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date: 23 October 2019

N-Methyl-D-Aspartate Receptors

Abstract and Keywords

Discovered more than 70 years ago due to advances in electrophysiology and cell culture techniques, N-methyl-D-aspartate (NMDA) receptors remain the target of assiduous basic and clinical research. This interest flows from their intimate engagement with fundamental processes in the mammalian central nervous system and the resulting natural desire to understand how this receptor’s genetically encoded structural properties generate their distinctive functional features and how in turn these unique functional attributes play into the larger opus of physiological and pathological processes. From the overwhelming literature on the subject, the authors briefly outline contemporary understanding of the receptor’s evolutionary origins, molecular diversity, and expression patterns; sketch hypothesized correlations between structural dynamics, signal kinetics, and pathophysiological consequences; and highlight the breadth of processes in which NMDA receptors are implicated, many of which remain poorly understood. Continued developments in cryo-electron microscopy, whole-genome sequencing and editing, imaging, and other emerging technologies will likely confirm some of the current hypotheses and challenge others to produce a more accurate reflection of these receptors’ complex operation and myriad roles in health and disease.

Keywords: synaptic transmission, ligand-gated channel, molecular evolution, protein structure–function, electrophysiology, central nervous system

Introduction and Historical Perspective

N-Methyl-D-aspartate (NMDA) receptors are glutamate- and glycine-gated, cation-permeable channels with primary expression in the central nervous system (CNS), where they mediate the development, transmission, and plasticity of excitatory synapses. Along with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), kainate, and delta receptors, they form the superfamily of ionotropic glutamate receptors (iGluRs), a class of mainly postsynaptic proteins that generate the majority of excitatory synaptic transmission in the brain and spinal cord. It will surprise most of today’s students just how controversial this fact has been over more than a century of neurophysiology research (Meldrum, 2000).

The first hypothesis for how neurotransmission occurs in the vertebrate brain held electricity to be the main information carrier. This idea was based on experiments pioneered by Fritsch and Hitzig (1870), who showed that electrical stimulation of cortical brain regions in vivo can elicit involuntary motor movement of specific body parts. This electrical hypothesis remained firmly ingrained for the next half-century (Fulton, 1940) despite Cajal’s exquisite neuroanatomical drawings, which depicted synapses as inter-neuronal junctions that contained a physical gap (Ramon y Cajal, 1906). Evidence favoring a diffusible chemical as the carrier of information across this gap between two neurons accumulated slowly and gained universal acceptance only after winning over deeply entrenched and domineering critics who fought bitterly what has become known as “the war of soups and sparks” (Eccles, Fatt, & Koketsu, 1954).

The quest for the nature of the endogenous chemical responsible for excitation across central synapses was similarly sinuous and polarizing (Paton, 1959). Many scientists believed firmly that the substance serving as a neurotransmitter in the brain must be highly specialized for this function and must play no other physiological role. Therefore, glutamate was dismissed by many as an implausible candidate, given its prominent roles as a universal building block of proteins and principal actor in basic metabolic processes. Yet, when injected directly into primate brains, glutamate produced immediate and violent convulsions, an incontrovertible proof of its strong and direct excitatory action (Hayashi, 1954). Speculations flourished to explain away this obvious result, and it took more than 20 years of increasingly precise electrophysiological measurements to establish glutamate as the principal endogenous excitatory neurotransmitter at the central vertebrate synapse (Watkins, 2000).

Equally elusive was the molecular nature of the excitatory proteins that respond to glutamate. Using newly developed spinal cell preparations and extracellular recording technologies, Curtis and Watkins first identified, and then synthesized, numerous chemical analogues of glutamate, including NMDA and 2-amino-5-phosphonopentanoate (AP5), which either had intrinsic excitatory activity or interfered specifically with the glutamate-elicited excitation, respectively (Curtis & Watkins, 1960; Watkins, Curtis, & Brand, 1977). By examining the geometric arrangement of their functional moieties, the authors concluded that, whether acting as agonists or antagonists, the excitatory chemicals fell into three structural classes. Watkins and Evans inferred correctly that this fact likely reflected intrinsic differences in the chemical and geometrical features of the agonist-binding sites of three distinct classes of glutamate-gated excitatory channels, which they named AMPA, kainate, and NMDA receptors according to their most effective synthetic agonists (Watkins, 2000). The cloning revolution of the 1990s certified this influential insight by identifying a large family of homologous yet molecularly distinct proteins, whose pharmacology largely mirrored their sequence homology (Hollmann & Heinemann, 1994). Even if cumbersome, this nomenclature remains in effect today for this historical reason and because the pharmacologic approach continues to be the primary means of identifying the types of receptors responsible for excitation across the myriad synapses of the mammalian CNS (Collingridge, Olsen, Peters, & Spedding, 2009; Lodge, 2009).

Family-specific pharmacology was also instrumental in delineating differential biological roles for the three glutamate receptor classes. Specifically, these approaches have helped to galvanize massive interest in NMDA receptors by identifying their critical roles in synaptic plasticity, a form of cellular memory (Bliss & Gardner-Medwin, 1973), and in excitotoxicity, a type of glutamate-induced neuronal death (Choi, 1985; Lucas & Newhouse, 1957; Olney, 1969). Here, we briefly summarize the current knowledge of the properties and biological functions of NMDA receptors. Despite these substantial advances, given their key roles as mediators of fundamental processes in the CNS, the basis of many higher brain functions, and as important actors in neuropsychiatric conditions, NMDA receptors remain the target of assiduous basic and clinical research and no doubt still hold many surprises.

Molecular Identity, Evolutionary Origins, and Protein Expression

Interest in the structure, function, and biological roles of NMDA receptors originates with the critical and powerful signals they generate in the human CNS (Traynelis et al., 2010). Likely, the fundamental roles in the development and physiology of excitatory synapses in humans mirror those they play in other mammals, such as rats and mice, which have provided the majority of the current experimental evidence. As for many other signaling proteins, the distribution of NMDA receptors, and indeed of all iGluR proteins in neuronal membranes, is relatively sparse. In consequence, their molecular identification had to await the development of technologies that allowed functional cloning, including patch clamp electrophysiology (Hamill, Marty, Neher, Sakmann, & Sigworth, 1981) and the exogenous expression of mammalian genetic material (Sumikawa, Houghton, Emtage, Richards, & Barnard, 1981). Functional cloning and subsequently homology cloning led to the identification of a family of 18 homologous iGluR subunits in mammals (Hollmann & Heinemann, 1994) and an abundance of orthologs across virtually all species (De Bortoli, Teardo, Szabo, Morosinotto, & Alboresi, 2016).

These observations placed iGluR research on a firm molecular foundation but also produced significant surprises. First, they demonstrated that glutamate receptors were unrelated to the only family of neurotransmitter receptors known at the time, the pentameric Cys-loop receptors, thus revealing unsuspected, at the time, diversity among synaptic excitatory channels. Second, iGluR subunits appeared to have wide-ranging nonsynaptic expression and, therefore, broad biological effects apart from their conspicuous participation in neurotransmission. Last, by identifying GluD subunits, which form a class of iGluRs that appear impermeable to ions, it was suggested that proteins in the iGluR superfamily may also have non-ionotropic signaling functions (Dore, Aow, & Malinow, 2015).

With sequences in hand for all mammalian iGluR-encoded peptides, homology analyses provided definitive proof that iGluRs represented a new class of synaptic proteins, separate from other neurotransmitter receptors, and identified partial homology domains with other known proteins. These early bioinformatics analyses and subsequent biochemical evidence for a unique membrane topology led to the influential insight that iGluR subunits are modular in structure (Wo & Oswald, 1995; Wood, VanDongen, & VanDongen, 1995). This seminal observation had two immediate and powerful implications. On the one hand, it ushered in new hypotheses that iGluRs may have evolved by repeated gene duplication and fusion events; and on the other, it was suggested that individual modules may retain three-dimensional structure and perhaps functionality, even when separated from the entire protein. Presently, definitive evidence backs both of these hypotheses.

Molecular Diversity and Modular Structure

Mammalian iGluR subunits fall into four homology groups: GluA, GluK, GluN, and GluD (Figure 1A). Within each group, functional proteins consist of tetrameric assemblies. Further, of these, only GluA, GluK, and GluN tetramers form glutamate-gated pores. The presence of GluD tetramers at synapses is necessary for normal synaptic functions, but glutamate does not agonize an ionotropic function from these proteins. Therefore, synaptic GluD proteins may be orphan ligand-gated channels, or they may have purely non-ionotropic roles (Yuzaki & Aricescu, 2017). Of the iGluRs with demonstrated ionotropic function, AMPA and kainate receptors, often referred to as non-NMDA receptors, assemble as homo- or heterotetramers of GluA (1–4) and GluK (1–5) subunits, respectively. In contrast, NMDA receptors are necessarily heterotetramers that contain at least one GluN1 subunit and at least two GluN2 and/or GluN3 subunits.

Of the 18 mammalian iGluR genes, seven encode NMDA receptor subunits (Figure 1A, B). A single gene encodes the obligatory GluN1 subunit, which binds the required co-agonist glycine. Its transcript is subject to alternative pre-mRNA splicing of exons 5, 21, and/or 23, resulting in eight molecularly distinct variants (Zukin & Bennett, 1995). Four separately encoded GluN2 subunits, A–D, bind the neurotransmitter glutamate. The remaining two genes encode GluN3 subunits, A and B, which bind glycine or d-serine (Ciabarra et al., 1995; Nishi, Hinds, Lu, Kawata, & Hayashi, 2001; Sucher et al., 1995) (Figure 1B).

N-Methyl-D-Aspartate ReceptorsClick to view larger

Figure 1 Diversity, structure, and molecular evolution of NMDA receptors. (A) Eighteen mammalian iGluR subunits segregate into four homology classes. Tetrameric proteins produce AMPA, kainate, and NMDA-gated excitatory channels and orphan GluD channels/receptors. (B) Seven mammalian NMDA receptor subunits share membrane topology and overall three-dimensional architecture. (C) Phylogeny of taxons expressing iGluRs with divergence dates (Timetree, in million years). Red lines, taxons with functional synapses. (Adapted from Ryan and Grant, 2009). Structure of hypothesized evolutionary bacterial precursors: K+ channels (KcsA, PBD: 5J9P), bacterial periplasmic binding proteins (QBP, PDB: 1WDN; and LIVBP, PDB: 2LIV), and Glu-gated K+ channels (GluR0, hypothetical structure based on PDB ID 1IIT and 5J9P) and modern mammalian eukaryotic iGluR (GluN2B, PDB: 4PE5).

The NMDA receptor subunits have membrane topologies similar to all iGluR subunits, including external N-terminal (NTD) and ligand-binding (LBD) domains, which are distal and proximal to the membrane, respectively, connected to a transmembrane domain (TMD) formed by three transmembrane helices and a re-entrant loop, which extends into the cytoplasm a C-terminal domain (CTD). Homologous modules interact across subunits to form extracellular tetrameric NTD and LBD layers, respectively (Figure 1B). Within each subunit, the two external domains organize as two lobes connected by a flexible hinge, which allows relative movement of lobes and variable interlobe aperture. The LBD lobe connects through three short flexible linkers to the three transmembrane helices within the TMD, which contain the channel gate and the cation-selective pore. The cytoplasmic domain is intrinsically disordered and harbors many post-translational modifications and protein–protein interaction sites. As with most modular proteins, each domain has its own unique evolutionary origins (Anderson & Greenberg, 2001). Thus, examining the evolutionary history of each domain offers important clues into the NMDA receptors’ ancestors.

Evolutionary Origin

Bioinformatics approaches made possible by a rapidly expanding database of genomic and protein sequences from an increasing variety of organisms provided initial clues for the evolutionary origin of iGluR subunits (Figure 1C). In prokaryotes, a single gene, encoding GluR0, has been identified to date, strongly suggesting that the four mammalian iGluR subtypes (A, K, D, and N) likely arose within the eukaryotic lineage. Functionally, the GluR0 subunit forms a homotetrameric K+-selective channel that lacks the mammalian NTDs, is gated by glutamate, but is insensitive to AMPA, kainate, or NMDA (Chen, Cui, Mayer, & Gouaux, 1999). More specifically, the differentiation of mammalian subtypes likely occurred after the evolution of plant species because the plant iGluR-like genes, identified in Arabidopsis, form a separate homology clade (Wudick, Michard, Oliveira Nunes, & Feijo, 2018). Among eukaryotes, genetic evidence identifies all four mammalian iGluR subtypes (A, K, D, and N) as far back as invertebrates, in Drosophila and Caenorhabditis, which diverged from the Homo lineage about 797 million years ago (mya). Functional results from testing AMPA, kainate, and NMDA agonism on Hydra vulgaris suggest the presence of different subtypes in cnidarians, which diverged from Homo sapiens ~824 mya (Kumar, Stecher, Suleski, & Hedges, 2017). Thus, pharmacologic diversity, whether or not supported by genetic diversity, appeared within the eukaryotic lineage after the divergence from plants but before the divergence from invertebrates and Cnidaria. Rotifers, such as Adineta vaga, which appear to have a single iGluR gene, respond functionally to all three mammalian agonists, with preference decreasing from kainate to AMPA and to NMDA (Janovjak, Sandoz, & Isacoff, 2011). Possibly, GluK subunits are the most ancient of the specialized mammalian iGluRs. Alternatively, the ancestral iGluR subunit recognized all three mammalian agonists prior to their genetic divergence.

Given their widespread roles in inter-neuronal communication, the function of iGluRs in unicellular organisms and in species that predate the evolution of synapses is unclear. Genomic analyses have identified iGluR genes in unicellular eukaryotic organisms, such as Choanoflagellides (Burkhardt, 2015). Evolutionarily, these organisms existed before the appearance of the first ancestral synapse, the ursynapse, an assembly hypothesized to foreshadow the collection of synaptic proteins identified in the genomes of early marine animals such as cnidarians (Figure 1C). In plants such as Arabidopsis, iGluRs may serve as amino acid sensors to alert the plant to cell damage from potential threats like insects or fungi (Toyota et al., 2018). Understanding the function of these early precursors may provide clues for possible roles of non-neuronal NMDA receptors in mammals and presumably in humans.

The strong sequence homology within the NMDA receptor subfamily of genes suggests that they originate from a common eukaryotic GluN ancestor, although it remains unclear when the separation happened. Likely, the GluN2 subfamily arose by gene duplication. Invertebrates, such as insects and nematodes, have a single GluN2 ortholog (Nmdar2 in Drosophila, nmr-2 in Caenorhabditis). High similarity in exon structure of GluA2 genes and the analysis of paralogous chromosomal regions surrounding the GluN2 genes (Teng et al., 2010) support the hypothesis that the GluN2 subfamily arose from two rounds of gene duplication, which occurred ~550 mya, at the point of divergence between arthropods and vertebrates (McLysaght, Hokamp, & Wolfe, 2002). The first round of duplication resulted in GluN2A/B and GluN2C/D ancestors, and the second round led to the four individual genes that currently exist in vertebrates (Figure 1C).

Partial sequence homology between iGluRs and voltage-gated channels introduced the now widely accepted hypothesis that the two families share the pore of a common ancestor (Beck, Wollmuth, Seeburg, Sakmann, & Kuner, 1999; Kuner, Wollmuth, Karlin, Seeburg, & Sakmann, 1996; Panchenko, Glasser, & Mayer, 2001; Wood et al., 1995). Further, structural and functional evidence indicates that, like potassium-selective channels, functional iGluRs assemble as tetrameric proteins (Karakas & Furukawa, 2014; Laube, Kuhse, & Betz, 1998; Lee et al., 2014; Mano & Teichberg, 1998; Rosenmund, Stern-Bach, & Stevens, 1998; Sobolevsky, Rosconi, & Gouaux, 2009). Finally, the discovery of prokaryotic glutamate-gated K+-selective channels such as GluR0 provides a potential timeline for the evolutionary development of eukaryotic iGluRs (Figure 1C).

The iGluRs also share partial sequence homology with the large family of structurally characterized periplasmic bacterial proteins (PBPs) (Quiocho, Phillips, Parsons, & Hogg, 1974). This observation invited the hypothesis that the extracellular portion of each iGluR subunit may consist of two adjacent modules each related to leucine–isoleucine–valine-binding protein (LIVBP) and to glutamine-binding protein (QBP) (Moriyoshi et al., 1991; Stern-Bach et al., 1994; Wo & Oswald, 1994). The idea that the extracellular domains of iGluR subunits may exist as quasi-independent domains energized efforts to isolate and produce these domains, leading to the consequential observation that the separated peptides not only folded correctly but also retained some of the pharmacological properties characteristic of the intact receptor (Lampinen, Pentikainen, Johnson, & Keinanen, 1998). Indeed, structural determination of iGluR LBDs and later of NTDs confirmed this hypothesis and led to more detailed views of the structures and activation mechanisms of iGluRs.

The intracellular domain of iGluRs is the most variable portion of the protein. Conspicuously, vertebrates have a much longer (up to 647 residues in humans) cytoplasmic domain relative to their invertebrate counterparts. In addition, the cytoplasmic domain is the least conserved region of iGluRs, with only 29% sequence identity across the mouse GluN2 paralogs (Ryan, Emes, Grant, & Komiyama, 2008). This domain is unrelated in sequence to known proteins and is intrinsically disordered (Ryan et al., 2008). Clear distinctions of CTD functions have been observed in NMDA receptors even for the closest relatives. For example, truncation of the GluN2B CTD is lethal, similar to complete GluN2B knockout (Kutsuwada et al., 1996; Mori et al., 1998; Sprengel et al., 1998). In contrast, GluN2A knockouts and animals with GluN2A subunits that lack cytoplasmic tails are viable (Sakimura et al., 1995; Sprengel et al., 1998). Consistent with distinct roles of CTDs across NMDA receptor subtypes, genetically swapping the CTDs between GluN2A and GluN2B subunits, produced separate behavioral phenotypes across domains of learning, emotion/motivation, and motor skills (Ryan et al., 2013). Interestingly, electrophysiological recordings demonstrate wild-type properties for these mutant channels (Maki, Aman, Amico-Ruvio, Kussius, & Popescu, 2012). Therefore, the evolutionary divergence of C-termini may have afforded adaptive advantage as a means for bidirectional communication with cell-specific factors. Consistent with this hypothesis, invertebrate GluN orthologs, which have shorter C-termini, lack many of the known protein-binding motifs present on the vertebrate subunits (Ryan et al., 2008).

Expression Across the Life Span, Cell Types, and Specialized Membrane Segments

The seven GluN subunits display unique and highly regulated expression patterns across development, in specific cell types, and across subcellular locations (Paoletti, Bellone, & Zhou, 2013). Controlled expression of NMDA receptor subunits represents a major mechanism regulating neuronal excitability and the physiology of excitatory synapses. Several GluN subunits co-localize at synaptic and nonsynaptic locations, and the observed glutamate-elicited response varies with the identity and amount of the specific subunits expressed.

The GluN1 subunit occurs ubiquitously throughout the embryonic and adult mammalian brain and spinal cord, reflecting its critical role in the assembly and surface trafficking of functional NMDA receptors. Differential splicing generates eight molecularly distinct GluN1 subunits, and additional cellular mechanisms regulate their differential regional and subcellular distribution. Two types of splice variants, GluN1-a and -b, differ in the sequence of the external NTD and produce receptors with distinct kinetic and pharmacological properties. The expression of GluN1-a/b variants responds to physiologic cues, such as patterns of activity, and to pathologic cues, such as following experimental spinal cord injury. Four GluN1 variants (1–4) differ in the molecular structure of the intracellular CTD. GluN1-2 is enriched in cortical and hippocampal regions, whereas GluN1-4 has a complementary profile. Within a given neuron, GluN1-1 localizes more to synaptic regions relative to GluN1-2, which is found mostly in nonsynaptic regions. This may reflect differences in cytoplasmic domain sequences that are critical for synaptic targeting such as binding to neurofilament-L and PDZ proteins. The functional significance of these distributions is unknown as no differences in electrophysiological properties have been identified so far.

