Alternative titles; symbols
HGNC Approved Gene Symbol: GRIN1
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38) : 9:137,139,154-137,168,756 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Developmental and epileptic encephalopathy 101 | 619814 | Autosomal recessive | 3 |
| Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant | 614254 | Autosomal dominant | 3 | |
| Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive | 617820 | Autosomal recessive | 3 |
The GRIN1 gene encodes subunit 1 of the N-methyl-D-aspartate (NMDA) receptor, which is a heteromeric glutamate-gated calcium ion channel essential for synaptic function in the brain (summary by Hamdan et al., 2011 and Ohba et al., 2015).
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. Thus, 1 class, the NMDA receptors, have N-methyl-D-aspartate as an agonist. Moriyoshi et al. (1991) cloned and characterized a cDNA encoding the rat NMDA receptor. The protein had a significant sequence similarity to the AMPA/kainate receptors (see 600282) and contained 4 putative transmembrane segments following a large extracellular domain. The NMDA receptor mRNA was expressed in neuronal cells throughout the brain, particularly in the hippocampus, cerebral cortex, and cerebellum. Kumar et al. (1991) isolated and characterized a protein complex of 4 major proteins that represent an intact complex of the NMDA receptor ion channel. Furthermore, they cloned the cDNA for one of the subunits of this receptor complex, the glutamate-binding protein, from rat brain; see 138251.
Karp et al. (1993) cloned a cDNA encoding the key subunit of the human NMDA receptor, NMDAR1. It encodes a 938-amino acid protein which showed high evolutionary conservation in structure and physiologic properties.
The 8 splice variants of vertebrate NR1 have 4 different C-terminal cytoplasmic tails consisting of different combinations of C-terminal cassettes, designated C0, C1, C2, and C2-prime. By functional assays and sequence analysis, Standley et al. (2000) identified an endoplasmic reticulum (ER) retention signal in the C1 cassette. They also found a PDZ-interacting domain in the C2-prime cassette that could mask the ER retention of the C1 cassette and lead to surface expression.
Zimmer et al. (1995) cloned the human NMDAR1 gene and showed that it consists of 21 exons distributed over about 31 kb. Three of the exons that are alternatively spliced in the rat and which produce 8 isoforms in that species were also present in the human sequence. The promoter region contained 2 DNA binding sites for the homeobox proteins 'even-skipped' (see EVX1, 142996 and EVX2, 142991).
Karp et al. (1993) mapped the NMDAR1 gene to 9q34.3 by analysis of blot hybridization of a DNA panel of human/hamster somatic cell hybrids and by fluorescence in situ hybridization (FISH). By the same method, Collins et al. (1993) mapped the NMDAR1 gene to 9q34.3 and Takano et al. (1993) mapped the gene, which they referred to as the zeta-1 subunit, to 9q34. Collins et al. (1993) and Takano et al. (1993) pointed out that the gene is a candidate for the site of the mutation in torsion dystonia (see 128100).
Brett et al. (1994) also mapped the GRIN gene to 9q34.3 by FISH, using a genomic clone. Cutting a panel of genomic DNAs with 20 restriction enzymes, they demonstrated a VNTR sequence 5-prime to the gene that was polymorphic for a number of the enzymes. Using one of these markers for linkage analysis in the CEPH families, the GRIN1 gene was found to be linked to D9S7 with a maximum lod score of 20.09 at zero recombination in males and 0.03% recombination in females.
Following up on the studies in rodents and nonhuman primates (see later) that linked the activity of NMDA receptors within the hippocampus to animals' performance on memory-related tasks, Grunwald et al. (1999) studied whether hippocampal NMDA receptors, most likely within the CA1 region, participate in human verbal memory processes. They presented behavioral, anatomic, and electrophysiologic results indicating that hippocampal NMDA receptors indeed are involved in human memory.
Hardingham et al. (2002) reported that synaptic and extrasynaptic NMDA receptors have opposite effects on CREB (123810) function, gene regulation, and neuronal survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF; 113505) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have antiapoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death.
Sin et al. (2002) used in vivo time-lapse imaging of optic tectal cells in Xenopus laevis tadpoles to demonstrate that enhanced visual activity driven by a light stimulus promotes dendritic arbor growth. The stimulus-induced dendritic arbor growth requires glutamate receptor-mediated synaptic transmission, decreased RhoA (165390) activity, and increased RAC (see 602048) and CDC42 (116952) activity. Sin et al. (2002) concluded that their results delineated a role for Rho GTPases in the structural plasticity driven by visual stimulation in vivo.
