Recurrent mutations in the GRIN2B gene have been identified in multiple individuals with ASD as described below. Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia cases (PMID 21383861). O'Roak et al., 2011 identified an ASD proband from a simplex family with a de novo splice-site variant in GRIN2B; three additional de novo loss-of-function variants in GRIN2B were identified in ASD probands from simplex families in two subsequent reports from O'Roak and colleagues in 2012 (PMIDs 22495309 and 23160955). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified GRIN2B as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified GRIN2B as a gene reaching exome-wide significance (P < 2.5E-06). Platzer et al., 2017 evaluated 48 novel and 43 previously published individuals with de novo GRIN2B variants; 13 of the 48 novel individuals in this report were reported to have ASD as a phenotype (PMID 28377535). Yoo et al. (2012) showed association of GRIN2B markers in a Korean ASD cohort of 151 families (PMID 22326929); other studies have also found genetic association of the GRIN2B gene with schizophrenia (Ohtsuki et al., 2001) and obsessive-compulsive disorder (Arnold et al., 2004).
Molecular Function
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.
Changes in learning, especially flexibility or reversal learning are seen in mouse models that have conditional deletions in Grin2b ( knocked out post natally in specific parts of the forebrain).
References
Type
Title
Author, Year
Additional
Genetic enhancement of learning and memory in mice.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Grin2B transgenic mouse, named Doogie, over-express the Grin2B (NR2B) subunit postnatally in the forebrain under the CaM-kinase-II promoter. Two independently generated transgenic lines were used.
Allele Type: Transgenic
Strain of Origin: C57B/6
Genetic Background: C57B/6 *B6/CBF1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon9 of the Grin2B gene using CamkII-cre promoter region from Cre4, which is activated postnally,in forebrain principal neurons of hippocampus, striatum, thalamus, amygdala, cortex, and olfactory bulb
Allele Type: Conditional loss-of-function
Strain of Origin: Unreported
Genetic Background: Unreported
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 9 of the Grin2b gene using CamkII-cre in the background of double transgenes CN12-itTA and LC1-cre, pregrant females were treated with doxycycline to keep the cre recombinase under the LC1 transgene silenced, postnatally the pups were transferred to an untreated foster mother leading to activation of the cre recombinase in dorsal region of CA1 and the entire dentate gyrus of the hippocampus
Allele Type: Conditional loss-of-function
Strain of Origin: Unreported
Genetic Background: CN12-itTA/LC1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 2 (or 5, depending on the alternative transcripts) of the GluN2B or Grin2B using CamkII-Cre recombinase containing transgenic mice. Postnatal activation of Cre produces nullizygous Grin2B mice with no Glun2B in the cortex and hippocampal CA1 region.
Allele Type: Conditional loss-of-function
Strain of Origin: 129/SvEvTac
Genetic Background: 129S6/SvEvTac * BALB/c * C57BL/6 (95% C57BL/6)
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The first coding exon of Grin2B was replaced with a targeted construct including the full-length cDNA encoding the rat Grin2A subunit that lacked the translation start codon of GluN2B and included a pgk-Neomycin resistance cassette used for in vitro selection. The resultingGrin-2B/2A inserted allele replaced the Grin2B gene with Grin2A.
Allele Type: Targeted; Transgenic
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The first coding exon of Grin2B was replaced with a targeted construct including the full-length cDNA encoding the rat Grin2A subunit that lacked the translation start codon of GluN2B and included a pgk-Neomycin resistance cassette used for in vitro selection. The resultingGrin-2B/2A inserted allele replaced the Grin2B gene with Grin2A.
Allele Type: Targeted; Transgenic
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homozygous Grin2B knockout mice were generated (as previously reported in PMID 8789948) by homologous recombination with the construct pTVGRe2 containing a neomycin selection cassette.
Allele Type: Targeted
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: TT2 embryonic stem cells
Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 3 (or 5 depending on the alternative transcript) of the Grin2B gene using Nex-Cre, in neurons and glia of the neocortex, hippocampus and pallium, E10.5 onwards
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 2 (or 5, depending on the alternative transcripts) of the GluN2B or Grin2B using Rgs9-cre, in the striatal neurons postnatally
Allele Type: Conditional loss-of-function
Strain of Origin: 129/SvEvTac
Genetic Background: 129S6/SvEvTac * BALB/c * C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
The antagonist Ro 25-6981 is a selective inhibitor of the Grin2B gene product- GluN2B, one of the modulatory subunits for NMDA receptors in the brain.It was infused into the dorsal straitum in wild type mice during behavioral testing.
