World Journal of Neuroscience, 2011, 1, 38-44
doi:10.4236/wjns.2011.13006 Published Online November 2011 (http://www.SciRP.org/journal/wjns/
Published Online November 2011 in SciRes. http://www.scirp.org/journal/WJNs
The influence of NMDA receptor 2B subunit (GRIN2B) on
cortical electrical oscillation
Tien-Wen Lee1,2, Younger W -Y Yu3, Chen-Jee Hong 4,5, Shih-Jen Tsai 4,5, Hung-Chi Wu6, Tai-Jui Chen7,8
1Department of Psychiatry, Chang Gung Memorial Hospital, Taoyuan County, Chinese Taipei;
2College of Medicine, Chang Gung University, Taoyuan County, Chinese Taipei;
3Yu’s Psychiatric Clinic, Kaohsiung, Chinese Taipei;
4Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Chinese Taipei;
5School of Medicine, National Yang-Ming University, Taipei, Chinese Taipei;
6Kai-Suan Psychiatric Hospital, Kaohsiung, Chinese Taipei;
7Department of Psychiatry, E-DA Hospital, Kaohsiung County, Chinese Taipei;
8Department of Occupational Therapy, I-Shou University, Kaohsiung County, Chinese Taipei.
Received 21 June 2011; revised 26 September 2011; accepted 9 October 2011.
The N-methyl D-aspartate receptor (NMDAR) is com-
posed of several subunits. Among them, the N2B is of
interest, given its dominance in early development
and its significant impact on neuronal channel func-
tioning and the formation or maintenance of cellular
architecture. NMDAR-N2B, also named GRIN2B,
has been implicated in broad neuro-psychiatric con-
ditions. However, the genetic impact on cortical os-
cillation in the human brain is still unclear. This study
examined the modulatory effects of a silent mutation
C2644T polymorphism on the EEG oscillation. Blood
samples were collected and resting state eyes-closed
EEG signals were recorded in 256 young healthy fe-
males, stratified into three groups according to geno-
types C/C, C/T and T/T. The values of the mean po wer
of 18 electrodes across delta, theta, alpha, beta and
gamma frequencies were analyzed. Between-gr oup sta-
tistics were determined by ANOVA and independent
t-test; and a global trend of regional power was quan-
tified by non-parametric analyses. No significant be-
tween-group differences were noticed with the statis-
tical threshold after Bonferroni correction. At less con-
servative threshold of P < 0.01, C/T group had higher
regional power at sparse electrode-frequency pairs in
posterior brain regions. However, a consistent global
trend was noticed wherein the C/T group possessed
higher EEG pow ers, r e gardless of spectral bands. Non-
parametric analyses confirmed this observation. Our
results implied that the heterozygous group of GRIN2B
C2744T was associated with higher neural synchro-
nization during relaxation, which may be relevant to
the impact of GRIN2B in early development and the
inverted-U-shaped response in the NMDA system.
Keywords: Electroencephalography (EEG); Power Spec-
trum; NMDA; Polymorphism
The NMDA (N-methyl D-aspartate) receptor (NMDAR)
is a specific type of ligand-gated ionotropic glutamate
receptor named after the selective agonist. NMDA system
plays significant roles in synaptic plasticity, learning and
memory, and in the pathological processes in the brain.
Functional NMDA receptors are composed of several
subunits, namely NR1, NR2A-D and NR3A-B, with their
various heteromeric assemblies determining the physio-
logical properties of NMDAR. The activation of NMDAR
results in the opening of an ion channel that is non-se-
lective to cations, and which requires the presence of an
agonist (e.g. glutamate), a co-transmitter (glycine or dserine)
and depolarization, rendering the property of coincidence
detector. The excitatory postsynaptic potential produced
by the activation of NMDAR increases the concentration
of Ca2+ in the cell, which in turn functions as a second
messenger in various signaling pathways. NMDAR is
widely distributed in the central nervous system, and the
antagonist of NMDAR is well-known to induce psycho-
sis, which has contributed to the development of the
NMDAR hypofunction hypothesis of schizophrenia .
Although still debated, NMDAR has been implicated in
broad neuro-psychiatric conditions, such as Alzheimer’s
disease, Huntington’s disease, neuronal damage after stroke,
epileptogenesis in cortical dysplasia, anorexia nervosa,
obsessive-compulsive disorder and alcohol-related risk,
behaviors and neural changes [2-16].
T.-W. Lee et al. / World Journal of Neuroscience 1 38-44 39
Unlike the NR1 subunit common to all NMDAR, NR2
subunits are expressed differentially across various cell
types and hence affect the electrophysiological kinetics
of NMDARs. In normal development, there is a pheno-
menon called NR2B-NR2A switch of NMDAR. NR2B
is predominant in the early postnatal brain; however,
during development, the subunit composition of synaptic
NMDARs changes, switching from predominance of
NR2B-containing receptors to NR2A-containing recep-
tors. This process is critical to survival, given that ani-
mal studies demonstrated perinatal lethality after a dis-
ruption of the gene for NR2B, whereas the disruption of
the NR2A gene produced viable mice, although with
impaired hippocampal plasticity [17-19]. In the rat mo-
del of focal ischemic stroke, activation of synaptic/extra-
synaptic NR2A-containing and NR2B-containing NMDAR
imposed opposite effects on neurons, with the former ex-
erting a protective action that promoted neuronal sur-
vival and the latter enhancing excitotoxicity, which in-
creased neuronal apoptosis . The NR2B subunit is in-
volved in the synapse development, macro-molecular or-
ganization, the actin cytoskeleton and plasticity ; how-
ever, its precise function is relatively hard to access be-
cause the knock-out manipulation would lead to lethality.
The NMDAR-NR2B (GRIN2B) gene, consisting of 13
exons, is located at 12p12, with a size of 419 kb. It is ex-
pressed in the hippocampus, basal ganglia and cerebral
cortex , and was implicated in the risk or suscepti-
bility of schizophrenia, obsessive-compulsive disorder, Al-
zheimer’s disease and alcohol consumption patterns [1,3,6-
8,12]. The behavioral profiles of pre-pulse inhibition were
also affected by GRIN2B [22,23]. A polymorphism C2664T
of GRIN2B at exon 13, rs1806201, results in a silent
mutation (synonymous mutation) where the codon of ACC
is replaced by ACT, both encoding the same amino acid
Threonine. Although silent mutations do not alter protein
function, they are not always evolutionarily neutral. It may
be due to codon usage biases that there is selection for
the use of particular codons due to different translational
stability. Silent mutations may also affect splicing or tran-
scriptional control. Association studies suggested that
GRIN2B C2664T polymorphism may possess clinical
significance, such as differentiating the anti-psychotic
dosage in psychosis and the susceptibility to alcoholism
[8,12,24]. Whether GRIN2B C2664T polymorphism mo-
dulate brain activity is still unclear. This study planned
to investigate the effect of GRIN2B C2664T polymer-
phism on resting EEG, which has never been examined
Different genotypes GRIN2B C2664T may affect the
quantity, not the quality, of NR2B. It is noteworthy that,
as with the dopamine system, the dose response of NMDAR
also follows a non-linear, inverted-U-shaped, pharmaco-
logical profile [25-27]. To delineate the genetic influence
of GRIN2B C2664T polymorphisms on the cortico-elec-
trical activities at the resting state, we stratified our par-
ticipants into three groups: C/C, C/T and T/T; in case the
two-group approach based on the carriage of C or T allele
may mask significant differences if the polymorphism
exerts impact on the ascending and/or the descending
limbs of the inverted-U-response curve. Resting EEG
carries abundant information predictive of performance
in several neuro-psychological tasks, and even the early
stage of Alzheimer’s disease or the treatment response of
major depressive disorder [28-33]. Recent studies have
suggested that polymorphisms of GRIN2B influence phe-
notypic behavior and pathological condition in a gen-
der-dependent manner [34,35]. For this pilot study, we
restricted our sample to the female gender and to a lim-
ited age range to simplify any gender or chronological in-
teraction. Regional as well as global effects were exam-
ined. See method section for details.
2. MATERIALS ANd METHODS
We recruited 256 right-handed healthy young females,
aged 19 to 21 years. Licensed medical doctors and psy-
chiatrists respectively examined their neurological/phy-
sical and psychiatric conditions. The exclusion criteria
included major medical or neurological disorders, sub-
stance abuse or psychiatric disease. All participants had
been medication-free for at least two weeks. This project
was approved by the local ethical committee, and written
informed consent was obtained from all subjects prior to
participation in this study.
2.2. EEG Recordings and Analyses
We recorded 3-minute resting digital EEG with cup-
shaped passive electrodes in both the eyes-closed and
awake state (Brain Atlas III computer, Biologic System
Company, Chicago). The recording started after a 5-mi-
nute habituation to the experimental environment, fol-
lowing the standard of the international 10-20 system
with earlinked reference, at a 128 Hz sampling rate, high
pass filter 0.05 Hz, low pass filter 70 Hz, notch filter 60
Hz and impedance below 3 kΩ after skin preparation
. Vertical and horizontal eyeball movements were
respecttively monitored from the electrodes placed
above and below the right eye, and the electrodes placed
at the left outer canthus. EEG artifacts were handled by
semi-automated module provided by software EEGLAB
(http://sccn.ucsd.ed u/eeglab). The artifact segments from
various sources, such as external artifact, movements,
oculogenic potentials and myogenic potentials and so on,
were detected and deleted via visual inspection by ex-
perienced EEG technician and then the signal quality
was examined by channel statistics and QQ-plot. The
EEG channels were re-checked and trimmed until passing
opyright © 2011 SciRes. WJNS
T.-W. Lee et al. / World Journal of Neuroscience 1 (2011) 38-44
Kolmogorov–Smirnov test (P < 0.05), i.e. the EEG sig-
nals acting like normal distribution. The electrodes F7,
F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6,
O1, Oz and O2 were included in the analyses. The fre-
quency bands were defined as follows: theta 4 to 8 Hz,
alpha 8 to 12 Hz, beta 12 to 24 Hz, beta1 12 to 18 Hz
and beta2 18 to 24 Hz, gamma 25 to 60 Hz, gamma1 25
to 35 Hz and gamma2 35 to 60 Hz. Fast Fourier Trans-
form (FFT) was used to derive the mean EEG power for
each electrode at a specified frequency band for each
artifact-free segment (unit: μV2). The mean power spec-
trum were further normalized and weighted by the lengths
of artifact-free segments, and summed to generate the
reported mean power spectrum.
2.3. Genotyping of GRIN2B Polymorphism
Genomic DNA was extracted from peripheral blood leu-
kocytes and was amplified using polymerase chain reac-
tion (PCR). The genotypes of GRIN2B C2664T were iden-
tified following reported methods [5,37]. In brief, we de-
signed primers 5’-AGA CTA TTC GCT TCA TGC-3’
and 5’-GTG TGT TGT TCA TGG CTG-3’ to create
210bp PCR product with a PstI restriction site, which
enables differentiating the 2664T and 2664C polymer-
2.4. Statistical Analyses
The participants were categorized into 3 groups accord-
ing to the GRIN2B C2664T polymorphism, namely C/C,
C/T and T/T groups. Analysis of variance (ANOVA) and
independent t-test with assumed unequal variance were
performed to elucidate the electrodes with values of mean
power showing significant between-group differences. For
each test set in this study, the criterion for significance
was set at P < 0.05, two-tailed. We assumed the inde-
pendency of each frequency band and performed the Bon-
ferroni correction based on P = 1 − (1 − 0.05)1/n, where n
equals the number of comparisons, with n = 18 equi-
valent to the electrode number. For each comparison, we
reported both the P value < 0.01 and the P value ad-
justed for multiple comparisons, in case the Bonferroni
correction might be too stringent since the cortical elec-
trical activities are interactive rather than totally inde-
pendent. The regional mean EEG power at frontal (F7,
F3, Fz, F4, F8), temporal (T3, T4, T5, T6), centro-pa-
rietal (P3, Pz, P4) and occipital (O1, Oz, O2) regions
were computed to compare the between-group differ-
ences (n = 4, P = 0.0127 after Bonferroni correction). To
test whether there was a global trend difference in the
mean power across regions and frequency bands between
the three genotyped groups, we performed non-parametric
analyses. Our null hypothesis assumed that the probabil-
ity of a certain index (i.e., mean power) for a particular
electrode at a specific frequency band that one group is
greater than another group equals the probability that
group two is greater than group one (i.e., the probability
was 0.5). The probability of obtaining j or more “group
one > group two” indices by chance can be calculated by:
where s is the total number of comparisons, with s = 18
× 9 when taking all the electrode(18)-frequency(9) pairs
The GRIN2B C2664T genotypes of the participants in-
cluded C/C (N = 61), C/T (N = 126) and T/T (N = 69),
distributed in Hardy-Weinberg equilibrium (χ2 = 0.055,
P = 0.815). The subjects were divided into three groups
according to their genotypes, so there were three be-
tween-group comparisons, C/C vs. C/T, C/C vs. T/T and
C/T vs. T/T. The ANOVA analyses of mean power did
not reveal significant between-group differences at all
the electrode-frequency pairs (minimum of P = 0.0124)
after the Bonferroni correction (P = 0.0028). At a looser
threshold with P 0.01, independent t-tests revealed that
the C/T group had a higher mean power at Fz gamm2
and P4 gamma/gamma1/gamma2 when compared with
the C/C group, and had a higher mean power at T3
beta/beta1/beta2, T4 gamma/gamma2, Pz gamma/gamma2,
T6 gamma1, O1 gamma/gamma1, Oz gamma/gamma1
and O2 beta2 when compared with the T/T group. None
of the power differences reached P < 0.01 for C/C and
We performed non-parametric analyses to examine the
genetic effect of GRIN2B on the global trend of EEG
power. Strikingly, we discovered that out of the 162 elec-
trode-frequency pairs (18 electrode and 9 frequency bands),
there were 161 comparisons that C/T > C/C and 159
comparisons that C/T > T/T, with respective P value
2.771 × exp(−47) and 1.212 × exp(−43). The C/C group
had 79 electrode-frequency pairs showing a smaller
mean power than the T/T group, with P value 0.6527. In
summary, the heterozygous C/T group had a global trend
of higher cortico-electrical power than the C and T ho-
mozygous counterparts, which seemed more prominent
in posterior brain regions. Interested readers may refer to
the supplementary material of the detailed results (Table
S1 to S3 for three between-group comparisons, at
To ensure that our results were not caused by outliers,
we made another analyses that for each genotypic group,
each frequency band and each electrode site, we regis-
tered the participants with power value deviating the mean
by greater than 3 standard deviations and then remove
all of them from the non-parametric analyses. We have
196 subjects left, with C/C = 46, C/T = 97, T/T = 53.
opyright © 2011 SciRes. WJNS
T.-W. Lee et al. / World Journal of Neuroscience 1 38-44
Copyright © 2011 SciRes.
Among the 162 electrode-frequency pairs (18 electrode
and 9 frequency bands), there were 151 comparisons that
C/T > C/C and 147 comparisons that C/T > T/T, with
respective P value 6.581 × exp(−33) and 1.035 × exp(−28).
The C/C group had 108 electrode-frequency pairs show-
ing a smaller mean power than the T/T group, with P
value 0.1535. See Figure 1 and 2 to appreciate the global
trend in between-group comparisons.
significant between-group differences at occipital-gam-
ma1 (P = 0.0102), see Table 1 for detail.
There are several subunits of the NMDA receptor, in-
cluding NR1, NR2A-D and NR3A-B. The composite he-
teromers of NMDAR subunits carry varied physiological
properties. NR2B of NMDA receptor, GRIN2B, has been
of interest given its significant impact on neural devel-
opment, excitotoxicity and plasticity. The polymorphism
of GRIN2B has been associated with various neuro-psy-
chiatric diseases and with the behavioral manifestation
of pre-pulse inhibition [1,3,6-8,12,22,23]. The usual
technique of gene knock-out is not applicable to explor-
ing GRIN2B functioning because of consequent perinatal
lethality. Akashi et al. tackled this issue by generating a
conditional GRIN2B ablation in hippocampal CA3 py-
ramidal cells and discovered that the GRIN2B is not
only important in NMDAR channel function but also in
the formation/maintenance/regulation of the neuronal
cyto-architecture . We investigated the neural influ-
ence of GRIN2B via an approach of imaging genetics by
combining GRIN2B C2664T polymorphism and resting
EEG in the healthy young female population. The result
of our regional power analysis was generally negative,
with no significant between-group differences over 18
electrodes and 9 frequency bands with respect to the
results of ANOVA and independent t-tests. At a looser
statistical threshold with P < 0.01, the heterozygous C/T
group had higher regional power at sparse electrodefre-
quency pairs, especially in posterior brain regions, when
compared with the two homozygous groups C/C and T/T.
It is interesting that our non-parametric analysis demon-
strated a trend of higher global power in the heterozy-
gous group, regardless of spectrum, with very striking sta-
tistics. The global power was equivalent between the
two homozygous groups.
The analyses of regional mean power demonstrated
that C/T group is greater than C/C group and T/T group
at each frequency-region pair, consistent with the non-
parametric analyses described above. The F-test showed
Figure 1. The topography of EEG power differences at 8 fre-
quencies, from the comparison of the group C/T minus the group
C/C for GRIN2B. Right lower corner is the alignment of sub-
plots based on frequency.
Our prominent finding at the scale of a global trend
was compatible with the wide distribution of NMDAR in
the brain . The observation that the heterozygous group
had the higher global power was of particular interest
given that it is also concordant with the well-known in-
verted-U-shaped response curve of the NMDAR system.
The inverted-U response curve has been observed over
board contexts of NMDAR modulation using various
agonists and antagonists, including avoidance learning,
spatial learning, memory performance, the breaking point
for cocaine self-administration, messenger RNA expres-
sion, expression and phosphorylation of NMDA-signal-
ing related proteins and the neuro-protection effect in global
ischemia and so on [26,27,38-43]. This study complemented
previous findings and showed a possible inverted-U-shaped
impact of NMDAR on neural synchronization, manifested
Figure 2. The topography of EEG power differences at 8 fre-
quencies, from the comparison of the group C/T minus the
group T/T for GRIN2B. Right lower corner is the alignment of
subplots based on frequency.
T.-W. Lee et al. / World Journal of Neuroscience 1 (2011) 38-44
Table 1. The mean EEG power of frontal, temporal, centro-parietal and occipital regions across 8 frequency bands of the 3 genotypes
of GRIN2B (C/C, C/T and T/T).
theta alpha beta beta1 beta2 gamma gamma1 gamma2
C/C 0.164 0.340 0.039 0.049 0.030 0.008 0.013 0.006 Frontal
0.253 0.601 0.062 0.080 0.045 0.008 0.014 0.005 Centro-Parietal
0.258 1.182 0.095 0.125 0.064 0.011 0.019 0.008 Occipital
C/T 0.195 0.350 0.049 0.059 0.039 0.011 0.017 0.009 Frontal
0.175 0.512 0.068 0.085 0.050 0.016 0.023 0.014 Temporal
0.309 0.685 0.078 0.099 0.058 0.011 0.019 0.007 Centro-Parietal
0.311 1.505 0.142 0.195 0.089 0.016 0.027 0.012 Occipital
T/T 0.182 0.345 0.039 0.047 0.031 0.009 0.014 0.007 Frontal
0.153 0.461 0.047 0.058 0.035 0.010 0.014 0.008 Temporal
0.280 0.645 0.060 0.076 0.044 0.008 0.014 0.005 Centro-Parietal
0.261 1.235 0.088 0.117 0.058 0.012 0.018 0.010 Occipital
The mean power C/T group is greater than that of C/C group and T/T group at each frequency-region pair. The F-test showed significant between-group differ-
ences at occipital-gamma1 (P = 0.0102 < threshold 0.0127).
as cortico-electrical power.
In this study, the impact of GRIN2B C2664T polymer-
phism neither showed region preference nor spectrum
specificity on cortical EEG oscillation, implying a very
fundamental neural property mediated by GRIN2B.
GRIN2B is important in the post-synaptic macro-mole-
cular organization, formation/maintenance of the dendritic
spine, and cytoskeleton, predominant in the early post-
natal brain and followed by the NR2B-NR2A switch
where NR2A-containing NMDAR gradually outnumbered
the NR2B-containing analog . Neural modeling sug-
gested that the generation of neural oscillation relies on
the interaction between the sub-components of neural
mass [44-46]. We thus speculated that the differential
influence of GRIN2B C2664T genotypes on the global
electrical activities may have to do with its crucial roles
in channel functioning and in neural architecture regula-
tion shaped during early development, and lasting through
adulthood. It is also possible that our finding reflected
the influence of GRIN2B on the deep subcortical struc-
tures, such as reticular formation, which resonate with
the cortical network to generate the EEG oscillatory
Together with the early influence of GRIN2B on neu-
ral development and the inverted-U-shaped response in
the NMDA system, our EEG finding further implicated a
different strategy to probe the genetic association of
GRIN2B. Unlike the traditional approach to access allele
risk to certain disease or allele contribution to the bio-
psychological profile, it may be informative to compare
heterozygote and homozygote groups. This stratification
strategy could be particularly worthwhile to examine with
respect to the NMDA and dopamine system [25-27].
The NMDA gene has been linked to a variety of neu-
rological and psychiatric conditions. There are few re-
ports exploring the influence of NMDA-NR2B polymer-
phism on the regional neural activity in the human brain.
We demonstrated that the silent mutation C2664T of
GRIN2B differentiated cortical electrical power at the
scale of global trend, with the homozygous group, C/C
and T/T, associated with reduced EEG power regardless
of frequency bands. Clarifying whether this finding pos-
sesses clinical implication, gender bias, or reflects only
the GRIN2B influence in early developmental stage war-
rants further studies.
This work was supported by grant DOH94-NNB-1035 from the De-
partment of Health, Taiwan, ROC, and grant KS92-015 from the Kai-
Suan Psychiatric Hospital-Kaohsiung. We are grateful to Mr. Gosalia who
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