Lee et al. (2002) reported that dopamine D1 receptors (126449) modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A and NR2A (138253). While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see 171833)-dependent pathway.
Nong et al. (2003) reported that stimulation of the glycine site of the NMDA receptor initiates signaling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. Glycine binding alone does not cause the receptor to be endocytosed; this requires both glycine and glutamate site activation of NMDARs. The priming effect of glycine is mimicked by the NMDAR glycine site agonist D-serine, and is blocked by competitive glycine site antagonists. Synaptic as well as extrasynaptic NMDARs are primed for internalization by glycine site stimulation. Nong et al. (2003) concluded that their results demonstrated transmembrane signal transduction through activating the glycine site of NMDARs, and elucidated a model for modulating cell-cell communication in the central nervous system.
By examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, Popescu et al. (2004) showed that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predicted that, after binding neurotransmitter, receptors hesitate for approximately 4 milliseconds in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initial fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on the pulse frequency.
Karadottir et al. (2005) demonstrated that precursor, immature, and mature oligodendrocytes in the white matter of the cerebellum and corpus callosum exhibit NMDA-evoked currents, mediated by receptors that are blocked only weakly by magnesium and that may contain NR1, NR2C (138254), and NR3 (see 606650) NMDA receptor subunits. NMDA receptors are present in the myelinating processes of oligodendrocytes, where the small intracellular space could lead to a large rise in intracellular ion concentration in response to NMDA receptor activation. Karadottir et al. (2005) found that simulating ischemia led to development of an inward current in oligodendrocytes, which was partly mediated by NMDA receptors.
Salter and Fern (2005) independently showed NMDA receptor subunit expression on oligodendrocyte processes and the presence of NMDA receptor subunit mRNA in isolated white matter. NR1, NR2A (138253), NR2B (138252), NR2C, NR2D, and NR3A subunits showed clustered expression in cell processes, but NR3B (606651) was absent. During modeled ischemia, NMDA receptor activation resulted in rapid calcium-dependent detachment and disintegration of oligodendroglial processes in the white matter of mice expressing green fluorescent protein (GFP) specifically in oligodendrocytes. This effect occurred at mouse ages corresponding to both the initiation and the conclusion of myelination. NR1 subunits were found mainly in oligodendrocyte processes, whereas AMPA/kainate receptor subunits (see 600282) were found mainly in the somata. Consistent with this observation, injury to the somata was prevented by blocking AMPA/kainate receptors, and preventing injury to oligodendroglial processes required the blocking of NMDA receptors. Salter and Fern (2005) suggested that the presence of NMDA receptors in oligodendrocyte processes may explain why previous studies that focused on the somata did not detect a role for NMDA receptors in oligodendrocyte injury. These NMDA receptors bestow a high sensitivity to acute injury.
Tashiro et al. (2006) developed a retrovirus-mediated single-cell gene knockout technique in mice and showed that the survival of new neurons is competitively regulated by their own NMDA-type glutamate receptor during a short, critical period soon after neuronal birth. This finding indicated that the survival of new neurons and the resulting formation of new circuits are regulated in an input-dependent, cell-specific manner. Therefore, Tashiro et al. (2006) suggested that the circuits formed by new neurons may represent information associated with input activity within a short time window in the critical period. This information-specific addition of new circuits through selective survival or death of new neurons may be a unique attribute of new neurons that enables them to play a critical role in learning and memory.
Micu et al. (2006) showed that NMDA glutamate receptors mediate calcium ion accumulation in central myelin in response to chemical ischemia in vitro. Using 2-photon microscopy, they imaged fluorescence of the calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA/kainate receptor antagonist NBQX completely blocked the ischemic calcium ion increase in oligodendroglial cell bodies, but only modestly reduced the calcium ion increase in myelin. In contrast, the calcium ion increase in myelin was abolished by broad-spectrum NMDA receptor antagonists but not by more selective blockers of NR2A and NR2B subunit-containing receptors. In vitro ischemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits were present for the formation of functional NMDA receptors. Micu et al. (2006) concluded that their data showed that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, the finding that the calcium ion increase is mediated in large part by activation of myelinic NMDA receptors suggested a new mechanism of axomyelinic signaling.
In mice, Clem et al. (2008) examined the effect of ongoing whisker stimulation on synaptic strengthening at layer 4-2/3 synapses in the barrel cortex. Although N-methyl-D-aspartate receptors were required to initiate strengthening, they subsequently suppressed further potentiation at these synapses in vitro and in vivo. Despite this transition, synaptic strengthening continued with additional sensory activity but instead required the activation of metabotropic glutamate receptors (see 604473), suggesting a mechanism by which continued experience can result in increasing synaptic strength over time.