GluN2 and GluN3 subunits have differential and often complementary expression patterns across the life span and cell types. GluN2B, GluN2D, and GluN3A subunits predominate early in development. GluN2B displays a broad expression level shortly after birth and becomes largely restricted to the forebrain as the animal develops. GluN2D expression declines during transition to adulthood and becomes restricted in the diencephalon and mesencephalon. GluN3A has a characteristic peak in expression after birth and drops to low but constant levels in adults. In contrast, the expression levels of GluN2A increase gradually throughout development, and this subunit becomes predominant in adult tissue. GluN2C expression levels are relatively constant throughout the life span, dominating only in the cerebellum and the olfactory bulb.

Accumulating evidence suggests that in aged animals NMDA receptor expression levels decrease, and this correlates functionally with reduced NMDA receptor–mediated signals and behaviorally with cognitive deficits. As individuals age, memory is among the earliest cognitive functions to decline (Gallagher & Nicolle, 1993). Specifically, aging associates with deficits in spatial, short-term, and long-term memory in humans, non-human primates, and rodents. Consistent with the pervasive role of NMDA receptors in memory formation, storage, and retrieval, advanced aging correlates strongly with reduced NMDA receptor function.

Evidence from radiolabeled binding studies in mammals indicates that aging-related receptor hypofunction relates primarily to decreased receptor density in cortical and hippocampal tissue and to decreased performance in long-term and spatial memory tasks in rodents. Consistent with these observations, aged animals display reduced long-term potentiation. Specifically, the expression of GluN1 and GluN2B subunits declines with age in rodents and primate models (Gazzaley, Siegel, Kordower, Mufson, & Morrison, 1996; Magnusson, Nelson, & Young, 2002; Sheng, Cummings, Roldan, Jan, & Jan, 1994).

Unique Functional Properties

Relative to other members of the iGluR family, NMDA receptors possess a variety of properties which distinguish them functionally and physiologically. Given the overall similarity in quaternary structure, these significant divergences in function likely reflect subtle structural differences between iGluR subtypes. A thorough understanding of the breadth of NMDA receptor functional properties provides insight into the role of these receptors in physiological and pathophysiological contexts.

Kinetic Properties of the NMDA Receptor EPSC

Most excitatory synapses express several types of iGluRs; therefore, the excitatory postsynaptic current (EPSC) reflects the combined response of all the receptors present. Presently, methods to ascertain the molecular identity and amount of iGluR types at a given synapse are imprecise; moreover, the composition of synaptic receptors is dynamic, changing with the physiological state of the synapse. To date, the majority of the information regarding the types of functional iGluRs at mammalian synapses relies largely on pharmacologic methods of isolating and characterizing the component ionic fluxes of the observed overall current.

The NMDA receptor–mediated synaptic current was revealed experimentally when synaptic activity was recorded in the absence of Mg2+, which in physiologic conditions blocks the channel, and in the presence of exogenous glycine, which is an obligatory co-agonist. Thus enhanced, the NMDA receptor–mediated EPSC was isolated from the co-localized non-NMDA receptors, using AMPA receptor–specific inhibitors such as cyanquixaline. These and other pharmacologic manipulations revealed that the EPSC rise phase closely followed the kinetics of the AMPA-sensitive component, whereas the decay phase followed the decay of the NMDA-responsive component (50–500 ms). Further, because the NMDA component lasted longer than the lifetime of synaptically released glutamate (~1.2 ms), it became clear that the EPSC decay time, which is critical to synaptic processing, integration, and plasticity, depended primarily on properties intrinsic to the postsynaptic NMDA receptors present, especially their gating kinetics (Lester, Clements, Westbrook, & Jahr, 1990). For this reason, over the past two decades, the gating kinetics of NMDA receptors has represented an important area of research. The mechanisms that control the activation of NMDA receptors are most accurately investigated by examining the behaviors of single molecules with statistical methods.

As for most ion channels, currents recorded from a single NMDA receptor display complex patterns of activity. These reflect the stochastic transitions between closed- and open-channel conformations and are governed primarily by thermodynamic constraints (Figure 2A) (Iacobucci & Popescu, 2017). Experimental conditions that enhance the signal amplitude and simplify its kinetics allowed the accumulation of sufficient one-channel current records, which when processed with statistical methods exposed a multistate kinetic model for NMDA receptor gating. This model has been extensively validated across the four diheteromeric GluN1/GluN2(A–D) receptor types (Figure 2A, inset). It proposes that the rising phase of the macroscopic current reflects the rate with which individual agonist-bound receptors transition across at least three kinetically distinct closed states (families of conformations) to slowly reach open states which allow transmembrane ionic flux. Conversely, the macroscopic current decay phase reflects the rate with which individual open-channel receptors, whose occupancy is maximal during the peak of the macroscopic current, transition back into closed-channel conformations, whose structure restricts the passage of current but allows agonist dissociation to prevent subsequent openings. The model also incorporates off-path desensitized states, whose time-dependent increase in occupancy corresponds to the slow (1–2 s) fade of the macroscopic response recorded during prolonged exposures to agonists, as is likely the case with extra synaptic receptors.

This high-resolution understanding of the NMDA receptor gating process represents a springboard from which to address two important and yet unanswered questions. First, combining macroscopic current recordings and statistical analyses of one-channel currents may reveal how pharmacologic and endogenous ligands, as well as intracellular signaling, impact NMDA receptor gating kinetics and, therefore, the time course of the EPSC (Figure 2A). Second, combining electrophysiological approaches with molecular dynamics simulations of transitions between structural conformations may expose the sequence of intramolecular rearrangements that represent receptor activation and therefore the structural identity and lifetime of each of the functional states assumed in the kinetic model (Figure 2B).

N-Methyl-D-Aspartate ReceptorsClick to view larger

Figure 2 NMDA receptor gating: kinetic and structural models. (A) Top, Current trace recorded from a channel exposed to high concentrations of agonists (Glu, Gly) in the absence of divalent cations (Na+ currents) illustrates stochastic oscillations between 0 and 10 pA (70 pS) current levels, indicative of thermodynamically controlled transitions between conformations with closed (C) and open (O) pores. Middle, Histogram illustrates the compound distribution of closed event durations inferred from experimentally recorded one-channel currents; black line illustrates the distribution predicted by the multistate model at right. Bottom, Macroscopic responses predicted by the model under brief repetitive stimulation with Glu and under prolonged exposure to agonists reproduce well experimentally recorded NMDA receptor currents (Iacobucci & Popescu 2017). (B) Highlighted in gray, three conformations of GluN1/GluN2B receptors observed with cryo-electron microscopy (EM) likely represent closed (Cx, Cy) and open (O) receptors (Tajima et al. 2016; PDB 5FXH, 5FXI, and 5FXG); they are arranged in a temporal sequence that may underlie receptor gating. Molecular modeling and dynamic simulations of the GluN1/GluN2A receptor suggest a temporal sequence of intramolecular conformational change by which closed conformations can transition into open conformations. Heat map illustrates the magnitude of displacement in alpha-carbon positions between closed and open states and identifies hot spots of conformational change (Zheng et al. 2017).

Reaction Mechanism

Historically, the NMDA receptor activation mechanism has been modeled intuitively as a simple two-step binding/gating reaction, where binding referred collectively to the four required association/dissociation equilibria (two for glutamate and two for glycine) and gating referred globally to any host of conformational changes that transformed the closed (impermeable) receptor into an open (permeable) receptor. However, it became quickly apparent that in most experimental conditions, NMDA receptor current, even when recorded in the continuous presence of agonists, faded in time and that this loss of activity could be reversed with rest. To account for this behavior, the binding/gating scheme was amended with a desensitization step, imagined to represent transitions into a family of closed receptor conformations (states) that required (agonist) binding but did not allow (channel) gating (Lester & Jahr, 1992).

Since the advent of single-channel electrophysiological recordings, NMDA receptor activity has been probed in exquisite detail over several time domains (milliseconds to tens of minutes). In certain experimental conditions, where single NMDA receptors produce uniformly large currents, it is possible to measure the duration of all periods when channels are closed (C) or open (O) as they occur during the normal operation of the channel. The observed distributions of closed and open event durations always include multiple kinetic components that can be queried with statistical methods to develop models of receptor activation, which include all the observed kinetic states (Figure 2A) (Iacobucci & Popescu, 2017; Popescu, 2012). Although this method simplifies the underlying reality of myriad conformations, which intermorph during receptor activity, into a bare minimum of kinetically and functionally distinct states (thermodynamically equivalent conformations), it has the power to first approximate transition rates between states based on the single-molecule record and then predict macroscopic current responses to countless stimulation protocols and conditions (Figure 2A). This approach has produced a general understanding of the functional changes that a receptor experiences during periods of activity, their relative timing, and how these are modified by mutations and modulators (Popescu, 2005).

A complementary line of investigation seeks to define with atomic resolution the structural arrangement of all functionally relevant conformations. The present knowledge of structure–function relationships in iGluR proteins originates with the influential observation that NTDs and LBDs share homology with bacterial amino-acid binding proteins. This observation motivated efforts to produce the individual domains as water-soluble proteins and thus facilitated structure determination by nuclear magnetic resonance (McFeeters & Oswald, 2002) and later X-ray crystallography (Furukawa & Gouaux, 2003; Inanobe, Furukawa, & Gouaux, 2005; Karakas, Regan, & Furukawa, 2015). Results showed that the external portion of the NMDA receptor can be envisioned as a collection of semi-independent globular domains, which like their ancestors (QBP and LIVBP) bind agonist at the interface between two lobes and can move around a flexible linker. Agonist binding changes the relative position of the two lobes, and in intact receptors, this movement can be communicated as mechanical force to covalently connected sequences (linkers) or to adjacent domains. Given the interleaved structure of the functional tetramers, one can imagine that the initially small local movement produced by agonist binding can ripple onto adjacent domains and produce a chain of back-and-forth conformational changes. The sequence of conformational change likely mirrors the sequence of state transitions inferred with kinetic approaches and explains the probability of populating open receptor conformations and therefore the time course of the NMDA receptor current.

Such a view of receptor activity has been substantiated recently by a series of cryo-electron microscopic structures of intact GluN1/GluN2B receptors that appear to represent closed and open receptor conformations. Comparing these structures revealed two positions for each heterodimer pair within the LBD that differ by a 13.5º rotation. This difference likely places tension on the short linkers between the LBD and TMD, as envisioned for a gating movement (Tajima et al., 2016) (Figure 2B). Based on these observed structures, molecular modeling predicts a substantial wave of spatially and temporally organized motions as the physical origin for NMDA receptor gating (Figure 2B) (Zheng, Wen, Iacobucci, & Popescu, 2017). Importantly, areas predicted to be most dynamic during gating overlap with disease-related sites identified in human patients (Hu, Chen, Myers, Yuan, & Traynelis, 2016) (Figure 3). Present efforts seek to match functionally defined states with structurally defined conformations in a way that would integrate structural, thermodynamic, and kinetic considerations to produce a satisfying understanding of the physical basis of the NMDA receptor signal.

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Figure 3 Disease-associated mutations mapped onto GluN1-a (left, PDB ID 4PE5), GluN2A (middle, homology model), and GluN2B (right, PDB ID 4PE5) subunits. C-terminal structures are not resolved and are displayed in schematic format here. In all subunits, disease-associated mutations span all major receptor domains: extracellular (top), transmembrane (middle), and intracellular (bottom).

Permeation Properties of NMDA Receptors

Aside from their unique gating kinetics, NMDA receptors also have characteristic permeation properties, including relatively large conductance and high Ca2+ permeability. In physiologic conditions, the currents gated by NMDA receptors consist primarily of inward Na+ and Ca2+ fluxes (Jahr & Stevens, 1993; Maki & Popescu, 2014). Unitary conductance can reach ~70 pS for GluN1/GluN2(A-B) receptors and ~50 pS for GluN1/GluN2(C-D) (Glasgow, Siegler, Retchless, & Johnson, 2015). Notably, up to 11% of this current may be carried by Ca2+.

Together, long activations and large unitary conductance allow NMDA receptors to produce substantial increases in spine and dendritic Na+. Ratiometric Na+ imaging showed that a transient NMDA receptor activation can elevate dendritic spine Na+ concentrations to 30–40 mM, and during trains of activity produced by high-frequency stimulation, this value can reach 100 mM (Rose & Konnerth, 2001), as was observed in neural networks under epileptic activity (Karus, Mondragao, Ziemens, & Rose, 2015). These substantial alterations in the Na+ electrochemical gradient can significantly influence excitatory synaptic current reversal potentials and influence global neuronal activity by membrane depolarization, affecting the activity of Na+ transporters (Blaustein & Lederer, 1999; Mondragao et al., 2016). Surprisingly, increases in intracellular Na+ can itself alter NMDA receptor function. Single-channel current recordings revealed that Na+ influx through neighboring glutamate receptors boosts the receptor’s open probability. Pharmacological manipulations revealed that this sensitivity to modulation by intracellular Na+ is determined by Src kinases (Yu & Salter, 1998).

Simultaneously, their high unitary Ca2+ flux and prolonged activations result in substantial increases in dendritic Ca2+, whose bulk concentration can reach 10 μM (Sabatini, Oertner, & Svoboda, 2002). Due to these unique properties, NMDA receptors are the predominant source of Ca2+ in dendritic spines in a variety of brain regions (Higley & Sabatini, 2012). The intracellular Ca2+ flux generated by NMDA receptor activation follows the same kinetics as the macroscopic current and is governed by the receptor gating kinetics (Kovalchuk, Eilers, Lisman, & Konnerth, 2000; Murthy, Sejnowski, & Stevens, 2000). Several endogenous mechanisms increase specifically the amplitude of the Ca2+ current, by changing the fractional content of Ca2+ in the total current. The metabolic status of the neuron, explicitly through protein kinase A, modulates Ca2+ permeability of the NMDA receptor by direct phosphorylation of intracellular residues of the GluN1 subunit (Aman, Maki, Ruffino, Kasperek, & Popescu, 2014; Skeberdis et al., 2006). Separately, protein kinase C may enhance the NMDA component of synaptic transmission by relieving Mg2+ block and increasing the lifetime of open receptor states (Chen & Huang, 1992). Importantly, pharmacological inhibition of these kinases interferes with the induction of NMDA receptor–dependent synaptic plasticity.

NMDA Receptors as Nonionic Signaling Hubs

In addition to their critical ionotropic function in shaping the EPSCs, NMDA receptors can execute signal transduction that is independent of their ionic current. This function depends critically on the large intracellular domains of GluN subunits, which include numerous protein–protein interaction sites (Figure 3).

Repeated glutamate applications onto NMDA receptors induce dephosphorylation of tyrosine residues on intracellular GluN domains and correlate with a use-dependent decrease in current. Surprisingly, this effect persists when currents are blocked with high levels of extracellular Mg2+ (Vissel, Krupp, Heinemann, & Westbrook, 2001) and can result in dendritic spine shrinkage (Stein, Gray, & Zito, 2015). Conversely, glycine applications prime NMDA receptors for subsequent activity-dependent internalization, a form of NMDA receptor plasticity (Han, Campanucci, Cooke, & Salter, 2013; Nong et al., 2003).

Consistent with a biologically important non-ionotropic function of NMDA receptors, transgenic mice engineered to express GluN2 subunits lacking cytoplasmic domains have altered synaptic plasticity, although this manipulation leaves unchanged the NMDA receptor permeation properties (Kohr et al., 2003). Additionally, animals that express GluN2A and GluN2B subunits whose C-termini were swapped have severe behavioral deficits but normal synaptic transmission (Ryan et al., 2013). In vitro, exchanging the C-termini of GluN2A and GluN2B subunits produced NMDA receptors with wild type–like conductance and gating (Maki et al., 2012). More recently, fluorescence resonance energy transfer studies revealed that sustained NMDA applications onto neurons produced conformational shifts in the CTDs of the NMDA receptor. Importantly, competitive antagonists (AP5) prevented the agonist-induced conformational change, whereas pore blockers (MK801 and 7CK) did not prevent these structural rearrangements (Dore et al., 2015). Together these observations support an important biological role for NMDA receptors in signal transduction, aside from their depolarizing and Ca2+-fluxing functions.

The cytoplasmic domains of each NMDA receptor subunit are responsible for extensive protein interactions. The GluN1 subunit is a converging point of interaction between actinin (Wyszynski et al., 1998), calmodulin (Ehlers, Zhang, Bernhadt, & Huganir, 1996), yotiao (Lin et al., 1998), neurofilament-L (Ehlers, Fung, O’Brien, & Huganir, 1998), spectrin (Wechsler & Teichberg, 1998), tubulin (van Rossum, Kuhse, & Betz, 1999), and membrane-associated guanylate kinases (Standley, Roche, McCallum, Sans, & Wenthold, 2000). The GluN2 subunits collectively interact with Ca2+/calmodulin-dependent protein kinase II (CaMKII), actinin (Wyszynski et al., 1998), postsynaptic density (PSD) protein-93, , PSD-95, synapse-associated protein-102 (Sheng & Sala, 2001), synaptic scaffolding molecule (Hirao et al., 1998), channel-interacting PDZ protein (Kurschner, Mermelstein, Holden, & Surmeier, 1998), Src kinase (Yu, Askalan, Keil, & Salter, 1997), spectrin (Wechsler & Teichberg, 1998), phospholipase C (Gurd & Bissoon, 1997), and tubulin (van Rossum et al., 1999). The GluN3A subunit associates with protein phosphatase 2A (Ma & Sucher, 2004), microtubule-associated protein 1B (Eriksson et al., 2010), cell cycle and apoptosis regulatory protein 1 (Jiang et al., 2010), G protein pathway suppressor 2 (Eriksson et al., 2007), and Rheb (Sucher et al., 2010). Therefore, in addition to the ionotropic roles of channel function, the extensive protein interaction network and metabotropic functions make the NMDA receptor a veritable hub of intracellular signaling.

Physiological Roles

The canonical role of NMDA receptors has been their function as postsynaptic responders to fluctuations in extracellular glutamate concentrations. This role is central to normal synaptic function and pathological missense variants in NMDA receptors have been causally associated with disease through perturbations in this process. However, since their original discovery as excitatory postsynaptic glutamate receptors, research has provided additional insights into their physiological roles in both presynaptic neuronal compartments and non-neuronal cell types.

Neuronal Postsynaptic Signal

The critical role of intracellular Ca2+ in the induction of synaptic plasticity was recognized by observations that Ca2+ chelators introduced in postsynaptic hippocampal neurons prevented activity-dependent changes in synaptic strength (Lynch, Larson, Kelso, Barrionuevo, & Schottler, 1983). Their high Ca2+ permeability over other non-NMDA receptors coupled with their higher sensitivity to synaptically released glutamate made NMDA receptors primary candidates as mediators of the intracellular Ca2+ signals that trigger synaptic changes (Jahr & Stevens, 1987; MacDermott, Mayer, Westbrook, Smith, & Barker, 1986; Mayer & Westbrook, 1987).