Allele Type: Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Homozygous Grin2B knockout mice were generated (as previously reported in PMID 8789948) by homologous recombination with the construct pTVGRe2 containing a neomycin selection cassette.
Allele Type: Targeted
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: TT2 embryonic stem cells
Model Source:
Description: Transgenics show larger potentiation with the same stimulus than control animals. in the first 10mins after tetanic stimulation transgenics showed no decay compared to the fast decay in control animals. similar results were obtained with prolonged, repetitive stimulation. stimulation at 10-hz for 1.5min (900 pulses) evoked robust synaptic potentiation in transgenic slices but no potentiation in controls.
Exp Paradigm: Synaptic plasticity with 1 to 100hz stimulation and prolonged repetitive stimulation, was measured.
Local field potential: nmda mediated local field epsps1
Increased
Description: Nmda-receptor-mediated field epsps in transgenic mice were greater than those in wild-type mice.
Exp Paradigm: Nmda receptor-mediated epsps were isolated in the presence of 10 mm cnqx and 0.1 mm mg ion. nmda specificity was demonstrated by nmda-receptor antagonist d(-)-amino-7-phosphonovaleric acid.
Cued or contextual fear conditioning: memory of cue1
Increased
Description: Transgenics show increased freezing in response to the tone at 1hr, 1 day and 10 days, compared to controls.
Exp Paradigm: The conditioned stimulus used was an 85db sound at 2,800 hz, and the unconditioned stimulus was a continuous scrambled foot shock at 0.75 ma.
Description: Transgenics show a clear preference for the quadrant where the platform was previously located compared to control animals.
Exp Paradigm: Time spent in the quadrant where the platform was earlier located was measured.
Cued or contextual fear conditioning: memory of context1
Increased
Description: Transgenics show increased freezing in response to the shock chamber at 1hr, 1 day and 10 days post training, compared to controls.
Exp Paradigm: The conditioned stimulus used was an 85db sound at 2,800 hz, and the unconditioned stimulus was a continuous scrambled foot shock at 0.75 ma. contextual memory was measured by freezing responses on placing the animal in the shock chamber for three minutes.
Description: Transgenics show decreased latency to escape to the platform compared to control mice.
Exp Paradigm: Latency to reach the hidden platform was measured.
Description: Transgenics show quicker dissociation of the previously learned conditional pairing in cued and contextual pairing, than control animals.
Exp Paradigm: The extinction was measured over 5 trials at 1 - 24 hours post training.
Description: Transgenics show increased retention of the memory of a novel object than control animals at 1 and 3 days post training but no change at 1 hour post training.
Exp Paradigm: Memory retention was measured 1 and 3 days post training. during the retention phase of the novel object recognition test one of the familiar objects used in the training session was replaced with a third novel object, and animals were allowed to explore for 5 min.
Description: Transgenics show increased expression of grin2b transgene protein product in the cortex and hippocampus with no increase of expression in the thalamus, brainstem and cerebellum, compared to controls. transgenics show increased gene expression of grin2b transgene in the cortex, striatum, hippocampus and amygdala compared to controls.
Exp Paradigm: Western blot
Description: Transgenics show increased expression of grin2b transgene protein product in the cortex and hippocampus with no increase of expression in the thalamus, brainstem and cerebellum, compared to controls. transgenics show increased gene expression of grin2b transgene in the cortex, striatum, hippocampus and amygdala compared to controls.
Exp Paradigm: Northern blot
Description: Transgenics show increased expression of grin2b transgene protein product in the cortex and hippocampus with no increase of expression in the thalamus, brainstem and cerebellum, compared to controls. transgenics show increased gene expression of grin2b transgene in the cortex, striatum, hippocampus and amygdala compared to controls.
Exp Paradigm: In situ hybridization (ish)
Decay kinetics of miniature post synaptic currents1
Decreased
Description: Mutants show decrease in mepsc amplitude 50ms after the onset of mepscs compared to controls.
Exp Paradigm: Nmdar mediated component of mepsps was measured 50ms after mepsp onset recorded in a mg ion free solution.
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Increased
Description: Mutants show increased ampa/nmda epsc ratios compared to controls.
Exp Paradigm: Epscs were evoked by the stimulation of schaffer collateral/commissural fibers in the stratum radiatum. 10microm ifenprodil was used to block grin2b.
Description: Mutants show smaller maximal depolarization of the epsp envelope and reduced epsp integral compared to controls.
Exp Paradigm: Epsps were evoked at 100hz for 1sec at a stimulation strength yielding ~2mv amplitude for the first epsp.
Decay kinetics of miniature post synaptic currents1
Increased
Description: Mutants show significantly faster decay measured by a faster weighted tau (time constant) than controls. however, mutants show no change in time constant (tau) of nmdar mediated currents in interneurons of the hippocampal stratum oriens that retains grin2b expression, compared to controls.
Exp Paradigm: NA
Description: Mutants show decreased magnitude of ltp induced by low frequency stimulation but no change in the magnitude of ltp induced by high frequency stimulation, compared to controls. mutants also show reduced charge transfer during low and high frequency ltp induction compared to controls. ltp was blocked in both mutants and controls in the presence of an nmdar antagonist (dl-ap5).
Exp Paradigm: High and low frequency stimulations of afferent fibers in stratum radiatum were used in separate paradigms.
Description: Mutants show decreased reward reinforced choice learning, compared to controls.
Exp Paradigm: Task floor inserts throughout the maze served as cues indicating which one of the arms was to be rewarded.
Description: Mutants show decrease in spatial working memory assessed by latency to escape to the visible platform, compared to controls.
Exp Paradigm: 24 training trials were performed over 9 training days.
Description: Mutants show decreased novel object recognition memory compared to controls as mutants did not show a preference for the novel object.
Exp Paradigm: Mice were exposed to two identical objects during the sample phase and to a familiar and novel object during the test phase.
Description: Mutants show decreased spatial reference memory assessed by time spent in the training quadrant, compared to controls.
Exp Paradigm: Probe tests were performed after removing the platform.
Description: Mutants show impaired spatial reversal learning compared to controls.
Exp Paradigm: Platform was moved to the opposite quadrant of the pool to assess spatial reversal learning.
Description: Mutants show decreased acquisition of spatial memory measured by an increase in latency to reach the hidden platform and an increase in pathlength, compared to controls.
Exp Paradigm: NA
Description: Mutants show decreased expression of grin2b protein in the whole hippocampus compared to controls (western blot). mutants show decreased grin2b mrna expression in the rostral forebrain compared to controls (ish).mutants show no change in grin2b expression in gabaergic interneurons and in the ventral hippocampus compared to controls.
Exp Paradigm: Radioactive ish was performed on coronal sections.-western blot
Description: Mutants show decreased expression of grin2b protein in the whole hippocampus compared to controls (western blot). mutants show decreased grin2b mrna expression in the rostral forebrain compared to controls (ish).mutants show no change in grin2b expression in gabaergic interneurons and in the ventral hippocampus compared to controls.
Exp Paradigm: Radioactive ish was performed on coronal sections.- in situ hybridization (ish)
Description: Mutants showed strong reduction in sensitivity to the grin2b specific antagonist, ifenprodil, compared to controls, in the generation of nmdar mediated epscs evoked by stimulation of schaeffer collateral fibers in the stratum radiatum, indicating the functional absence of grin2b in the mutants.
Exp Paradigm: Epscs were evoked by the stimulation of schaffer collateral/commissural fibers in the stratum radiatum. 10microm ifenprodil was used to block grin2b.
Description: Mutants show reduced spatial working memory assessed by latency to escape to the visible platform, compared to controls.
Exp Paradigm: 24 training trials were performed over 9 training days.-morris water maze test
Description: Mutants show reduced spatial working memory assessed by latency to escape to the visible platform, compared to controls.
Exp Paradigm: 24 training trials were performed over 9 training days.- t-maze test
Description: Mutants show impaired reversal of spatial learning compared to controls measured by a failure to show preference for the new training quadrant after the platform was moved.
Exp Paradigm: The platform was moved to the opposite quadrant followed 24 hrs. later by another probe test.
Description: Mutants show decreased expression of grin2b mrna in the dorsal ca1 region and in the entire dentate gyrus of the hippocampus compared to controls (ish).
Exp Paradigm: Radioactive ish was performed on coronal sections.- histology: lacz staining
Description: Mutants show decreased expression of grin2b mrna in the dorsal ca1 region and in the entire dentate gyrus of the hippocampus compared to controls (ish).
Exp Paradigm: Radioactive ish was performed on coronal sections.-in situ hybridization (ish)
Description: Spine density of dendrites in ca1 pyramidal neurons is significantly lower in nullizygotes compared to controls. spine head width did not differ between genotypes.
Exp Paradigm: Neurons were labeled with tungsten beads coated with dii and images were acquired using confocal microscopy.