Losonczy et al. (2008) demonstrated that the coupling between local dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons can be modified in a branch-specific manner through an NMDAR-dependent regulation of dendritic Kv4.2 (605410) potassium channels. These data suggested that compartmentalized changes in branch excitability could store multiple complex features of synaptic input, such as their spatiotemporal correlation. Losonczy et al. (2008) proposed that this 'branch strength potentiation' represents a previously unknown form of information storage that is distinct from that produced by changes in synaptic efficacy both at the mechanistic level and in the type of information stored.
Henneberger et al. (2010) demonstrated that clamping internal calcium ion in individual CA1 astrocytes of the hippocampus blocks long-term potentiation (LTP) induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR coagonist sites by D-serine. This LTP blockade can be reversed by exogenous D-serine or glycine, whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. Henneberger et al. (2010) concluded that calcium ion-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.
Using a self-paced operant task in which mice learn to perform a particular sequence of actions to obtain an outcome, Jin and Costa (2010) found neural activity in nigrostriatal circuits specifically signaling the initiation or the termination of each action sequence. This start/stop activity emerged during sequence learning, was specific for particular actions, and did not reflect interval timing, movement speed, or action value. Furthermore, genetically altering the function of striatal circuits by developing a nigrostriatal-specific deletion of the NMDAR1 gene disrupted the development of start/stop activity and selectively impaired sequence learning. Jin and Costa (2010) concluded that these results have important implications for understanding the functional organization of actions and the sequence initiation and termination impairments observed in basal ganglia disorders.
Attwood et al. (2011) demonstrated in mice that the serine protease neuropsin (605644) is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2 (605644)-NMDA receptor interaction, the expression of Fkbp5 (602623) and anxiety-like behavior. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala, causing dissociation of EphB2 from the NR1 subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1 interaction enhances NMDA receptor current, induces Fkpb5 gene expression, and enhances behavioral signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1, resulting in a static EphB2-NR1 interaction, attenuated induction of the Fkbp5 gene, and low anxiety. The behavioral response to stress can be restored by intraamygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wildtype mice. Attwood et al. (2011) concluded that their findings established a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.
Otsu et al. (2019) discovered that GRIN1/GRIN3A (606650) receptors are operational in neurons of the mouse adult medial habenula, an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the medial habenula, glial cells tuned neuronal activity via GRIN1/GRIN3A receptors. Reducing these receptor levels in the medial habenula prevented place-aversion conditioning. Otsu et al. (2019) concluded that their study extended the physiologic and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.
Crystal Structure
Furukawa et al. (2005) reported the crystal structure of the ligand-binding core of NR2A (GRIN2A; 138253) with glutamate and that of the NR1-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defined the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggested a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiologic experiments, confirmed that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyr535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.
Karakas et al. (2011) reported that the GluN1 and GluN2B (138252) amino-terminal domains forms a heterodimer and that phenylethanolamine binds at the interface between GluN1 and GluNB2, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b amino-terminal domain from Xenopus laevis and the GluN2B amino-terminal domain from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B amino-terminal domain, by engineering of an intersubunit disulfide bond, markedly decreased sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B amino-terminal domain is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. Karakas et al. (2011) concluded that their findings paved the way for improving the design of subtype-specific compounds with therapeutic value for neurologic disorders and diseases.
Cryoelectron Microscopy
Lu et al. (2017) reported structures of the triheteromeric GluN1 (GRIN1)/GluN2A (GRIN2A)/GluN2B (GRIN2B) receptor in the absence or presence of the GluN2B-specific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt 'closed' and 'open' clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. Lu et al. (2017) concluded that the triheteromeric NMDAR structures provided the first view of the most common NMDA receptor assembly and showed how incorporation of 2 different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.
Neurodevelopmental Disorder with or without Hyperkinetic Movements and Seizures, Autosomal Dominant
In 2 unrelated patients with autosomal dominant neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSD; 614254), Hamdan et al. (2011) identified 2 de novo heterozygous mutations in the GRIN1 gene (138249.0001 and 138249.0002), Both mutations resulted in decreased efficacy of the NMDAR channel.
