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.
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).
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.
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).
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.
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.
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.
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.
Acarin, L., Gonzalez, B., Castellano, B., & Castro, A. J. (1996). Microglial response to N-methyl-D-aspartate-mediated excitotoxicity in the immature rat brain. Journal of Comparative Neurology, 367(3), 361–374. doi:10.1002/(SICI)1096-9861(19960408)367:3<361::AID-CNE4>3.0.CO;2-3Find this resource:
Akazawa, C., Shigemoto, R., Bessho, Y., Nakanishi, S., & Mizuno, N. (1994). Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. Journal of Comparative Neurology, 347(1), 150–160. doi:10.1002/cne.903470112Find this resource:
Aman, T. K., Maki, B. A., Ruffino, T. J., Kasperek, E. M., & Popescu, G. K. (2014). Separate intramolecular targets for protein kinase A control N-methyl-D-aspartate receptor gating and Ca2+ permeability. Journal of Biological Chemistry, 289(27), 18805–18817. doi:10.1074/jbc.M113.537282Find this resource:
Anderson, P. A., & Greenberg, R. M. (2001). Phylogeny of ion channels: Clues to structure and function. Comparative Biochemistry and Physiology Part B Biochemistry & Molecular Biology, 129(1), 17–28.Find this resource:
Aoki, C., Venkatesan, C., Go, C. G., Mong, J. A., & Dawson, T. M. (1994). Cellular and subcellular localization of NMDA-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats. Journal of Neuroscience, 14(9), 5202–5222.Find this resource:
Banerjee, A., Meredith, R. M., Rodriguez-Moreno, A., Mierau, S. B., Auberson, Y. P., & Paulsen, O. (2009). Double dissociation of spike timing-dependent potentiation and depression by subunit-preferring NMDA receptor antagonists in mouse barrel cortex. Cerebral Cortex, 19(12), 2959–2969. doi:10.1093/cercor/bhp067Find this resource:
Banko, J. L., Poulin, F., Hou, L., DeMaria, C. T., Sonenberg, N., & Klann, E. (2005). The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. Journal of Neuroscience, 25(42), 9581–9590. doi:10.1523/JNEUROSCI.2423-05.2005Find this resource:
Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L., & Sabatini, B. L. (2011). Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. Journal of Neuroscience, 31(24), 8862–8869. doi:10.1523/JNEUROSCI.1617-11.2011Find this resource:
Beck, C., Wollmuth, L. P., Seeburg, P. H., Sakmann, B., & Kuner, T. (1999). NMDAR channel segments forming the extracellular vestibule inferred from the accessibility of substituted cysteines. Neuron, 22(3), 559–570. doi:10.1016/S0896-6273(00)80710-2Find this resource:
Bender, V. A., Bender, K. J., Brasier, D. J., & Feldman, D. E. (2006). Two coincidence detectors for spike timing-dependent plasticity in somatosensory cortex. Journal of Neuroscience, 26(16), 4166–4177. doi:10.1523/JNEUROSCI.0176-06.2006Find this resource:
Benke, T. A., Luthi, A., Isaac, J. T., & Collingridge, G. L. (1998). Modulation of AMPA receptor unitary conductance by synaptic activity. Nature, 393(6687), 793–797. doi:10.1038/31709Find this resource:
Bidoret, C., Ayon, A., Barbour, B., & Casado, M. (2009). Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule. Proceedings of the National Academy of Sciences of the United States of America, 106(33), 14126–14131. doi:10.1073/pnas.0904284106Find this resource:
Blaustein, M. P., & Lederer, W. J. (1999). Sodium/calcium exchange: Its physiological implications. Physiological Reviews, 79(3), 763–854. doi:10.1152/physrev.1918.104.22.1683Find this resource:
Bliss, T. V., & Gardner-Medwin, A. R. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path. Journal of Physiology, 232(2), 357–374.Find this resource:
Bouvier, G., Bidoret, C., Casado, M., & Paoletti, P. (2015). Presynaptic NMDA receptors: Roles and rules. Neuroscience, 311, 322–340. doi:10.1016/j.neuroscience.2015.10.033Find this resource:
Brasier, D. J., & Feldman, D. E. (2008). Synapse-specific expression of functional presynaptic NMDA receptors in rat somatosensory cortex. Journal of Neuroscience, 28(9), 2199–2211. doi:10.1523/JNEUROSCI.3915-07.2008Find this resource:
Burkhardt, P. (2015). The origin and evolution of synaptic proteins—Choanoflagellates lead the way. Journal of Experimental Biology, 218(Pt 4), 506–514. doi:10.1242/jeb.110247Find this resource:
Chen, G. Q., Cui, C., Mayer, M. L., & Gouaux, E. (1999). Functional characterization of a potassium-selective prokaryotic glutamate receptor. Nature, 402(6763), 817–821. doi:10.1038/45568Find this resource:
Chen, L., & Huang, L. Y. (1992). Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature, 356(6369), 521–523. doi:10.1038/356521a0Find this resource:
Choi, D. W. (1985). Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neuroscience Letters, 58(3), 293–297.Find this resource:
Ciabarra, A. M., Sullivan, J. M., Gahn, L. G., Pecht, G., Heinemann, S., & Sevarino, K. A. (1995). Cloning and characterization of chi-1: A developmentally regulated member of a novel class of the ionotropic glutamate receptor family. Journal of Neuroscience, 15(10), 6498–6508.Find this resource:
Collingridge, G. L., Olsen, R. W., Peters, J., & Spedding, M. (2009). A nomenclature for ligand-gated ion channels. Neuropharmacology, 56(1), 2–5. doi:10.1016/j.neuropharm.2008.06.063Find this resource:
Conti, F., DeBiasi, S., Minelli, A., & Melone, M. (1996). Expression of NR1 and NR2A/B subunits of the NMDA receptor in cortical astrocytes. Glia, 17(3), 254–258. doi:10.1002/(SICI)1098-1136(199607)17:3<254::AID-GLIA7>3.0.CO;2-0Find this resource:
Conti, F., Minelli, A., Molnar, M., & Brecha, N. C. (1994). Cellular localization and laminar distribution of NMDAR1 mRNA in the rat cerebral cortex. Journal of Comparative Neurology, 343(4), 554–565. doi:10.1002/cne.903430406Find this resource:
Corlew, R., Wang, Y., Ghermazien, H., Erisir, A., & Philpot, B. D. (2007). Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression. Journal of Neuroscience, 27(37), 9835–9845. doi:10.1523/JNEUROSCI.5494-06.2007Find this resource:
Crabtree, J. W., Lodge, D., Bashir, Z. I., & Isaac, J. T. (2013). GABAA, NMDA and mGlu2 receptors tonically regulate inhibition and excitation in the thalamic reticular nucleus. European Journal of Neuroscience, 37(6), 850–859. doi:10.1111/ejn.12098Find this resource:
Curtis, D. R., & Watkins, J. C. (1960). The excitation and depression of spinal neurones by structurally related amino acids. Journal of Neurochemistry, 6, 117–141.Find this resource:
De Bortoli, S., Teardo, E., Szabo, I., Morosinotto, T., & Alboresi, A. (2016). Evolutionary insight into the ionotropic glutamate receptor superfamily of photosynthetic organisms. Biophysical Chemistry, 218, 14–26. doi:10.1016/j.bpc.2016.07.004Find this resource:
Dore, K., Aow, J., & Malinow, R. (2015). Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow. Proceedings of the National Academy of Sciences of the United States of America, 112(47), 14705–14710. doi:10.1073/pnas.1520023112Find this resource:
Duguid, I. C., & Smart, T. G. (2004). Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar interneuron–Purkinje cell synapses. Nature Neuroscience, 7(5), 525–533. doi:10.1038/nn1227Find this resource:
Eccles, J. C., Fatt, P., & Koketsu, K. (1954). Cholinergic and inhibitory synapses in a pathway from motor-axon collaterals to motoneurones. Journal of Physiology, 126(3), 524–562.Find this resource:
Ehlers, M. D. (2000). Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron, 28(2), 511–525.Find this resource:
Ehlers, M. D., Fung, E. T., O’Brien, R. J., & Huganir, R. L. (1998). Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. Journal of Neuroscience, 18(2), 720–730.Find this resource:
Ehlers, M. D., Zhang, S., Bernhadt, J. P., & Huganir, R. L. (1996). Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell, 84(5), 745–755.Find this resource:
Eriksson, M., Nilsson, A., Samuelsson, H., Samuelsson, E. B., Mo, L., Akesson, E., … Sundstrom, E. (2007). On the role of NR3A in human NMDA receptors. Physiology & Behavior, 92(1–2), 54–59. doi:10.1016/j.physbeh.2007.05.026Find this resource:
Eriksson, M., Samuelsson, H., Bjorklund, S., Tortosa, E., Avila, J., Samuelsson, E. B., … Sundstrom, E. (2010). MAP1B binds to the NMDA receptor subunit NR3A and affects NR3A protein concentrations. Neuroscience Letters, 475(1), 33–37. doi:10.1016/j.neulet.2010.03.039Find this resource:
Farb, C. R., Aoki, C., & Ledoux, J. E. (1995). Differential localization of NMDA and AMPA receptor subunits in the lateral and basal nuclei of the amygdala: A light and electron microscopic study. Journal of Comparative Neurology, 362(1), 86–108. doi:10.1002/cne.903620106Find this resource:
Feldman, D. E. (2012). The spike-timing dependence of plasticity. Neuron, 75(4), 556–571. doi:10.1016/j.neuron.2012.08.001Find this resource:
Fortin, D. A., Davare, M. A., Srivastava, T., Brady, J. D., Nygaard, S., Derkach, V. A., & Soderling, T. R. (2010). Long-term potentiation–dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I. Journal of Neuroscience, 30(35), 11565–11575. doi:10.1523/JNEUROSCI.1746-10.2010Find this resource:
Fritsch, G., & Hitzig, E. (1870). Über die elektrische Erregbarkeit des Grosshirns. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin, 3, 300–332.Find this resource:
Fulton, J. F. (1940). The central nervous system. Annual Review of Physiology, 2(1), 243–262.Find this resource:
Furukawa, H., & Gouaux, E. (2003). Mechanisms of activation, inhibition and specificity: Crystal structures of the NMDA receptor NR1 ligand-binding core. EMBO Journal, 22(12), 2873–2885.Find this resource:
Gallagher, M., & Nicolle, M. M. (1993). Animal models of normal aging: Relationship between cognitive decline and markers in hippocampal circuitry. Behavioural Brain Research, 57(2), 155–162. doi:10.1016/0166-4328(93)90131-9Find this resource:
Gazzaley, A. H., Siegel, S. J., Kordower, J. H., Mufson, E. J., & Morrison, J. H. (1996). Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys. Proceedings of the National Academy of Sciences of the United States of America, 93(7), 3121–3125.Find this resource:
Glasgow, N. G., Siegler Retchless, B., & Johnson, J. W. (2015). Molecular bases of NMDA receptor subtype-dependent properties. Journal of Physiology, 593(1), 83–95. doi:10.1113/jphysiol.2014.273763Find this resource:
Gottlieb, M., & Matute, C. (1997). Expression of ionotropic glutamate receptor subunits in glial cells of the hippocampal CA1 area following transient forebrain ischemia. Journal of Cerebral Blood Flow & Metabolism, 17(3), 290–300. doi:10.1097/00004647-199703000-00006Find this resource:
Gracy, K. N., & Pickel, V. M. (1995). Comparative ultrastructural localization of the NMDAR1 glutamate receptor in the rat basolateral amygdala and bed nucleus of the stria terminalis. Journal of Comparative Neurology, 362(1), 71–85. doi:10.1002/cne.903620105Find this resource:
Gross, C., Chang, C. W., Kelly, S. M., Bhattacharya, A., McBride, S. M., Danielson, S. W., … Bassell, G. J. (2015). Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Reports, 11(5), 727–736. doi:10.1016/j.celrep.2015.03.060Find this resource:
Gurd, J. W., & Bissoon, N. (1997). The N-methyl-D-aspartate receptor subunits NR2A and NR2B bind to the SH2 domains of phospholipase C-gamma. Journal of Neurochemistry, 69(2), 623–630.Find this resource:
Hamill, O. P., Marty, A., Neher, E., Sakmann, B., & Sigworth, F. J. (1981). Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Archiv, 391(2), 85–100.Find this resource:
Hamilton, N., Vayro, S., Wigley, R., & Butt, A. M. (2010). Axons and astrocytes release ATP and glutamate to evoke calcium signals in NG2-glia. Glia, 58(1), 66–79. doi:10.1002/glia.20902Find this resource:
Han, L., Campanucci, V. A., Cooke, J., & Salter, M. W. (2013). Identification of a single amino acid in GluN1 that is critical for glycine-primed internalization of NMDA receptors. Molecular Brain, 6, 36. doi:10.1186/1756-6606-6-36Find this resource:
Hardingham, N., Wright, N., Dachtler, J., & Fox, K. (2008). Sensory deprivation unmasks a PKA-dependent synaptic plasticity mechanism that operates in parallel with CaMKII. Neuron, 60(5), 861–874. doi:10.1016/j.neuron.2008.10.018Find this resource:
Hayashi, T. (1954). Effects of sodium glutamate on the nervous system. Keio Journal of Medicine, 3, 192–193.Find this resource:
Higley, M. J., & Sabatini, B. L. (2012). Calcium signaling in dendritic spines. Cold Spring Harbor Perspectives in Biology, 4(4), a005686. doi:10.1101/cshperspect.a005686Find this resource:
Hirao, K., Hata, Y., Ide, N., Takeuchi, M., Irie, M., Yao, I., … Takai, Y. (1998). A novel multiple PDZ domain-containing molecule interacting with N-methyl-D-aspartate receptors and neuronal cell adhesion proteins. Journal of Biological Chemistry, 273(33), 21105–21110.Find this resource:
Hollmann, M., & Heinemann, S. (1994). Cloned glutamate receptors. Annual Review of Neuroscience, 17, 31–108. doi:10.1146/annurev.ne.17.030194.000335Find this resource:
Holtmaat, A., & Svoboda, K. (2009). Experience-dependent structural synaptic plasticity in the mammalian brain. Nature Reviews Neuroscience, 10(9), 647–658. doi:10.1038/nrn2699Find this resource:
Hu, C., Chen, W., Myers, S. J., Yuan, H., & Traynelis, S. F. (2016). Human GRIN2B variants in neurodevelopmental disorders. Journal of Pharmacological Sciences, 132(2), 115–121. doi:10.1016/j.jphs.2016.10.002Find this resource:
Huber, K. M., Gallagher, S. M., Warren, S. T., & Bear, M. F. (2002). Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proceedings of the National Academy of Sciences of the United States of America, 99(11), 7746–7750. doi:10.1073/pnas.122205699Find this resource:
Iacobucci, G. J., & Popescu, G. K. (2017). NMDA receptors: Linking physiological output to biophysical operation. Nature Reviews Neuroscience, 18(4), 236–249. doi:10.1038/nrn.2017.24Find this resource:
Inanobe, A., Furukawa, H., & Gouaux, E. (2005). Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. Neuron, 47(1), 71–84.Find this resource:
Jahr, C. E., & Stevens, C. F. (1993). Calcium permeability of the N-methyl-D-aspartate receptor channel in hippocampal neurons in culture. Proceedings of the National Academy of Sciences of the United States of America, 90(24), 11573–11577.Find this resource:
Jahr, C. E., & Stevens, C. F. (1987). Glutamate activates multiple single channel conductances in hippocampal neurons. Nature, 325(6104), 522–525.Find this resource:
Janovjak, H., Sandoz, G., & Isacoff, E. Y. (2011). A modern ionotropic glutamate receptor with a K+ selectivity signature sequence. Nature Communications, 2, 232. doi:10.1038/ncomms1231Find this resource:
Jiang, Y., Puliyappadamba, V. T., Zhang, L., Wu, W., Wali, A., Yaffe, M. B., … Rishi, A. K. (2010). A novel mechanism of cell growth regulation by cell cycle and apoptosis regulatory protein (CARP)-1. Journal of Molecular Signaling, 5, 7. doi:10.1186/1750-2187-5-7Find this resource:
Karadottir, R., Cavelier, P., Bergersen, L. H., & Attwell, D. (2005). NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature, 438(7071), 1162–1166. doi:10.1038/nature04302Find this resource:
Karakas, E., & Furukawa, H. (2014). Crystal structure of a heterotetrameric NMDA receptor ion channel. Science, 344(6187), 992–997. doi:10.1126/science.1251915Find this resource:
Karakas, E., Regan, M. C., & Furukawa, H. (2015). Emerging structural insights into the function of ionotropic glutamate receptors. Trends in Biochemical Sciences, 40(6), 328–337. doi:10.1016/j.tibs.2015.04.002Find this resource:
Karus, C., Mondragao, M. A., Ziemens, D., & Rose, C. R. (2015). Astrocytes restrict discharge duration and neuronal sodium loads during recurrent network activity. Glia, 63(6), 936–957. doi:10.1002/glia.22793Find this resource:
Kelleher, R. J., 3rd, Govindarajan, A., & Tonegawa, S. (2004). Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron, 44(1), 59–73. doi:10.1016/j.neuron.2004.09.013Find this resource:
Kohr, G., Jensen, V., Koester, H. J., Mihaljevic, A. L., Utvik, J. K., Kvello, A., … Hvalby, O. (2003). Intracellular domains of NMDA receptor subtypes are determinants for long-term potentiation induction. Journal of Neuroscience, 23(34), 10791–10799.Find this resource:
Kolodziejczyk, K., Hamilton, N. B., Wade, A., Karadottir, R., & Attwell, D. (2009). The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes. Brain, 132(Pt 6), 1496–1508. doi:10.1093/brain/awp087Find this resource:
Kovalchuk, Y., Eilers, J., Lisman, J., & Konnerth, A. (2000). NMDA receptor–mediated subthreshold Ca2+ signals in spines of hippocampal neurons. Journal of Neuroscience, 20(5), 1791–1799.Find this resource:
Krebs, C., Fernandes, H. B., Sheldon, C., Raymond, L. A., & Baimbridge, K. G. (2003). Functional NMDA receptor subtype 2B is expressed in astrocytes after ischemia in vivo and anoxia in vitro. Journal of Neuroscience, 23(8), 3364–3372.Find this resource:
Kumar, S., Stecher, G., Suleski, M., & Hedges, S. B. (2017). TimeTree: A resource for timelines, timetrees, and divergence times. Molecular Biology and Evolution, 34(7), 1812–1819. doi:10.1093/molbev/msx116Find this resource:
Kuner, T., Wollmuth, L. P., Karlin, A., Seeburg, P. H., & Sakmann, B. (1996). Structure of the NMDA receptor channel M2 segment inferred from the accessibility of substituted cysteines. Neuron, 17(2), 343–352. doi:S0896-6273(00)80165-8Find this resource:
Kurschner, C., Mermelstein, P. G., Holden, W. T., & Surmeier, D. J. (1998). CIPP, a novel multivalent PDZ domain protein, selectively interacts with Kir4.0 family members, NMDA receptor subunits, neurexins, and neuroligins. Molecular and Cellular Neuroscience, 11(3), 161–172. doi:10.1006/mcne.1998.0679Find this resource:
Kutsuwada, T., Sakimura, K., Manabe, T., Takayama, C., Katakura, N., Kushiya, E., … Mishina, M. (1996). Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron, 16(2), 333–344.Find this resource:
Lampinen, M., Pentikainen, O., Johnson, M. S., & Keinanen, K. (1998). AMPA receptors and bacterial periplasmic amino acid–binding proteins share the ionic mechanism of ligand recognition. EMBO Journal, 17(16), 4704–4711. doi:10.1093/emboj/17.16.4704Find this resource:
Larsen, R. S., Corlew, R. J., Henson, M. A., Roberts, A. C., Mishina, M., Watanabe, M., … Philpot, B. D. (2011). NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nature Neuroscience, 14(3), 338–344. doi:10.1038/nn.2750Find this resource:
Larsen, R. S., Smith, I. T., Miriyala, J., Han, J. E., Corlew, R. J., Smith, S. L., & Philpot, B. D. (2014). Synapse-specific control of experience-dependent plasticity by presynaptic NMDA receptors. Neuron, 83(4), 879–893. doi:10.1016/j.neuron.2014.07.039Find this resource:
Laube, B., Kuhse, J., & Betz, H. (1998). Evidence for a tetrameric structure of recombinant NMDA receptors. Journal of Neuroscience, 18(8), 2954–2961.Find this resource:
Lee, C. H., Lu, W., Michel, J. C., Goehring, A., Du, J., Song, X., & Gouaux, E. (2014). NMDA receptor structures reveal subunit arrangement and pore architecture. Nature, 511(7508), 191–197. doi:10.1038/nature13548Find this resource:
Lee, M. C., Ting, K. K., Adams, S., Brew, B. J., Chung, R., & Guillemin, G. J. (2010). Characterisation of the expression of NMDA receptors in human astrocytes. PLoS One, 5(11), e14123. doi:10.1371/journal.pone.0014123Find this resource:
Lester, R. A., Clements, J. D., Westbrook, G. L., & Jahr, C. E. (1990). Channel kinetics determine the time course of NMDA receptor–mediated synaptic currents. Nature, 346(6284), 565–567.Find this resource:
Lester, R. A., & Jahr, C. E. (1992). NMDA channel behavior depends on agonist affinity. Journal of Neuroscience, 12(2), 635–643. Retrieved from http://www.jneurosci.org/cgi/reprint/12/2/635Find this resource:
Lin, J. W., Wyszynski, M., Madhavan, R., Sealock, R., Kim, J. U., & Sheng, M. (1998). Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. Journal of Neuroscience, 18(6), 2017–2027.Find this resource:
Lodge, D. (2009). The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology, 56(1), 6–21.Find this resource:
Lucas, D. R., & Newhouse, J. P. (1957). The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Archives of Ophthalmology, 58(2), 193–201.Find this resource:
Luque, J. M., & Richards, J. G. (1995). Expression of NMDA 2B receptor subunit mRNA in Bergmann glia. Glia, 13(3), 228–232. doi:10.1002/glia.440130309Find this resource:
Lynch, G., Larson, J., Kelso, S., Barrionuevo, G., & Schottler, F. (1983). Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature, 305(5936), 719–721.Find this resource:
Ma, C. L., Kelly, J. B., & Wu, S. H. (2002). AMPA and NMDA receptors mediate synaptic excitation in the rat’s inferior colliculus. Hearing Research, 168(1–2), 25–34.Find this resource:
Ma, O. K., & Sucher, N. J. (2004). Molecular interaction of NMDA receptor subunit NR3A with protein phosphatase 2A. Neuroreport, 15(9), 1447–1450. doi:10.1097/01.wnr.0000132773.41720.2dFind this resource:
MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. J., & Barker, J. L. (1986). NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature, 321(6069), 519–522.Find this resource:
Magnusson, K. R., Nelson, S. E., & Young, A. B. (2002). Age-related changes in the protein expression of subunits of the NMDA receptor. Brain Research Molecular Brain Research, 99(1), 40–45.Find this resource:
Makhro, A., Hanggi, P., Goede, J. S., Wang, J., Bruggemann, A., Gassmann, M., … Bogdanova, A. (2013). N-Methyl-D-aspartate receptors in human erythroid precursor cells and in circulating red blood cells contribute to the intracellular calcium regulation. American Journal of Physiology Cell Physiology, 305(11), C1123–C1138. doi:10.1152/ajpcell.00031.2013Find this resource:
Makhro, A., Wang, J., Vogel, J., Boldyrev, A. A., Gassmann, M., Kaestner, L., & Bogdanova, A. (2010). Functional NMDA receptors in rat erythrocytes. American Journal of Physiology Cell Physiology, 298(6), C1315–C1325. doi:10.1152/ajpcell.00407.2009Find this resource:
Maki, B. A., Aman, T. K., Amico-Ruvio, S. A., Kussius, C. L., & Popescu, G. K. (2012). C-terminal domains of N-methyl-D-aspartic acid receptor modulate unitary channel conductance and gating. Journal of Biological Chemistry, 287(43), 36071–36080. doi:10.1074/jbc.M112.390013Find this resource:
Maki, B. A., & Popescu, G. K. (2014). Extracellular Ca2+ ions reduce NMDA receptor conductance and gating. Journal of General Physiology, 144(5), 379–392. doi:10.1085/jgp.201411244Find this resource:
Malenka, R. C. (1994). Synaptic plasticity in the hippocampus: LTP and LTD. Cell, 78(4), 535–538.Find this resource:
Mameli, M., Carta, M., Partridge, L. D., & Valenzuela, C. F. (2005). Neurosteroid-induced plasticity of immature synapses via retrograde modulation of presynaptic NMDA receptors. Journal of Neuroscience, 25(9), 2285–2294. doi:10.1523/JNEUROSCI.3877-04.2005Find this resource:
Maneshi, M. M., Maki, B., Gnanasambandam, R., Belin, S., Popescu, G. K., Sachs, F., & Hua, S. Z. (2017). Mechanical stress activates NMDA receptors in the absence of agonists. Scientific Reports, 7, 39610. doi:10.1038/srep39610Find this resource:
Manning, S. M., Talos, D. M., Zhou, C., Selip, D. B., Park, H. K., Park, C. J., … Jensen, F. E. (2008). NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia. Journal of Neuroscience, 28(26), 6670–6678. doi:10.1523/JNEUROSCI.1702-08.2008Find this resource:
Mano, I., & Teichberg, V. I. (1998). A tetrameric subunit stoichiometry for a glutamate receptor-channel complex. Neuroreport, 9(2), 327–331.Find this resource:
Mayer, M. L., & Westbrook, G. L. (1987). Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones. Journal of Physiology, 394, 501–527.Find this resource:
McFeeters, R. L., & Oswald, R. E. (2002). Structural mobility of the extracellular ligand-binding core of an ionotropic glutamate receptor. Analysis of NMR relaxation dynamics. Biochemistry, 41(33), 10472–10481.Find this resource:
McGuinness, L., Taylor, C., Taylor, R. D., Yau, C., Langenhan, T., Hart, M. L., … Emptage, N. J. (2010). Presynaptic NMDARs in the hippocampus facilitate transmitter release at theta frequency. Neuron, 68(6), 1109–1127. doi:10.1016/j.neuron.2010.11.023Find this resource:
McLysaght, A., Hokamp, K., & Wolfe, K. H. (2002). Extensive genomic duplication during early chordate evolution. Nature Genetics, 31(2), 200–204. doi:10.1038/ng884Find this resource:
Meldrum, B. S. (2000). Glutamate as a neurotransmitter in the brain: Review of physiology and pathology. Journal of Nutrition, 130(4S Suppl.), 1007S–1015S.Find this resource:
Micu, I., Jiang, Q., Coderre, E., Ridsdale, A., Zhang, L., Woulfe, J., … Stys, P. K. (2006). NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature, 439(7079), 988–992. doi:10.1038/nature04474Find this resource:
Mondragao, M. A., Schmidt, H., Kleinhans, C., Langer, J., Kafitz, K. W., & Rose, C. R. (2016). Extrusion versus diffusion: Mechanisms for recovery from sodium loads in mouse CA1 pyramidal neurons. Journal of Physiology, 594(19), 5507–5527. doi:10.1113/JP272431Find this resource:
Mori, H., Manabe, T., Watanabe, M., Satoh, Y., Suzuki, N., Toki, S., … Mishina, M. (1998). Role of the carboxy-terminal region of the GluR epsilon2 subunit in synaptic localization of the NMDA receptor channel. Neuron, 21(3), 571–580.Find this resource:
Moriyoshi, K., Masu, M., Ishii, T., Shigemoto, R., Mizuno, N., & Nakanishi, S. (1991). Molecular cloning and characterization of the rat NMDA receptor. Nature, 354(6348), 31–37.Find this resource:
Mulkey, R. M., Endo, S., Shenolikar, S., & Malenka, R. C. (1994). Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature, 369(6480), 486–488. doi:10.1038/369486a0Find this resource:
Murthy, V. N., Sejnowski, T. J., & Stevens, C. F. (2000). Dynamics of dendritic calcium transients evoked by quantal release at excitatory hippocampal synapses. Proceedings of the National Academy of Sciences of the United States of America, 97(2), 901–906.Find this resource:
Murugan, M., Sivakumar, V., Lu, J., Ling, E. A., & Kaur, C. (2011). Expression of N-methyl D-aspartate receptor subunits in amoeboid microglia mediates production of nitric oxide via NF-kappaB signaling pathway and oligodendrocyte cell death in hypoxic postnatal rats. Glia, 59(4), 521–539. doi:10.1002/glia.21121Find this resource:
Nabavi, S., Kessels, H. W., Alfonso, S., Aow, J., Fox, R., & Malinow, R. (2013). Metabotropic NMDA receptor function is required for NMDA receptor–dependent long-term depression. Proceedings of the National Academy of Sciences of the United States of America, 110(10), 4027–4032. doi:10.1073/pnas.1219454110Find this resource:
Ngo-Anh, T. J., Bloodgood, B. L., Lin, M., Sabatini, B. L., Maylie, J., & Adelman, J. P. (2005). SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nature Neuroscience, 8(5), 642–649.Find this resource:
Niere, F., Wilkerson, J. R., & Huber, K. M. (2012). Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression. Journal of Neuroscience, 32(17), 5924–5936. doi:10.1523/JNEUROSCI.4650-11.2012Find this resource:
Nishi, M., Hinds, H., Lu, H. P., Kawata, M., & Hayashi, Y. (2001). Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner. Journal of Neuroscience, 21(23), RC185.Find this resource:
Nong, Y., Huang, Y. Q., Ju, W., Kalia, L. V., Ahmadian, G., Wang, Y. T., & Salter, M. W. (2003). Glycine binding primes NMDA receptor internalization. Nature, 422(6929), 302–307.Find this resource:
Nowak, L., Bregestovski, P., Ascher, P., Herbet, A., & Prochiantz, A. (1984). Magnesium gates glutamate-activated channels in mouse central neurones Nature, 307(5950), 462–465.Find this resource:
Olney, J. W. (1969). Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science, 164(3880), 719–721.Find this resource:
Panchenko, V. A., Glasser, C. R., & Mayer, M. L. (2001). Structural similarities between glutamate receptor channels and K+ channels examined by scanning mutagenesis. Journal of General Physiology, 117(4), 345–360.Find this resource:
Paoletti, P., Bellone, C., & Zhou, Q. (2013). NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nature Reviews Neuroscience, 14(6), 383–400. doi:10.1038/nrn3504Find this resource:
Paton, W. D. (1959). Mechanisms of transmission in the central nervous system. Anaesthesia, 14(1), 3–27.Find this resource:
Popescu, G. (2005). Principles of N-methyl-D-aspartate receptor allosteric modulation. Molecular Pharmacology, 68(4), 1148–1155. doi:10.1124/mol.105.013896Find this resource:
Popescu, G. K. (2012). Modes of glutamate receptor gating. Journal of Physiology, 590(1), 73–91. doi:10.1113/jphysiol.2011.223750Find this resource:
Quiocho, F. A., Phillips, G. N., Jr., Parsons, R. G., & Hogg, R. W. (1974). Letter: Crystallographic data of an L-arabinose-binding protein from Escherichia coli. Journal of Molecular Biology, 86(2), 491–493.Find this resource:
Ramon y Cajal, S. (1906). The structures and connections of neurons. Amsterdam, the Netherlands: Elsevier. (Reprinted 1967)Find this resource:
Rodriguez-Moreno, A., Gonzalez-Rueda, A., Banerjee, A., Upton, A. L., Craig, M. T., & Paulsen, O. (2013). Presynaptic self-depression at developing neocortical synapses. Neuron, 77(1), 35–42. doi:10.1016/j.neuron.2012.10.035Find this resource:
Rose, C. R., & Konnerth, A. (2001). NMDA receptor-mediated Na+ signals in spines and dendrites. Journal of Neuroscience, 21(12), 4207–4214.Find this resource:
Rosenmund, C., Stern-Bach, Y., & Stevens, C. F. (1998). The tetrameric structure of a glutamate receptor channel. Science, 280(5369), 1596–1599.Find this resource:
Ryan, T. J., Emes, R. D., Grant, S. G., & Komiyama, N. H. (2008). Evolution of NMDA receptor cytoplasmic interaction domains: Implications for organisation of synaptic signalling complexes. BMC Neuroscience, 9, 6. doi:10.1186/1471-2202-9-6Find this resource:
Ryan, T. J. & Grant, S. G. (2009). The origin and evolution of synapses. Nature Reviews Neuroscience, 10(10), 701–712. doi:10.1038/nrn2717Find this resource:
Ryan, T. J., Kopanitsa, M. V., Indersmitten, T., Nithianantharajah, J., Afinowi, N. O., Pettit, C., … Komiyama, N. H. (2013). Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior. Nature Neuroscience, 16(1), 25–32. doi:10.1038/nn.3277Find this resource:
Sabatini, B. L., Oertner, T. G., & Svoboda, K. (2002). The life cycle of Ca2+ ions in dendritic spines. Neuron, 33(3), 439–452.Find this resource:
Sakimura, K., Kutsuwada, T., Ito, I., Manabe, T., Takayama, C., Kushiya, E., … Mishina, M. (1995). Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature, 373(6510), 151–155. doi:10.1038/373151a0Find this resource:
Salter, M. G., & Fern, R. (2005). NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature, 438(7071), 1167–1171. doi:10.1038/nature04301Find this resource:
Sharp, C. D., Fowler, M., Jackson, T. H., Houghton, J., Warren, A., Nanda, A., … Alexander, J. S. (2003). Human neuroepithelial cells express NMDA receptors. BMC Neuroscience, 4, 28. doi:10.1186/1471-2202-4-28Find this resource:
Sheng, M., Cummings, J., Roldan, L. A., Jan, Y. N., & Jan, L. Y. (1994). Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature, 368(6467), 144–147. doi:10.1038/368144a0Find this resource:
Sheng, M., & Sala, C. (2001). PDZ domains and the organization of supramolecular complexes. Annual Review of Neuroscience, 24, 1–29. doi:10.1146/annurev.neuro.24.1.1Find this resource:
Sjostrom, P. J., Turrigiano, G. G., & Nelson, S. B. (2003). Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron, 39(4), 641–654.Find this resource:
Skeberdis, V. A., Chevaleyre, V., Lau, C. G., Goldberg, J. H., Pettit, D. L., Suadicani, S. O., … Zukin, R. S. (2006). Protein kinase A regulates calcium permeability of NMDA receptors. Nature Neuroscience, 9(4), 501–510. doi:10.1038/nn1664Find this resource:
Sobolevsky, A. I., Rosconi, M. P., & Gouaux, E. (2009). X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature, 462(7274), 745–756. doi:10.1038/nature08624Find this resource:
Sprengel, R., Suchanek, B., Amico, C., Brusa, R., Burnashev, N., Rozov, A., … Seeburg, P. H. (1998). Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell, 92(2), 279–289.Find this resource:
Standley, S., Roche, K. W., McCallum, J., Sans, N., & Wenthold, R. J. (2000). PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron, 28(3), 887–898.Find this resource:
Stein, I. S., Gray, J. A., & Zito, K. (2015). Non-ionotropic NMDA receptor signaling drives activity-induced dendritic spine shrinkage. Journal of Neuroscience, 35(35), 12303–12308. doi:10.1523/JNEUROSCI.4289-14.2015Find this resource:
Stern-Bach, Y., Bettler, B., Hartley, M., Sheppard, P. O., O’Hara, P. J., & Heinemann, S. F. (1994). Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins. Neuron, 13(6), 1345–1357. doi:0896-6273(94)90420-0Find this resource:
Sucher, N. J., Akbarian, S., Chi, C. L., Leclerc, C. L., Awobuluyi, M., Deitcher, D. L., … Lipton, S. A. (1995). Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. Journal of Neuroscience, 15(10), 6509–6520.Find this resource:
Sucher, N. J., Yu, E., Chan, S. F., Miri, M., Lee, B. J., Xiao, B., … Jensen, F. E. (2010). Association of the small GTPase Rheb with the NMDA receptor subunit NR3A. Neurosignals, 18(4), 203–209. doi:10.1159/000322206Find this resource:
Sumikawa, K., Houghton, M., Emtage, J. S., Richards, B. M., & Barnard, E. A. (1981). Active multi-subunit ACh receptor assembled by translation of heterologous mRNA in Xenopus oocytes. Nature, 292(5826), 862–864.Find this resource:
Tajima, N., Karakas, E., Grant, T., Simorowski, N., Diaz-Avalos, R., Grigorieff, N., & Furukawa, H. (2016). Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature, 534(7605), 63–68. doi:10.1038/nature17679Find this resource:
Teng, H., Cai, W., Zhou, L., Zhang, J., Liu, Q., Wang, Y., … Sun, Z. (2010). Evolutionary mode and functional divergence of vertebrate NMDA receptor subunit 2 genes. PLoS One, 5(10), e13342. doi:10.1371/journal.pone.0013342Find this resource:
Tigaret, C. M., Olivo, V., Sadowski, J. H., Ashby, M. C., & Mellor, J. R. (2016). Coordinated activation of distinct Ca2+ sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity. Nature Communications, 7, 10289. doi:10.1038/ncomms10289Find this resource:
Toyota, M., Spencer, D., Sawai-Toyota, S., Jiaqi, W., Zhang, T., Koo, A. J., … Gilroy, S. (2018). Glutamate triggers long-distance, calcium-based plant defense signaling. Science, 361(6407), 1112–1115. doi:10.1126/science.aat7744Find this resource:
Traynelis, S. F., Wollmuth, L. P., McBain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., … Dingledine, R. (2010). Glutamate receptor ion channels: Structure, regulation, and function. Pharmacological Reviews, 62(3), 405–496. doi:10.1124/pr.109.002451Find this resource:
van Rossum, D., Kuhse, J., & Betz, H. (1999). Dynamic interaction between soluble tubulin and C-terminal domains of N-methyl-D-aspartate receptor subunits. Journal of Neurochemistry, 72(3), 962–973.Find this resource:
Vissel, B., Krupp, J. J., Heinemann, S. F., & Westbrook, G. L. (2001). A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux. Nature Neuroscience, 4(6), 587–596.Find this resource:
Wang, C., Pralong, W. F., Schulz, M. F., Rougon, G., Aubry, J. M., Pagliusi, S., … Kiss, J. Z. (1996). Functional N-methyl-D-aspartate receptors in O-2A glial precursor cells: A critical role in regulating polysialic acid–neural cell adhesion molecule expression and cell migration. Journal of Cell Biology, 135(6 Pt. 1), 1565–1581.Find this resource:
Watkins, J. C. (2000). l-Glutamate as a central neurotransmitter: Looking back. Biochemical Society Transactions, 28(4), 297–309.Find this resource:
Watkins, J. C., Curtis, D. R., & Brand, S. S. (1977). Phosphonic analogues as antagonists of amino acid excitants. Journal of Pharmacy and Pharmacology, 29(5), 324.Find this resource:
Wechsler, A., & Teichberg, V. I. (1998). Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO Journal, 17(14), 3931–3939. doi:10.1093/emboj/17.14.3931Find this resource:
Wiegert, J. S., & Oertner, T. G. (2013). Long-term depression triggers the selective elimination of weakly integrated synapses. Proceedings of the National Academy of Sciences of the United States of America, 110(47), E4510–E4519. doi:10.1073/pnas.1315926110Find this resource:
Wo, Z. G., & Oswald, R. E. (1994). Transmembrane topology of two kainate receptor subunits revealed by N-glycosylation. Proceedings of the National Academy of Sciences of the United States of America, 91(15), 7154–7158. doi:10.1073/pnas.91.15.7154Find this resource:
Wo, Z. G., & Oswald, R. E. (1995). Unraveling the modular design of glutamate-gated ion channels. Trends in Neurosciences, 18(4), 161–168.Find this resource:
Wood, M. W., VanDongen, H. M., & VanDongen, A. M. (1995). Structural conservation of ion conduction pathways in K channels and glutamate receptors. Proceedings of the National Academy of Sciences of the United States of America, 92(11), 4882–4886.Find this resource:
Wu, S. H., Ma, C. L., & Kelly, J. B. (2004). Contribution of AMPA, NMDA, and GABA(A) receptors to temporal pattern of postsynaptic responses in the inferior colliculus of the rat. Journal of Neuroscience, 24(19), 4625–4634. doi:10.1523/JNEUROSCI.0318-04.2004Find this resource:
Wudick, M. M., Michard, E., Oliveira Nunes, C., & Feijo, J. A. (2018). Comparing plant and animal glutamate receptors: Common traits but different fates? Journal of Experimental Botany, 69(17), 4151–4163. doi:10.1093/jxb/ery153Find this resource:
Wyszynski, M., Kharazia, V., Shanghvi, R., Rao, A., Beggs, A. H., Craig, A. M., … Sheng, M. (1998). Differential regional expression and ultrastructural localization of alpha-actinin-2, a putative NMDA receptor-anchoring protein, in rat brain. Journal of Neuroscience, 18(4), 1383–1392.Find this resource:
Yoshioka, A., Ikegaki, N., Williams, M., & Pleasure, D. (1996). Expression of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor genes in neuroblastoma, medulloblastoma, and other cells lines. Journal of Neuroscience Research, 46(2), 164–178. doi:10.1002/(SICI)1097-4547(19961015)46:2<164::AID-JNR4>3.0.CO;2-FFind this resource:
Yu, X. M., Askalan, R., Keil, G. J., 2nd, & Salter, M. W. (1997). NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science, 275(5300), 674–678.Find this resource:
Yu, X. M., & Salter, M. W. (1998). Gain control of NMDA-receptor currents by intracellular sodium. Nature, 396(6710), 469–474.Find this resource:
Yuzaki, M., & Aricescu, A. R. (2017). A GluD coming-of-age story. Trends in Neurosciences, 40(3), 138–150. doi:10.1016/j.tins.2016.12.004Find this resource:
Zheng, W., Wen, H., Iacobucci, G. J., & Popescu, G. K. (2017). Probing the structural dynamics of the NMDA receptor activation by coarse-grained modeling. Biophysical Journal, 112(12), 2589–2601. doi:10.1016/j.bpj.2017.04.043Find this resource:
Zhou, Q., Homma, K. J., & Poo, M. M. (2004). Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron, 44(5), 749–757. doi:10.1016/j.neuron.2004.11.011Find this resource:
Zukin, R. S., & Bennett, M. V. (1995). Alternatively spliced isoforms of the NMDARI receptor subunit. Trends in Neurosciences, 18(7), 306–313.Find this resource: