical properties of NMDARs and the resultant functional impact on temporal summation and firing output

A) Top; current-voltage relationship comparison between AMPARs and NMDARs. NMDARs exhibit a characteristic region of negative slope from approximately −70 to −35 mV, a property that enables positive feedback, and allows for signal amplification. Bottom; Dual (AMPAR and NMDAR) component EPSPs elicited at −70 and −40 mV membrane potential, highlighting the enhancement of the slow NMDAR component at −40 mV, whereas the fast AMPAR component is diminished. B) Left; Representation of temporal summation of dual (gray) and pharmacologically isolated AMPAR (black) and NMDAR (red) EPSPs elicited by a train of subthreshold synaptic stimulation (vertical black arrows). The relative difference between the AMPAR and NMDAR-mediated responses likely reflects both voltage-dependent Mg²⁺ block and slow decay kinetics. Right; Suprathreshold repetitive stimulation illustrating the contribution of NMDARs (red) to spike output relative to AMPARs (black). The temporal summation afforded by NMDARs leads to more reliable spike output throughout the train. Modified with permission from Augustinaite & Heggelund, J Physiol 582: 297–315, 2007.

Figure 2. Common pathways of NMDAR plasticity

Left: Induction of NMDAR plasticity has been shown to be triggered by postsynaptic Ca²⁺ rise that can be achieved through NMDARs and voltage gated calcium channels (VGCCs). Metabotropic receptors, such as group I mGluR, mAChR, D₂R, A_2AR, can also contribute by releasing Ca²⁺ from internal stores (either via inositol triphosphate receptors, IP3Rs or rynanodine receptors, RyRs). Postsynaptic calcium signals activate enzymatic activity required for plasticity, including PKC, PKA, Src, PP1/PP2A. Metabotropic receptors could also directly activate the enzymatic activity (gray dash arrow). Right: Diverse modes of expression have been identified for NMDAR plasticity that involve NMDAR exo/endocytosis as well as lateral mobility between synaptic and extrasynaptic pools. Expression of NMDAR plasticity can also involve changes in the magnitude of fractional Ca²⁺ current through NMDARs. Modes of expression can also be associated with a shift in NMDAR subunit composition (*).

Figure 3. Functional consequences of NMDAR plasticity

A) NMDAR plasticity can modify the threshold for the initiation of an NMDA spike or plateau potential, an important integrative property of cortical neurons. B) NMDARs have been shown to be critical for the transition between single spike and complex spike/bursting output modes in several cell types, enabling the regulation of information transfer. C) Schematic representing the effects of AMPAR (black) vs. NMDAR (red) plasticity in response to repetitive synaptic activation (e.g. bursts like those depicted in Fig. 1B) where AMPAR plasticity generally leads to linear changes in gain while NMDAR plasticity enables nonlinear shifts in output.