In 4 unrelated children with NDHMSD, Ohba et al. (2015) identified 4 different de novo heterozygous missense mutations at highly conserved residues in the GRIN1 gene (see, e.g., 138249.0003 and 138249.0005). The mutations were found by exome sequencing of 88 patients with early-onset epileptic encephalopathy and confirmed by Sanger sequencing. One of the patients was somatic mosaic for the mutation, with a mutant allele frequency ranging from 13.4 to 19.7% in various tissue samples. Functional studies of the variant and studies of patient cells were not performed, but structural analysis predicted that the mutations would impair NMDAR channel function.
Lemke et al. (2016) reported 14 unrelated patients with NDHMSD who carried heterozygous missense mutations in the GRIN1 gene and (see, e.g., 138249.0006 and 138249.0007) and reevaluated 9 previously reported patients with a similar phenotype and similar missense mutations. Twenty-two of the 23 mutations were demonstrated to occur de novo; parental DNA from 1 patient was not available. The patients were ascertained from several diagnostic and research studies, and the mutations were found by next-generation sequencing methods. There were 16 different mutations identified in the 23 novel and published cases. All missense mutations clustered within or in close proximity to the transmembrane domains forming the intrinsic ion channel pore of the receptor, which shows a high level of conservation in different species. Electrophysiologic studies in Xenopus oocytes showed variable detrimental effects of the mutations on channel function when coexpressed with wildtype GRIN2B (138252). Some mutants resulted in a complete loss of channel function with no response to glutamate or glycine, whereas others resulted in partial loss of channel function with decreased affinity for glutamate and glycine compared to wildtype. Two mutations (A645S and R844C) showed no significant effects on current or agonist affinity, suggesting that they may alter receptor function through other mechanisms. Lemke et al. (2016) concluded that the disease mechanism is loss of NMDAR receptor function with a dominant-negative effect in patients with de novo heterozygous GRIN1 missense mutations, underscoring the importance of receptor subunits in neurodevelopment.
In 2 unrelated patients with NDHMSD, Chen et al. (2017) identified 2 different de novo heterozygous mutations in the GRIN1 gene, both of which resulted in the same G620R substitution (138249.0011 and 138249.0012). In vitro functional expression assays showed that the G620R mutation caused a significant decrease in the potency of glutamate and glycine and a decrease in current amplitude when coexpressed with both GRIN2A (138253) and GRIN2B (138252). G620R/GRIN2A complexes showed a mild reduction in trafficking of NMDAR to the cell surface, a strong decrease in sensitivity to magnesium inhibition, and enhanced sensitivity to zinc. G620R/GRIN2B complexes showed significantly reduced delivery of NMDAR protein to the cell surface and altered electrophysiology in response to extracellular modulators. Chen et al. (2017) concluded that the neurodevelopmental deficits resulted from complex effects on channel function, with a combination of decreased presence of G620R/GRIN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of G620R-containing NMDARs after birth.
Neurodevelopmental Disorder with or without Hyperkinetic Movements and Seizures, Autosomal Recessive
In 2 sibs, born of consanguineous parents (family 1), with autosomal recessive neurodevelopmental disorder with hyperkinetic movements and with or without seizures (NDHMSR; 617820), Lemke et al. (2016) identified a homozygous missense mutation in the GRIN1 gene (R217W; 138249.0008). The mutation, which was found by next-generation sequencing approaches, segregated with the disorder in the family. In vitro functional expression studies showed that the R217W mutation did not affect channel current, but resulted in a significant increase in zinc inhibition when coexpressed with wildtype GRIN2A (138253). The carrier parents were unaffected, suggesting that haploinsufficiency for GRIN1 can be tolerated and is not pathogenic.
In 2 sibs, born of consanguineous Moroccan parents, with autosomal recessive neurodevelopmental disorder with hyperkinetic movements with or without seizures, Rossi et al. (2017) identified a homozygous missense mutation in the GRIN1 gene (D227H; 138249.0010). The mutation, which was found by massive parallel sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but Rossi et al. (2017) hypothesized that missense variants in the amino-terminal domain of the protein may be hypomorphic and pathogenic in the homozygous state, whereas the functionality of 1 allele, as observed in the parents, is sufficient to avoid clinical expression in heterozygous carriers. Another homozygous missense mutation in the amino-terminal domain (R217W; 138249.0008) was identified in 2 brothers with NDHMSR (Lemke et al., 2016).