Description: There was a partial deficiency in ltp in the schaffer collateral- commissural fibere in nullizygotes, in a protocol that is designed to evoke subsaturating levels of ltp.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Nullizygotes froze significantly less that controls during retrieval of trace conditioned fear memory, but not delay-conditioned fear memory.
Exp Paradigm: Trace and delay fear conditioning. novel context (context discrimination)
Description: The nullizygotes did not spontaenous alternate above chance, differed significantly with controls
Exp Paradigm: Spontaneous alternation was calculated in the t maze
Cued or contextual fear conditioning: memory of cue2
Decreased
Description: Learning was impaired in nullizygotes, compared to the floxed controls as they had increased errors, in the task that required making a choice. however simply touching a screen ( no choice) for reward was normal similar in nullizygotes compared to floxed controls
Exp Paradigm: Mice were presented with a touchscreen containing two images ( choice). touching the right (conditioned stimulus) is rewarded by food. mice are trained until they learn to pick the right image on the screen. in the 'no choice' paradigm, they only learn to touch the screen for a reward
Description: Reversal learning was severely impaired in nullizygotes compared to floxed controls
Exp Paradigm: After discriminating the correct stimulus/ image from the incorrect one, mice are trained in the reverse manner- to test for flexibility
Description: Nullizygotes had significantly longer latencies to find the hidden platform compared to controls. in the visible platform test both genotypes performed similarly. the swimming speeds were similar between genotypes.
Exp Paradigm: Visible and hidden platform test
Description: Mutants show increased expression of grin2a compared to controls (western).
Exp Paradigm: Cage transect counts were measured in a familiar setting over 3 mins.- quantitative pcr (qrt-pcr)
Description: Mutants show increased expression of grin2a compared to controls (western).
Exp Paradigm: Cage transect counts were measured in a familiar setting over 3 mins.- histology: map2, grin1, vglut1
Description: Mutants show increased expression of grin2a compared to controls (western).
Exp Paradigm: Cage transect counts were measured in a familiar setting over 3 mins.-western blot
Description: Mutants showed similar outward currents with increased peak current amplitude and decreased decay time constant evoked by the application of 100microm nmda and 10microm d-serine in neurones voltage clamped at +50mv, compared to controls. these currents were sensitive to the nmdar antagonist mk801 and apv but insensitive to the glun2b selective antagonist ifenprodil and more sensitive to the zinc ion chelator tpen.
Exp Paradigm: NA
Description: Mutants show less interaction with their litter mates compared to controls measured by increase in time spent isolated from their cage mates.
Exp Paradigm: NA
Description: looking at the brainstem trigeminal complex, compared to the discernable barrelettes with 5 distinct rows of patches corresponding to 5 rows of whiskers in WT mice, mutant mice had diffuse staining and barrelette patches were missing.
Description: cholera toxin b labeled terminal arbors were found in the ventrolateral region of the subnucleus interpolaris of the spinal trigeminal nucleus, similar to WT mice, indicating preservation of connectivity and somatotopy of the primary afferent fibers. Although terminal arbors were distributed diffusely with no distinct clustering over the rostrocaudal axis.
Exp Paradigm: Cholera toxin B labeling
Description: homozygous Grin2b mice were defective in the suckling response responding only with a retration of the tongue, suckling movements were scarcely observed
Description: when homozygous mice were intervened with handfeeding, they were able to survive to the neonatal time period, there was no systematic study of low long the mice could grow in this way although one mouse survived to P 6
Description: Mutants show less interaction with their litter mates compared to controls measured by increase in time spent isolated from their cage mates.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Learning was impaired in nullizygotes, compared to the floxed controls as they had increased errors, in the task that required making a choice. however simply touching a screen ( no choice) for reward was normal similar in nullizygotes compared to floxed controls
Exp Paradigm: Mice were presented with a touchscreen containing two images ( choice). touching the right (conditioned stimulus) is rewarded by food. mice are trained until they learn to pick the right image on the screen. in the 'no choice' paradigm, they only learn to touch the screen for a reward
Description: Reversal learning was severely impaired in nullizygotes compared to floxed controls
Exp Paradigm: After discriminating the correct stimulus/ image from the incorrect one, mice are trained in the reverse manner- to test for flexibility
Description: However, if it was infused in the mid stages of reversal training, there were increased errors and correct choices in antagonist infused mice
Exp Paradigm: Wild type mice were first trained in a reward based discrimination task, via cued learning. in the reversal phase, cognitive flexibility was tested, as the incorrect response was interachanged with the correct response in the same reward based discrimination task.