Further, the ability of NMDA receptors to respond to a diverse array of cellular stimuli allows them to integrate a variety of inputs and thus to function as crucial signaling nodes in the neuron. The sensitivity of NMDA receptors to membrane voltage is imparted by the constitutive block by Mg2+ in the pore which is released during depolarization (Nowak, Bregestovski, Ascher, Herbet, & Prochiantz, 1984). During an EPSC event initiated by vesicular glutamate release, the initial depolarization produced by AMPA receptor activation and the resultant Na+ influx alleviates the blocking effect of Mg2+ to allow Ca2+ entry. NMDA receptor–mediated Ca2+ flux activates Ca2+-dependent signaling cascades that control the surface expression of postsynaptic AMPA receptors to modify the EPSC amplitude and in effect produce long-term potentiation (LTP) or depression (LTD). Alternatively, the postsynaptic depolarization necessary to relieve NMDA receptor blockade can occur due to the back-propagation of an action potential. The ability of NMDA receptors to respond to postsynaptic action potentials provides the basis of spike timing–dependent plasticity. The sensitivity to synaptic inputs tends to increase when the synaptic input immediately precedes the output action potential. Conversely, the synaptic strength is weakened when the EPSC immediately follows the output action potential (Feldman, 2012). The slow gating kinetics of NMDA receptors, which prolongs the time course of the synaptic signal, facilitates the temporal summation of excitatory signals generated by neighboring spines. This allows for spatial integration of numerous synaptic inputs to regulate the action potential probability of the neuron. Thus, NMDA receptors have an important role in the final neuronal firing pattern, which represents the interaction of all excitatory and inhibitory components in the neuron (Ma, Kelly, & Wu, 2002; Wu, Ma, & Kelly, 2004).

In addition to activating intracellular cascades directly involved in synaptic plasticity, the large intracellular Ca2+ signals generated by NMDA receptors modulate the activity of surrounding Ca2+-activated K+ channels (SK channels) (Ngo-Anh et al., 2005). SK channels mediate K+ efflux to repolarize the postsynaptic membrane. This repolarization forms a negative feedback loop on NMDA receptors by reinstating the Mg2+ block. Furthermore, the inhibition of SK channels by the coordinated activation of type I mGluRs is required for LTP induction in spike timing-dependent plasticity (Tigaret, Olivo, Sadowski, Ashby, & Mellor, 2016).

During development, the establishment and maintenance of mature neuronal networks depend on the activity-dependent pruning of synaptic circuits. The coordination between excitatory and inhibitory inputs dictates the extent of structural plasticity of dendritic spines (Holtmaat & Svoboda, 2009). NMDA receptor–dependent processes involved in synaptic plasticity, LTP and LTD, are associated with synaptic spine development. LTP and LTD are associated with dendritic spine enlargement and shrinkage, respectively (Fortin et al., 2010; Wiegert & Oertner, 2013; Zhou, Homma, & Poo, 2004).

The composite model for synaptic strengthening involves NMDA receptors responding to high-amplitude, brief glutamate concentration released at high frequencies. The resultant activation of NMDA receptors initiates mitogen-activated protein kinase signaling to induce LTP in hippocampal synapses (Banko et al., 2005; Bateup, Takasaki, Saulnier, Denefrio, & Sabatini, 2011; Kelleher, Govindarajan, & Tonegawa, 2004; Malenka, 1994). The Ca2+ influx into the dendritic spine through NMDA receptors activated from high-frequency stimuli recruits CaMKII. This activation of CaMKII results in the phosphorylation of AMPA receptors to increase their unitary conductance (Benke, Luthi, Isaac, & Collingridge, 1998) and facilitates trafficking and insertion to the membrane (Ehlers, 2000). In contrast, lower-frequency synaptic stimuli are associated with LTD. The association between LTD and dendritic spine shrinkage led to the hypothesis that the magnitude of Ca2+ influx induced by low-frequency stimuli activates protein phosphatases (calcineurin and protein phosphatase 1) in the dendritic spine that reduce AMPA expression and induce spine shrinkage (Mulkey, Endo, Shenolikar, & Malenka, 1994). In addition to this model of synaptic weakening, low-amplitude, steady glutamate concentration (as from spillover from neighboring spines) selectively activate type I mGluRs, which trigger protein phosphatase 2A to initiate AMPA receptor removal (Gross et al., 2015; Huber, Gallagher, Warren, & Bear, 2002; Niere, Wilkerson, & Huber, 2012). This model of NMDA receptor involvement in synaptic plasticity accounts for synaptic excitatory/inhibitory coordination among a region of proximal dendritic spines.

However, the recent evidence that agonist binding alone was sufficient to induce LTP independent of ionic flux led to the hypothesis that ionic flux may not be involved in spine shrinkage (Dore et al., 2015; Nabavi et al., 2013; Stein et al., 2015). Consistent with this hypothesis, glutamate uncaging at LTD-inducing frequencies in hippocampal slices in the presence of the NMDA channel blocker MK801 did not interfere with dendritic spine shrinkage (Stein et al., 2015). Thus, structural rearrangements in the cytoplasmic domain of the NMDA receptor channel are sufficient to alter intracellular biochemical signals to initiate both functional and structural changes in spines.

Neuronal Presynaptic Signal

NMDA receptors can be expressed at presynaptic sites as well (Bouvier, Bidoret, Casado, & Paoletti, 2015). This hypothesis was ushered in by the observation that NMDA receptor antagonists decrease glutamate and aspartate release in CA1 hippocampal slices. Thus, in addition to their postsynaptic roles in controlling the direction and magnitude of long-term plasticity, NMDA receptors can control short-term synaptic plasticity by influencing the probability of neurotransmitter release. Presynaptic modulation of neurotransmitter may occur by several mechanisms: 1) Ca2+ influx via NMDA receptors directly activating vesicle fusion machinery, 2) membrane depolarization activating voltage-gated Ca2+ channels coupled to vesicle fusion machinery, or 3) modulation of downstream signaling pathways.

The spontaneous release of neurotransmitter can be either Ca2+-dependent or independent. Given the high permeability of NMDA receptors for Ca2+, it is likely that presynaptic regulation by NMDA receptors is largely Ca2+-driven. However, emergent research has indicated that, at specific subsets of synapses, presynaptic NMDA receptors exhibit a tonic enhancement of transmitter release (Brasier & Feldman, 2008; Corlew, Wang, Ghermazien, Erisir, & Philpot, 2007; Crabtree, Lodge, Bashir, & Isaac, 2013; Duguid & Smart, 2004; Sjostrom, Turrigiano, & Nelson, 2003). This tonic enhancement likely involves NMDA receptor activation by ambient glutamate. In addition, the incorporation of receptor subunits with reduced Mg2+ sensitivity may further facilitate tonic activation (Banerjee et al., 2009; Larsen et al., 2011; Mameli, Carta, Partridge, & Valenzuela, 2005).

Unlike spontaneous transmitter release which is independent of a stimulus, the role of NMDA receptors in evoked neurotransmitter release is optimized to facilitate glutamate release at specific physiological stimuli frequencies in a given brain region. NMDA receptors in the visual cortex enhance glutamate release at 10 Hz (Larsen et al., 2014; Sjostrom et al., 2003), while receptors in the cerebellar fiber-to-Purkinje cell synapses work best between 40 Hz and 1 kHz (Bidoret, Ayon, Barbour, & Casado, 2009). In hippocampal CA3-to-CA1 synapses, presynaptic NMDA receptors facilitate glutamate release at theta-like, 5 Hz, frequencies (McGuinness et al., 2010). Thus, the sensitivity of presynaptic NMDA receptors to specific frequencies likely reflects brain region–specific subunit expression patterns and regulatory elements similar to their postsynaptic counterparts. The presynaptic composition of NMDA receptors also undergoes developmental changes.

Less understood is how presynaptic NMDA receptors modulate long-term synaptic plasticity. At L4-to-L2/3 synapses in the somatosensory cortex, spike timing–dependent LTD required the activation of presynaptic NMDA receptors, while LTP required only postsynaptic NMDA receptors (Bender, Bender, Brasier, & Feldman, 2006). In addition, this LTD required activation of voltage-gated Ca2+ channels, inositol 1,4,5-trisphosphate receptors, and metabotropic glutamate receptors and subsequent engagement of downstream endocannabinoid signaling. Work in L4-to-L2/3 synapses of the barrel cortex showed the same endocannabinoid signaling requirement (Banerjee et al., 2009; Hardingham, Wright, Dachtler, & Fox, 2008; Rodriguez-Moreno et al., 2013). Therefore, the role of presynaptic NMDA receptors in modulating long-term plasticity likely depends on synapse-specific factors that remain to be identified.

Glial Cells

Since their discovery, the majority of research efforts have focused on the eminent role of NMDA receptors in neuron physiology and plasticity. However, emerging research is providing evidence of ionotropic glutamate receptor expression in a much wider array of cell types than previously appreciated. Besides neurons, the prominent cell class within the CNS are glial cells. These cells maintain homeostasis in the CNS. Glia achieve this by regulating K+ levels, acidity, neurotransmitter levels, cerebral blood flow, antioxidant formation, and water transport. These regulatory roles imply a sensory mechanism for changes in the controlled variable. Expression of iGluRs on glial cells allows these cells to detect changes in glutamate concentration at and around synapses.

The first evidence of glial NMDA receptors came from mRNA work which detected expression of GluN2B and GluN2C in astrocytes from adult rats. However, no transcripts were found for GluN1, the obligatory subunit of NMDA receptors (Akazawa, Shigemoto, Bessho, Nakanishi, & Mizuno, 1994; Conti, Minelli, Molnar, & Brecha, 1994; Luque & Richards, 1995). Subsequent work in young and newborn animals showed that GluN1 expression decreases with culture time, suggesting that the methods of glial cell cultivation may affect gene expression. Human astrocytes have been shown to possess all known NMDA receptor subunit mRNA (Lee et al., 2010).

In addition to RNA expression, electron microscopy of immunolabeled subunits provided evidence for GluN1 and GluN2A/B subunit expression in astrocytes from the visual cortex (Aoki, Venkatesan, Go, Mong, & Dawson, 1994; Conti, DeBiasi, Minelli, & Melone, 1996) as well as in the amygdala, stria terminalis, and nucleus locus coeruleus (Farb, Aoki, & Ledoux, 1995; Gracy & Pickel, 1995). However, no immunoreactivity was detected in CA1 of the adult hippocampus (Gottlieb & Matute, 1997; Krebs, Fernandes, Sheldon, Raymond, & Baimbridge, 2003). Thus, the expression of functional NMDA receptors on astrocytes may be brain region–specific.

In addition to astrocytes, transcripts of GluN1 and GluN2D were identified in the CG-4 oligodendroglial cell line (Yoshioka, Ikegaki, Williams, & Pleasure, 1996). The expression of NMDA receptor subunits in oligodendrocytes was definitively confirmed in mouse oligodendrocytes where transcripts for GluN1, GluN2A-D, and GluN3A were detected, with GluN1, GluN2C, and GluN3A being most abundant (Salter & Fern, 2005). Electrophysiological studies provided direct evidence that these transcripts yield functional receptors in white matter oligodendrocytes in the cerebellum, corpus callosum, and rat optic nerve (Karadottir, Cavelier, Bergersen, & Attwell, 2005; Kolodziejczyk, Hamilton, Wade, Karadottir, & Attwell, 2009; Micu et al., 2006). Interestingly, these NMDA-evoked responses were largely restricted to the cell processes rather than the soma.

Another pioneering study suggested the expression of NMDA receptor subunits on polydendrocytes using neonatal rat oligodendrocyte precursors (Wang et al., 1996). This initial finding was later confirmed with the detection of GluN1 on O4-positive polydendrocytes in both human and postnatal rat white matter (Manning et al., 2008). In addition, GluN2A and GluN2C subunits were found on somas and processes of polydendrocytes in the transgenic NG2-dsRed mouse (Hamilton, Vayro, Wigley, & Butt, 2010).

Microglia also express NMDA receptors. Injection of NMDA into the somatosensory cortex of rats led to the transient activation of microglia as determined histologically (Acarin, Gonzalez, Castellano, & Castro, 1996). This finding was substantiated by detection of GluN1 and GluN2A-D transcripts (Murugan, Sivakumar, Lu, Ling, & Kaur, 2011).

Other Cell Types

Less well understood but beginning to come to light is the role of NMDA receptors in non-neuronal cell types. Recently, functional NMDA receptors have been found on erythrocytes, specifically erythroid precursor cells and immature red blood cells, reticulocytes. Their activation leads to a rapid increase in intracellular Ca2+ (Makhro et al., 2010). The function of NMDA receptors on erythrocytes is unclear. However, channel activation modulates intracellular pH, which is critical for hemoglobin oxygen affinity. Thus, NMDA receptors may play a role in tuning the availability of oxygen to peripheral tissues (Makhro et al., 2013). In addition to red blood cells, neuroepithelial cells, which form part of the blood–brain barrier, express GluN1 and GluN2A/B subunit transcripts and protein. Whether these subunits constitute functional receptors remains to be elucidated (Sharp et al., 2003).

The endogenous ligand for NMDA receptor activation in these peripheral tissues is less clear. A recent report shows that mechanical forces produced by cellular deformation can gate NMDA receptor currents in the absence of agonist (Maneshi et al., 2017). Such alternative modalities of NMDA receptor activation may provide clues to the function of these receptors in non-neuronal tissues.

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