Developmental and Epileptic Encephalopathy 101
In 3 infants (family 5) with developmental and epileptic encephalopathy-101 (DEE101; 619814), Lemke et al. (2016) identified a homozygous nonsense mutation in the GRIN1 gene (Q556X; 138249.0009). In vitro functional expression studies showed that the mutation rendered the channel nonfunctional, with no response to glycine or glutamate, resulting in a complete loss of function. The unaffected parents were heterozygous for the mutation, suggesting that heterozygous truncating mutations and haploinsufficiency for GRIN1 does not result in a neurologic phenotype.
In a Pakistani infant, born to consanguineous parents, with DEE101, Blakes et al. (2022) identified a homozygous splice site mutation in the GRIN1 gene (138249.0013). Functional studies were not reported.
Associations Pending Confirmation
Rice et al. (2001) identified several polymorphisms in the GRIN1 gene, including a 1001G-C change in the promoter region (rs1114620), in patients with schizophrenia (181500). Begni et al. (2003) investigated the potential role of the 1001G-C polymorphism in susceptibility to schizophrenia (181500) in a study of 139 Italian patients with schizophrenia and 145 healthy control subjects. Sequence analysis revealed that the C allele may alter the consensus sequence for the transcription factor NF-kappa-B (164011) and that the frequency of this allele was higher in patients than in control subjects (p = 0.0085). The genotype distribution of the C allele was also different, with p = 0.034; if the C allele was considered dominant, the difference was more significant, p = 0.0137. Begni et al. (2003) concluded that GRIN1 is a good candidate gene for susceptibility to schizophrenia.
Zhao et al. (2006) genotyped 5 SNPs in GRIN1 in 2,455 schizophrenic and nonschizophrenic Han Chinese subjects, including population- and family-based samples, and performed case-control and transmission disequilibrium test (TDT) analyses. A highly significant association with schizophrenia was detected at the 5-prime end of GRIN1. Analysis of single variants and multiple-locus haplotypes indicated that the association is mainly generated by rs11146020 (case-control study: p = 0.0000013, OR = 0.61, 95% CI = 0.50-0.74; TDT: p = 0.0019, T/NT = 79/123).
It has long been hypothesized that memory storage in the mammalian brain involves modifications of the synaptic connections between neurons. Hebb (1949) introduced an important principle, known as the Hebb rule, that of 'correlated activity': when the presynaptic and postsynaptic neurons are active simultaneously, their connections become strengthened. Tsien et al. (1996) reviewed reports suggesting that NMDARs can implement the Hebb rule at the synaptic level and thus are crucial synaptic elements for the induction of activity-dependent synaptic plasticity. Long-term potentiation (LTP) is a widely used paradigm for increasing synaptic efficiency, and its induction requires, in at least one of its forms, the activation of NMDARs. The hippocampus is the most intensely studied region for the importance of NMDARs in synaptic plasticity and memory. Lesions of the hippocampus in humans and other mammals produce severe amnesia for certain memories. Disruption of NMDARs in hippocampus leads to blockade of synaptic plasticity and also to memory malfunction. Tsien et al. (1996) produced a mouse strain in which the deletion of the Nmdar1 gene was restricted to the CA1 pyramidal cells of the hippocampus by use of a method that allowed CA1-restricted gene knockout. The mutant mice grew into adulthood without obvious abnormalities. Adult mice lacked NMDA receptor-mediated synaptic currents and long term potentiation in the CA1 synapses and exhibited impaired spatial memory but unimpaired nonspatial learning. Their results strongly suggested that activity-dependent modifications of CA1 synapses, mediated by NMDA receptors, play an essential role in the acquisition of spatial memories.
In further studies of the CA1-specific Nmdar1 knockout mice, McHugh et al. (1996) applied multiple electrode recording techniques to freely behaving mice. They discovered that although the CA1 pyramidal cells of these mice retain place-related activities, there is a significant decrease in the spatial specificity of individual place fields. They also found a striking deficit in the coordinated firing of pairs of neurons tuned to similar spatial locations. Pairs had uncorrelated firing even if their fields overlapped.
Rotenberg et al. (1996) studied the effects of an activated form (CaMKII-Asp286) of Ca(2+)/calmodulin-dependent protein kinase (114078) in transgenic mice. Normally, spatial location is encoded in the pattern of firing of individual hippocampal pyramidal cells. When an animal moves around in a familial environment, different place cells in the hippocampus fire as the animal enters different regions of space. Rotenberg et al. (1996) found that the CaMKII-Asp286 transgenic mice lacked low frequency LTP and did not form stable 'place cells' in the CA1 region of the hippocampus. Behaviorally, the mice were impaired in spatial memory tasks.
By insertion of a neomycin resistance gene into intron 20 of the Nmdar1 gene, Mohn et al. (1999) generated mice expressing only 5% of normal levels of the essential Nmdar1 subunit. Unlike Nmdar1 null mice, these mice survived to adulthood and displayed behavioral abnormalities, including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations were similar to those observed in pharmacologically induced animal models of schizophrenia and could be ameliorated by treatment with haloperidol or clozapine, antipsychotic drugs that antagonize dopaminergic and serotonergic receptors. These findings supported a model in which reduced NMDA receptor activity results in schizophrenic-like behavior and revealed how pharmacologic manipulation of monoaminergic pathways can affect this phenotype.
During et al. (2000) generated a recombinant adeno-associated virus containing the NMDAR1 subunit and administered this vector orally to rats. This vaccine generated polyclonal autoantibodies that targeted the NMDAR1 subunit of the N-methyl-D-aspartate receptor. Transgene expression persisted for at least 5 months and was associated with a robust humoral response in the absence of a significant cell-mediated response. The single-dose vaccine was associated with strong antiepileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination. During et al. (2000) concluded that a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurologic disorders.
Iwasato et al. (2000) generated mice in which the deletion of the Nmdar1 gene is restricted to excitatory cortical neurons, and demonstrated that sensory periphery-related patterns develop normally in the brainstem and thalamic somatosensory relay stations of these mice. In the somatosensory cortex, thalamocortical afferents corresponding to large whiskers formed patterns and display critical period plasticity, but their patterning was not as distinct as that seen in the cortex of normal mice. Other thalamocortical patterns corresponding to sinus hairs and digits were mostly absent. The cellular aggregates known as barrels and barrel boundaries did not develop, even at sites where thalamocortical afferents cluster. Iwasato et al. (2000) concluded that cortical NMDARs are essential for the aggregation of layer IV cells into barrels and for development of the full complement of thalamocortical patterns.
The hippocampal CA1 region is crucial for converting new memories into long-term memories, a process believed to continue for weeks after initial learning. Shimizu et al. (2000) developed an inducible, reversible, and CA1-specific knockout technique to switch an NMDA receptor function off or on in CA1 during the consolidation period in mice. The data indicated that memory consolidation depends on the reactivation of the NMDA receptor, possibly to reinforce site-specific synaptic modifications to consolidate memory traces. Shimizu et al. (2000) suggested that such a synaptic reinforcement process may also serve as a cellular means by which the new memory is transferred from the hippocampus to the cortex for permanent storage.
Nakazawa et al. (2002) generated and analyzed a genetically engineered mouse strain in which the NMDA receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. Nakazawa et al. (2002) concluded that their results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall. Nakazawa et al. (2003) found that the mouse strain generated by Nakazawa et al. (2002) showed impaired rapid acquisition of spatial memory in the delayed matching-to-place version of the Morris water maze task in which the animals are tested with novel locations of a hidden platform. However, the animals were normal in recalling the memory of familiar platform locations. Compared to control mice, the mutant mice had larger CA1 place field sizes in novel environments, but not in familiar environments. The authors concluded that CA3 NMDA receptors play a role in rapid hippocampal encoding of novel information for the learning of a one-time experience.
Cui et al. (2004) generated mice in which Nr1 can be temporarily switched off in the forebrain by doxycycline treatment. Nine months after conditioned fear training, untreated mice showed normal memory retention. However, mice with transient inactivation of Nr1 for 30 days starting at 6 months after initial training had defective memory retention at 9 months. In subsequent tasks after the 9-month test period, these mice showed normal learning and memory function. Cui et al. (2004) suggested that the NMDA receptor is required for the ongoing preservation of long-term memory storage.
Dang et al. (2006) observed that mice with striatum-specific Nmdar1 knockout using the CRE-loxP system showed impaired motor learning on the rotarod test compared to wildtype mice. No differences were observed between the 2 groups in inhibitory avoidance tests thought to involve the amygdala and hippocampus. In vitro studies of neurons from these mice showed absence of Nmdar-mediated currents, disruption of dorsal striatal long-term potentiation, and disruption of ventral striatal long-term depression. The findings suggested that the striatum is involved in a subset of motor learning.
In a 10-year-old girl with autosomal dominant neurodevelopmental disorder without hyperkinetic movements or seizures (NDHMSD; 614254), Hamdan et al. (2011) identified a de novo heterozygous c.1984G-A transition (c.1984G-A, NM_007327.3) in the GRIN1 gene, resulting in a glu662-to-lys (E662K) substitution. The patient had a normal neural exam and normal brain imaging by CT scan, and there was no evidence of epilepsy. Functional studies in Xenopus oocytes showed that this mutation produced a significant increase in NMDAR-induced calcium currents; excessive calcium influx through NMDAR could lead to excitotoxic neuronal cell damage. This mutation was not identified in 285 healthy controls.
Lemke et al. (2016) noted that the patient reported by Hamdan et al. (2011) with the E662K mutation had the mildest phenotype when compared to 22 other patients with GRIN1 mutations. E662K is located in the S2 ligand-binding domain; this was the only patient reported with a mutation in this domain.
In a 7.5-year-old boy with autosomal dominant neurodevelopmental disorder without hyperkinetic movements but with seizures (NDHMSD; 614254), Hamdan et al. (2011) identified a de novo heterozygous duplication of 3 nucleotides between positions 1679 and 1681 in the GRIN1 cDNA (c.1679_1681dup, NM_007327.3), resulting in duplication of serine at codon 560 (ser560dup). The mutation was not seen in 285 control chromosomes. The patient had partial complex seizures, hypotonia, and normal brain imaging by MRI. Functional studies showed near abolition of the activity of the NMDA receptor in Xenopus oocytes. The duplication at codon 560 altered the 3-dimensional structure at the receptor's channel pore entrance.
In a 7-year-old boy (patient 1) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements and seizures (NDHMSD; 614254), Ohba et al. (2015) identified a de novo heterozygous c.1656C-G transversion (c.1656C-G, NM_007327.3) in the GRIN1 gene, resulting in an asp552-to-glu (D552E) substitution at a conserved residue in the pre-M1 domain, which bridges the ligand-binding domain and the transmembrane domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138) or Exome Sequencing Project databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed.
Lemke et al. (2016) identified a D552E substitution in another patient that resulted from a different nucleotide change (138249.0004).
In a 10-year-old girl (patient 3) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements and seizures (NDHMSD; 614254), as well as cortical visual impairment, Lemke et al. (2016) identified a heterozygous de novo c.1656C-A transversion in the GRIN1 gene (c.1656C-A, NM_007327) that resulted in an asp-to-glu substitution at codon 552 (D552E). Functional studies of the variant and studies of patient cells were not performed.
Ohba et al. (2015) identified a D552E substitution in another patient that resulted from a different nucleotide change (138249.0003).
In a 5-year-old boy (patient 2) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements and seizures (NDHMSD; 614254), Ohba et al. (2015) identified a de novo heterozygous c.1950C-G transversion (c.1950C-G, NM_007327.3) in the GRIN1 gene, resulting in an asn650-to-lys (N650K) substitution at a conserved residue in the pore-lining M3 domain, which is crucial to the gating function of the NMDA receptor. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138) or Exome Sequencing Project databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed.
In 3 unrelated patients (patients 21, 22, and 23) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements and with or without seizures (NDHMSD; 614254), Lemke et al. (2016) identified a heterozygous c.2479G-A transition (c.2479G-A, NM_007327) in the GRIN1 gene, resulting in a gly827-to-arg (G827R) substitution at a conserved residue in the M4 domain. The mutations were found by next-generation sequencing approaches and confirmed by Sanger sequencing. The mutation was proven de novo in 2 patients; parental DNA from patient 22 was not available for segregation analysis. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in a complete loss of receptor function, with no response to glutamate or glycine; studies showed a dominant-negative effect of the G827R mutant when coexpressed with the wildtype GRIN2B (138252).
In 2 unrelated patients (patients 19 and 20) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements and without seizures (NDHMSD; 614254), Lemke et al. (2016) identified a de novo heterozygous c.2449T-C transition (c.2449T-C, NM_007327) in the GRIN1 gene, resulting in a phe817-to-leu (F817L) substitution at a conserved residue in the M4 domain. The mutations were found by next-generation sequencing approaches and confirmed by Sanger sequencing; patient 20 had previously been reported. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in a partial loss of receptor function, with decreased affinity for glutamate and glycine; studies showed a dominant-negative effect of the F817L mutant when coexpressed with wildtype GRIN2B (138252). Molecular modeling predicted that the mutation would destabilize the assembly of NMDAR.
In 2 sibs, born of consanguineous parents (family 1), with autosomal recessive neurodevelopmental disorder with hyperkinetic movements with or without seizures (NDHMSR; 617820), Lemke et al. (2016) identified a homozygous c.649C-T transition (c.649C-T, NM_007327) in the GRIN1 gene, resulting in an arg217-to-trp (R217W) substitution at a conserved residue in the zinc-binding domain in the N terminus. The mutation, which was found by next-generation sequencing approaches, segregated with the disorder in the family, and was not found in the ExAC database. In vitro functional expression studies showed that the R217W mutation did not affect channel current, but resulted in a significant increase in zinc inhibition when coexpressed with wildtype GRIN2A (138253). The carrier parents were unaffected, suggesting that haploinsufficiency for GRIN1 can be tolerated and is not pathogenic.
In 3 infants (family 5) with developmental and epileptic encephalopathy-101 (DEE101; 619814), Lemke et al. (2016) identified a homozygous c.1666C-T transition (c.1666C-T, NM_007327) in the GRIN1 gene, resulting in a gln556-to-ter (Q556X) substitution in the pre-M1 domain. Homozygous truncating mutations were not observed in the ExAC database. In vitro functional expression studies showed that the mutation rendered the channel nonfunctional, with no response to glycine or glutamate, resulting in a complete loss of function. The unaffected parents were heterozygous for the mutation, suggesting that heterozygous truncating mutations and haploinsufficiency for GRIN1 does not result in a neurologic phenotype.
In 2 sibs, born of consanguineous Moroccan parents, with autosomal recessive neurodevelopmental disorder with hyperkinetic movements with or without seizures (NDHMSR; 617820), Rossi et al. (2017) identified a homozygous c.679G-C transversion (c.679G-C, NM_007327.3) in the GRIN1 gene, resulting in an asp227-to-his (D227H) substitution at a conserved residue in the zinc-binding site within the amino-terminal domain. The mutation, which was found by massive parallel sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the Exome Variant Server, 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed, but Rossi et al. (2017) hypothesized that missense variants in the amino-terminal domain of the protein may be hypomorphic and pathogenic in the homozygous state, whereas the functionality of 1 allele, as observed in the parents, is sufficient to avoid clinical expression in heterozygous carriers. Another homozygous missense mutation in the amino-terminal domain (R217W; 138249.0008) was identified in 2 brothers with a similar intellectual disability phenotype without seizures (Lemke et al., 2016).
In a 12-year-old boy (patient 1) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements and without seizures (NDHMSD; 614254), Chen et al. (2017) identified a de novo heterozygous c.1858G-A transition in exon 13 of the GRIN1 gene, resulting in a gly620-to-arg (G620R) substitution at a conserved residue in the second transmembrane segment (TM2). Chen et al. (2017) also identified a c.1858G-C transversion in the GRIN1 gene, resulting in the same G620R substitution (138249.0012), in a 25-year-old woman with the disorder. The mutations, which were found by exome sequencing, were not found in the ExAC database. In vitro functional expression assays showed that the G620R mutation caused a significant decrease in the potency of glutamate and glycine and a decrease in current amplitude when coexpressed with both GRIN2A (138253) and GRIN2B (138252). G620R/GRIN2A complexes showed a mild reduction in trafficking of NMDAR to the cell surface, a strong decrease in sensitivity to magnesium inhibition, and enhanced sensitivity to zinc. G620R/GRIN2B complexes showed significantly reduced delivery of NMDAR protein to the cell surface and altered electrophysiology in response to extracellular modulators. Chen et al. (2017) concluded that the neurodevelopmental deficits resulted from complex effects on channel function, with a combination of decreased presence of G620R/GRIN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of G620R-containing NMDARs after birth.
In a 25-year-old woman (proband 2) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements without seizures (NDHMSD; 614254), Chen et al. (2017) identified a de novo heterozygous c.1858G-C transversion in exon 13 of the GRIN1 gene, resulting in a G620R substitution. Chen et al. (2017) noted that the G620R substitution resulting from a c.1858G-C transversion had been identified by Lemke et al. (2016) in a 7-year-old boy (patient 9) with a similar phenotype.
Chen et al. (2017) found the same G620R substitution but resulting from a different nucleotide change in an unrelated boy with the disorder (138249.0011).
In a Pakistani male infant, born to consanguineous parents, with developmental and epileptic encephalopathy-101 (DEE101; 619814), Blakes et al. (2022) identified a homozygous c.394-1G-C transversion (c.394-1G-C, NM_007327.4) in the GRIN1 gene at the splice acceptor site of exon 3, which was predicted to cause skipping of exon 3. The mutation was identified by sequencing of a panel of 82 genes associated with early infantile epileptic encephalopathy and confirmed by Sanger sequencing. Parental testing for the mutation was not performed. Functional studies were not reported.
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