T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1 (-∕-) mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs). Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, Tbr1 (+∕-) mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in Tbr1 (-∕-) mice, these features are not found in Tbr1 (+∕-) mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to Tbr1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections) and excitation/inhibition imbalance (NMDAR hypoactivity), two prominent models for ASD etiology, are present in Tbr1 (+∕-) mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK) was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in Tbr1 (+∕-) mice. In addition to Grin2b, cell adhesion molecules-including Ntng1, Cdh8, and Cntn2-are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of Tbr1 provide an integrated picture of ASD etiology at the cellular and circuit levels.

Epileptic encephalopathies (EE) include a range of severe epilepsies in which intractable seizures or severe sub-clinical epileptiform activity are accompanied by impairment of motor and cognitive functions. Mutations in several genes including ion channels and other genes whose function is not completely understood have been associated to some EE. In this report, we provide a detailed clinical description of a sporadic male patient with early-onset epilepsy and epileptic encephalopathy in whom we performed complete exome sequencing (WES) and identified a GRIN2B mutation. The GRIN2B splicing mutation in intron 10 (c.2011-1G>A) was revealed in a WES study. The result was confirmed by Sanger sequencing. No mutation was found in both parents. Our finding confirms that early-onset EE may be caused not only by gain-of-function variants but also by splice site mutations-in particular those affecting the splice acceptor site of the 10th intron of the GRIN2B gene. © 2016 Wiley Periodicals, Inc.

Prenatal hypoxia (PH) is one of the most common stresses on fetuses, and might lead to abnormal brain development. This work investigates whether PH affects behavioral development of the learning/memory ability in the adolescent offspring rats and the underlying molecular basis in the brain. In this study, pregnant rats used to generate PH offspring were treated with hypoxia (10.5% oxygen) from gestational day 4 to 21. Brain weights of either the fetuses or the 6-week old offspring in the PH group were found to be significantly lower compared with the control group. Morris water maze tests showed longer escape latency and swimming distance during navigation testing in the PH offspring; retention tests demonstrated less frequency of crossing target areas indicating impaired learning and memory ability in the PH offspring. The expressions of subunits of N-methyl-D-aspartate receptors (NMDARs), Grin1/NR1, Grin2a/NR2A, and Grin2b/NR2B, were significantly decreased in the hippocampus of adolescent offspring in the PH group. Wnt3a as well as active form of β-catenin protein were also significantly down-regulated. Furthermore, the expression of early response gene, Fosl1, was significantly reduced. The results above provide new evidence that PH might result in the spatial acquisition and retrieval deficits in the adolescent offspring, associated with dysregulation of NMDARs-Wnt-Catenin signaling in the hippocampus. This study result deepens the knowledge of the long-term influence of prenatal insults on the neuro-behavioral development.

BACKGROUND

The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.

OBJECTIVE

We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol.

RESULTS

We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia.

CONCLUSIONS

This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

TSPYL2 is an X-linked gene encoding a nucleosome assembly protein. TSPYL2 interacts with calmodulin-associated serine/threonine kinase, which is implicated in X-linked mental retardation. As nucleosome assembly and chromatin remodeling are important in transcriptional regulation and neuronal function, we addressed the importance of TSPYL2 through analyzing Tspyl2 loss-of-function mice. We detected down-regulation of N-methyl-D-aspartate receptor subunits 2A and 2B (GluN2A and GluN2B) in the mutant hippocampus. Evidence from luciferase reporter assays and chromatin immunoprecipitation supported that TSPYL2 regulated the expression of Grin2a and Grin2b, the genes encoding GluN2A and GluN2B. We also detected an interaction between TSPYL2 and CBP, indicating that TSPYL2 may activate gene expression through binding CBP. In terms of functional outcome, Tspyl2 loss-of-function impaired long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, mutant mice showed a deficit in fear learning and memory. We conclude that TSPYL2 contributes to cognitive variability through regulating the expression of Grin2a and Grin2b.

Rodent studies show how prenatal stress (PS) can alter morphology in the cortico-limbic structures that support emotional and cognitive functions. PS-induced alteration is less well described in species with a gyrencephalic brain and complex earlier fetal development, and never in sheep at birth to rule out postnatal environment effects or influences of maternal behavior. This study aimed to assess the consequences of a mild chronic stress in pregnant ewes on the neurobiological development of their lambs at birth. During the last third of gestation, 7 ewes were exposed daily to various unpredictable and negative routine management-based challenges (stressed group), while 7 other ewes were housed without any additional perturbation (control group). For each group, a newborn from each litter was sacrificed at birth to collect its brain and analyze its expression levels of genes involved in neuronal dendritic morphology (Dlg4, Rac1, RhoA, Doc2b), synaptic transmission (Nr1, Grin2A, Grin2B) and glucocorticoid receptor (Nr3C1) in hippocampus (HPC), prefrontal cortex (PFC) and amygdala (AMYG). Results revealed that lambs from stressed dam (PS lambs) showed under-expression of Rac1 and Nr1 in PFC and overexpression of Dlg4 in AMYG compared to controls. To assess the morphological consequences of gene dysregulations, the dendritic morphology of pyramidal neurons was explored by Golgi-Cox staining in HPC and PFC. PS lambs had higher dendritic spine density in both structures and more stubby-type spines in the CA1 area of HPC than controls. This is the first demonstration in sheep that PS alters fetal brain, possibly reflecting functional changes in synaptic transmission to cope with adversity experienced in fetal life.

BACKGROUND

Previous studies have indicated that dopamine interacts with glutamatergic projection neurons and that N-methyl-d-aspartate (NMDA) receptors might be involved in the pathogenesis of Tourette syndrome (TS). In this study, we examined whether two functional polymorphisms (rs1805476 and rs1805502) in the 3'UTR of the NMDA receptor 2B subunit gene (GRIN2B) were associated with TS in Chinese Han trios.

METHODS

DNA samples collected from 261 TS nuclear families were genotyped by PCR and direct sequencing technology. Haplotype relative risk (HRR), transmission disequilibrium test (TDT) and Haplotype-based haplotype relative risk (HHRR) analyses were performed on the genotype data.

RESULTS

We found an over-transmission of the A allele in rs1805476 and the T allele in rs1805502 from parents to their affected children, using the HRR (rs1805476: HRR=0.696, χ(2)=4.161, P=0.041, 95% CI: 0.491-0.986; rs1805502: HRR=0.697, χ(2)=3.954, P=0.047, 95% CI: 0.488-0.995). There was also strong evidence for a linkage between polymorphisms and TS using the TDT (rs1805476: TDT=5.447, df=1, P=0.024; rs1805502: TDT=5.233, df=1, P=0.027).

CONCLUSIONS

The sample is small and the current population is just limited to the Chinese Han population.

CONCLUSIONS

These data support the hypothesis that GRIN2B might play a major role in the pathogenesis of TS in Chinese Han trios. However, these results need to be replicated using larger datasets collected from different populations.

OBJECTIVE

To examine the association between variants of N-methyl-D-aspartate (NMDA) receptor subunit-encoding genes (GRIN2A and GRIN2B) and continuous performance test (CPT) variables in ADHD and healthy controls.

METHODS

In all, 253 ADHD patients and 98 controls were recruited. The diagnosis, genotype, and diagnosis-genotype interaction effects for the CPT variables were examined.

RESULTS

Significant diagnosis effects were detected for all CPT variables. There were significant genotype and interaction effects on response time variability (RTV) by the GRIN2B variant. The C/C subgroup had higher RTV than the C/T + T/T subgroup in ADHD, but not in controls. There were significant genotype effects on omission errors by the GRIN2A variant. The G/G subgroup had more omission errors than the G/A + A/A subgroup in ADHD patients, but not in controls.

CONCLUSIONS

These results suggest that the genetic variants of GRIN2B and GRIN2A confer an increased susceptibility to attentional impairment in ADHD patients.

BACKGROUND

Dopamine and glutamate are crucial neurotransmitters in Parkinson disease (PD). While recent large meta-analyses reported that genetic variation of dopamine (DRD2, DRD3) and glutamine (NMDA, GRIN2B) neurotransmitter receptors was not associated with PD risk, they could conceivably influence PD phenotype. We studied the association of these receptor polymorphisms relating to PD age of onset.

METHODS

There were 664 PD patients and 718 controls, all Caucasian, with stored DNA at Mayo Clinic, Jacksonville, Florida. Genotyping was performed for DRD2 (Taq 1A, rs1800497), DRD3 (rs6280), and NMDA (GRIN2B, rs7301328) polymorphisms with ABI Taqman assays. Single nucleotide polymorphism associations with age of onset were evaluated using dominant, recessive, and additive genotypic models.

RESULTS

DRD3 variant carriers had an approximate 4.4-year decrease in mean age of onset when both copies of the minor allele were present (P = 0.0034) and an approximate 1.5-year decrease in mean age at onset for every additional minor allele (P = 0.023) (recessive and additive models, respectively). There was no association with age of onset for DRD2 or GRIN2B under any statistical model (all P ≥ 0.22).

CONCLUSIONS

The DRD3 (rs6280) polymorphism, but not DRD2 (Taq1A) or GRIN2B, influences younger PD age of onset in the US Caucasian population. Validation of these findings in larger studies with other ethnic groups is indicated.

OBJECTIVE

Developmental dyslexia (DD) is a complex heritable condition associated with impairments in multiple neurocognitive domains. Substantial heritability has been reported for DD and related phenotypes, and candidate genes have been identified. Recently, a candidate gene for human cognitive processes, that is, GRIN2B, has been found to be associated significantly with working memory in a German DD sample. In this study, we explored the contribution of six GRIN2B markers to DD and key DD-related phenotypes by association analyses in a sample of Italian nuclear families. Moreover, we assessed potential gene-by-environment interactions on DD-related phenotypes.

METHODS

We carried out a family-based association study to determine whether the GRIN2B gene influences both DD as a categorical trait and its related cognitive traits in a large cohort of 466 Italian nuclear families ascertained through a proband affected by DD. Moreover, we tested the role of the selected GRIN2B markers and a set of commonly described environmental moderators using a test for G×E interaction in sib pair-based association analysis of quantitative traits in 178 Italian nuclear families.

RESULTS

Evidence for a significant association was found with the categorical diagnosis of DD, performance intelligence quotient, phonemic elision, and auditory short-term memory. No significant gene-by-environment effects were found.

CONCLUSIONS

Our results add further evidence in support of GRIN2B contributing toward DD and deficits in DD. More specifically, our data support the view that GRIN2B influences DD as a categorical trait and its related quantitative phenotypes, thus shedding further light on the etiologic basis and the phenotypic complexity of this disorder.

N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in the central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here, we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M2 re-entrant loop, a region that lines the pore and is intolerant to missense variation. These de novo variants were identified in children with a set of neurological and neuropsychiatric conditions. Evaluation of the receptor cell surface expression, pharmacological properties, and biophysical characteristics show that these variants can have modest changes in agonist potency, proton inhibition, and surface expression. However, voltage-dependent magnesium inhibition is significantly reduced in all variants. The NMDARs hosting a single copy of a mutant subunit showed a dominant reduction in magnesium inhibition for some variants. These variant NMDARs also show reduced calcium permeability and single-channel conductance, as well as altered open probability. The data suggest that M2 missense variants increase NMDAR charge transfer in addition to varied and complex influences on NMDAR functional properties, which may underlie the patients' phenotypes.

A number of candidate genes for lithium prophylactic efficacy have been proposed, some of them being also associated with a predisposition to bipolar illness. The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder, in relation to the putative role of these genes in the pathogenesis of this disorder. Some association with lithium prophylactic efficacy was found for the polymorphisms of 5HTT, DRD1, COMT, BDNF and FYN genes, but not for 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GSK-3, NTRK2, GRIN2B and MMP-9. Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed.

It is well established that adversities and GRIN2B (coding an N-methyl-D-aspartate receptor subunit) are independently associated with behavioral and cognitive impairments in childhood. However, a high proportion of children exposed to adversities have good, long-term outcomes. We hypothesized that among children exposed to adversities, GRIN2B variants would predict the worst cognitive and behavioral outcomes. 6 single nucleotide polymorphisms of GRIN2B were genotyped in 625 children aged 6-11 years from an Italian community-based sample. The interacting effect of GRIN2B variants with 4 measures of adversities [low socioeconomic status (SES), preterm delivery, maternal smoking during pregnancy, and absence of breastfeeding] was investigated upon blindly assessed cognitive abilities (vocabulary, block design, digit spans of Wechsler's Intelligence Scale, and Rey complex figure) and parents-rated behavioral problems (Child Behavior Checklist/6-18). Rs2268119 × SES interaction (Hotelling's Trace = 0.07; F(12,1154) = 3.53; p = 0.00004) influenced behavior, with more attention problems among children in the 'either A/T or T/T genotype and low SES' group, compared to all other groups. This interaction effect was not significant in an independent, replication sample of 475 subjects from an Italian community-based sample. GRIN2B variants predict children with the worst outcome in attention functioning among children exposed to low SES. Our findings, if replicated, could help in the identification of children with the highest risk and may prompt cost-effective preventive/treatment strategies.

Disturbances in glutamate signaling caused by disruption of N-methyl-D-aspartate-type glutamate receptor (NMDAR) have been implicated in schizophrenia. Findings suggested that miR-219, miR-132 and miR-107 could involve in NMDAR signaling by influencing the expression of pathway genes or the signaling transmission and single nucleotide polymorphisms (SNPs) within miRNA genes or miRNA target sites could result in their functional changes. Therefore, we hypothesized that SNPs in miRNAs and/or their target sites were associated with schizophrenia. 3 SNPs in hsa-pri-miR-219/132/107 and 6 SNPs in 3'UTRs of GRIN2A/2B/3A and CAMK2G were selected and genotyped in a case-control study of 1041 schizophrenia cases and 953 healthy controls in Chinese Han population. In the present study, GRIN2B rs890 showed significant associations with schizophrenia. Further functional analyses showed that the rs890 variant C allele led to significantly lower luciferase activity, compared with the A allele. MDR analysis showed that a 4-locus model including rs107822, rs2306327, rs890 and rs12342026 was the best model. These findings suggest that GRIN2B may be associated with schizophrenia and interaction effects of the polymorphisms in hsa-miR-219, CAKM2G, GRIN2B and GRIN3A may confer susceptibility to schizophrenia in the Chinese Han population.

This study tested the effects of long-term estradiol (E2) replacement on social behavior and gene expression in brain nuclei involved in the regulation of these social behaviors in adult female rats. We developed an ultrasonic vocalization (USV) test and a sociability test to examine communications, social interactions, and social preference, using young adult female cagemates. All rats were ovariectomized (OVX) and implanted with a Silastic capsule containing E2 or vehicle, and housed in same-treatment pairs for a 3-month period. Then, rats were behaviorally tested, euthanized, and 5 nuclei in the brain's social decision-making circuit were selected for neuromolecular profiling by a multiplex qPCR method. Our novel USV test proved to be a robust tool to measure numbers and types of calls emitted by cagemates that had been reintroduced after a 1-week separation. Results also showed that E2-treated OVX rats had profoundly decreased numbers of USV calls compared to vehicle-treated OVX rats. In a test of sociability, in which a female was allowed to choose between her cagemate or a same-treatment novel rat, we found few effects of E2 compared to vehicle, although interestingly, rats chose the cagemate over an unfamiliar conspecific. Gene expression results revealed that the supraoptic nucleus had the greatest number of gene changes caused by E2: Oxt, Oxtr and Avp were increased, and Drd2, Htr1a, Grin2b, and Gabbr1 were decreased, by E2. No genes were affected in the prefrontal cortex, and 1-4 genes were changed in paraventricular nucleus (Pgr), bed nucleus of the stria terminalis (Oxtr, Esr2, Dnmt3a), and medial amygdala (Oxtr, Ar, Foxp1, Tac3). Thus, E2 changes communicative interactions between adult female rats, together with selected expression of genes in the brain, especially in the supraoptic nucleus.

Based on the interplay between dopaminergic and glutamatergic systems, N-Methyl-D-Asparate (NMDA) receptor genes are thought to be involved in the pathophysiology of ADHD. However, the phenotypical correlates of brain functions associated with NMDA receptor genes and dopamine receptor genes in ADHD are yet to be investigated. We examined the diagnosis, genotype and the diagnosis-genotype interaction effects of GRIN2B and DRD4 variants on the local functional connectivity (by using the mean of static regional homogeneity (ReHo) and the mean and standard deviation (SD) of dynamic ReHo) in 67 ADHD subjects and 44 controls (aged 6-17 years). GRIN2B genotypes were divided into the C/C group and T allele carrier group; DRD4 genotypes were divided into the 2R group and non-2R group. The correlation between the ReHo values showing significant diagnosis-genotype interaction and Children's Color Trails Test (CCTT) scores were examined. CCTT measures processing speed, sustained and divided attention. There were significant diagnosis (p < 0.001) and interaction (p = 0.02) effects of the GRIN2B variant on the static ReHo mean in the left superior parietal cluster, and the ReHo value was positively correlated with the CCTT interference score in the ADHD with T allele carrier subgroup (p = 0.012). There were significant diagnosis (p < 0.001) and interaction (p = 0.03) effects of the DRD4 variant on the dynamic ReHo SD in the right superior parietal cluster. These results suggest that alterations in the glutamate and dopamine system in ADHD may contribute to abnormalities in local functional connectivity and its dynamic repertoire in the superior parietal area, and these abnormalities would be related to dysfunction in sustained and divided attention.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

UNASSIGNED

In the absence of cytogenetic abnormality, fetuses with congenital anomalies of the kidney and urinary tract (CAKUT) with/without other structural anomalies show a higher likelihood of monogenic causes; however, defining the underlying pathology can be challenging. Here, we investigate the value of whole-exome sequencing (WES) in fetuses with CAKUT but normal findings upon karyotyping and chromosome microarray analysis.

UNASSIGNED

WES was performed on DNA from the cord blood of 30 fetuses with unexplained CAKUT with/without other structural anomalies. In the first 23 cases, sequencing was initially performed on fetal DNA only; for the remaining seven cases, the trio of fetus, mother and father was sequenced simultaneously.

UNASSIGNED

Of the 30 cases, pathogenic variants were identified in 4 (13%) (UMOD, NEK8, HNF1B and BBS2) and incidental variants in 2 (7%) (HSPD1 and GRIN2B). Furthermore, two of the above four cases had other anomalies in addition to CAKUT. Thus, the detection rate was only 2/22 (9.1%) for isolated CAKUT and 2/8 (25%) for CAKUT with other abnormalities.

UNASSIGNED

Applying WES to the prenatal diagnostic approach in CAKUT fetuses with or without other anomalies allows for an accurate and early etiology-based diagnosis and improved clinical management. To expedite interpretation of the results, trio sequencing should be employed; however, interpretation may nevertheless be compromised by incomplete coverage of all relevant genes.

BACKGROUND

The GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects.

METHODS

We computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122).

RESULTS

Five polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex.

CONCLUSIONS

Multiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults.

Some genes involved in neurotransmission synthesis and transmission have been hypothesized to affect personality traits. To investigate the possible roles of these genes in personality traits of 16 Personality Factor Questionnaire, we performed a population-based study in a young Chinese Han cohort. In the study, we selected some functional variations in ten candidate genes (COMT, DBH, DRD(2), DRD(3), DAT, MAOA, GRM(1), GRIN2B, 5-TH(2A), and 5-TH(6)) encoding components in dopamine, glutamate, and 5-hydroxytryptamine pathways. The results showed the T102C in 5-TH(2A) was associated with X3 (emotional and quiet alertness) and B (reasoning) (F = 4.71 and 6.23; p = 0.009 and 0.002), Val158Met in COMT with E (dominance) (F = 7.01; p = 0.0009), while the variations in DBH, DRD(2), DRD(3), MAOA, GRM(1), GRIN2B, and 5-TH(6) were not associated with any of the personality traits. This finding suggests that T102C in 5-TH(2A) and Val158Met in COMT play roles in some human personality traits.

Drugs of abuse act as reinforcers because they influence learning and memory processes resulting in long-term memory of drug reward. We have previously shown that mice conditioned by fixed daily dose of cocaine (Fix-C) or daily escalating doses of cocaine (Esc-C) resulted in short- and long-term persistence of drug memory, respectively, suggesting different mechanisms in acquisition of cocaine memory. The present study was undertaken to investigate the differential contribution of N-methyl-D-aspartate receptor (NMDAR) subunits in the formation of Fix-C and Esc-C memory in C57BL/6J mice. Training by Esc-C resulted in marked elevation in hippocampal expression of Grin2b mRNA and NR2B protein levels compared with training by Fix-C. The NR2B-containing NMDAR antagonist ifenprodil had similar attenuating effects on acquisition and reconsolidation of Fix-C and Esc-C memory. However, the NMDAR antagonist MK-801 had differential effects: (1) higher doses of MK-801 were required for post-retrieval disruption of reconsolidation of Esc-C memory than Fix-C memory; and (2) pre-retrieval MK-801 inhibited extinction of Fix-C memory but it had no effect on Esc-C memory. In addition, blockade of NMDAR downstream signaling pathways also showed differential regulation of Fix-C and Esc-C memory. Inhibition of neuronal nitric oxide synthase attenuated acquisition and disrupted reconsolidation of Fix-C but not Esc-C memory. In contrast, the mitogen-activating extracellular kinase inhibitor SL327 attenuated reconsolidation of Esc-C but not Fix-C memory. These results suggest that NMDAR downstream signaling molecules associated with consolidation and reconsolidation of cocaine-associated memory may vary upon changes in the salience of cocaine reward during conditioning.

Semantic and episodic memories were two different attributes of long-term memory. In the past few years, plenty of physiological evidence has indicated that neural plasticity is involved in the formation of long-term memory. In the present study, we hypothesized that some functional variants of neural plasticity-related genes were related to episodic and semantic memories. To confirm this hypothesis, we examined the relationship of 13 plasticity-related genes with episodic and semantic memories. The results indicated that there was a statistically significant difference in semantic memory scores among the three genotype groups of T267C in 5-HT ( 6 ) (χ (2) = 16.638, p = 0.0002). However, the functional variations in BDNF, COMT, DBH, DRD ( 2 ), DRD ( 3 ), DRD ( 4 ), MAOA, TPH ( 2 ), 5-HT ( 2A ), GRM ( 1 ), and GRIN2B had no observable effects on the memories. Our preliminary results confirm the hypothesis that a small number of functional variants of the neural plasticity-related genes, such as T267C in 5-HT ( 6 ), play important roles in human specific memory.

Autoantibody profiling with a systems medicine approach can help identify critical dysregulated signaling pathways (SPs) in cancers. In this way, immunoglobulins G (IgG) purified from the serum samples of 92 healthy controls, 10 pre-treated (PR) non-Hodgkin lymphoma (NHL) patients, and 20 NHL patients who underwent chemotherapy (PS) were screened with a phage-displayed random peptide library. Protein-protein interaction networks of the PR and PS groups were analyzed and visualized by Gephi. The results indicated AXIN2, SENP2, TOP2A, FZD6, NLK, HDAC2, HDAC1, and EHMT2, in addition to CAMK2A, PLCG1, PLCG2, GRM5, GRIN2B, GRIN2D, CACNA2D3, and SPTAN1 as hubs in 11 and 7 modules of PR and PS networks, respectively. PR- and PS-specific hubs were evaluated in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. The PR-specific hubs were involved in Wnt SP, signaling by Notch1 in cancer, telomere maintenance, and transcriptional misregulation. In contrast, glutamate receptor SP, Fc receptor-related pathways, growth factors-related SPs, and Wnt SP were statistically significant enriched pathways, based on the pathway analysis of PS hubs. The results revealed that the most PR-specific proteins were associated with events involved in tumor development, while chemotherapy in the PS group was associated with side effects of drugs and/or cancer recurrence. As the findings demonstrated, PR- and PS-specific proteins in this study can be promising therapeutic targets in future studies.