RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains / 神经科学通报·英文版

The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.

Discussion on the discipline construction about National Clinical Research Center for mental disorders / 中华医学科研管理杂志

Objective:To provide reference for domestic colleagues by introducing the contents of the discipline construction of the National Clinical Research Center for mental disorders.Methods:By reviewing the original intention of the construction of the National Clinical Research Centers initiated by many ministries and departments, taking into account of the actual construction practice at hospital level in the field of mental disorders, this paper discusses the discipline construction of the National Clinical Research Center.Results:From the aspects of construction goals, purposes, overall operation modes, construction of collaborative innovation research network, the paper clarifies the concrete measures of the construction of the center.Conclusions:Through the evaluation of the current situation, the National Clinical Research Center for mental disorders has defined the focus of the construction: to build a management platform and two professional platforms, in order to provide support for the development of high-quality and high-level clinical research, and provide support for the transformation of clinical medicine.

Association study of MTHFR C677T polymorphism and birth body mass with risk of autism / 中华行为医学与脑科学杂志

Objective To explore the association of MTHFR C677T polymorphism and birth body mass with the vulnerability of autism in Chinese Han population. Methods Totally 1 505 children with au-tism have been recruited,using the diagnosis and statistical manual,4th revised version ( DSM-IV-R) diag-nostic criteria for autism. And 1 308 healthy control subjects sex matched with the children with autism were enrolled for the study. All the participants were identified the birth body mass ( kg) according to the birth medical recording. All the subjects were examined the MTHFR C677T genotypes,using the polymerase chain reaction- restrict fragment length polymorphism (PCR-RFLP) methods. The frequencies of genotypes,alleles and birth body mass were compared between autism and healthy control groups using the chi-square and other tests. Results The MTHFR C677T (P=0. 004,OR=1. 18,95% CI=1. 02-1. 29),low birth body mass (<2. 5 kg) (P=0. 001,OR=1. 04,95%CI=1. 02-1. 06),and their interactive effects ( P=0. 0001,OR=2. 18,95%CI=1. 44-3. 32) were associated with the vulnerability of autism. Conclusions The MTHFR C677T polymorphism,low birth body mass and their interactive effects might be associated with susceptibility of autism in Chinese Han population.

P-Rex1 Overexpression Results in Aberrant Neuronal Polarity and Psychosis-Related Behaviors / 神经科学通报·英文版

Neuronal polarity is involved in multiple developmental stages, including cortical neuron migration, multipolar-to-bipolar transition, axon initiation, apical/basal dendrite differentiation, and spine formation. All of these processes are associated with the cytoskeleton and are regulated by precise timing and by controlling gene expression. The P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1) gene for example, is known to be important for cytoskeletal reorganization, cell motility, and migration. Deficiency of P-Rex1 protein leads to abnormal neuronal migration and synaptic plasticity, as well as autism-related behaviors. Nonetheless, the effects of P-Rex1 overexpression on neuronal development and higher brain functions remain unclear. In the present study, we explored the effect of P-Rex1 overexpression on cerebral development and psychosis-related behaviors in mice. In utero electroporation at embryonic day 14.5 was used to assess the influence of P-Rex1 overexpression on cell polarity and migration. Primary neuron culture was used to explore the effects of P-Rex1 overexpression on neuritogenesis and spine morphology. In addition, P-Rex1 overexpression in the medial prefrontal cortex (mPFC) of mice was used to assess psychosis-related behaviors. We found that P-Rex1 overexpression led to aberrant polarity and inhibited the multipolar-to-bipolar transition, leading to abnormal neuronal migration. In addition, P-Rex1 overexpression affected the early development of neurons, manifested as abnormal neurite initiation with cytoskeleton change, reduced the axon length and dendritic complexity, and caused excessive lamellipodia in primary neuronal culture. Moreover, P-Rex1 overexpression decreased the density of spines with increased height, width, and head area in vitro and in vivo. Behavioral tests showed that P-Rex1 overexpression in the mouse mPFC caused anxiety-like behaviors and a sensorimotor gating deficit. The appropriate P-Rex1 level plays a critical role in the developing cerebral cortex and excessive P-Rex1 might be related to psychosis-related behaviors.

Association study of gamma-aminobutyric acid type A receptor genes cluster with autism in Chinese Han population / 中国心理卫生杂志

Objective:To investigate the genetic association of single nucleotide polymorphisms (SNPs) in gamma-aminobutyric acid type A (GABAA) receptor genes cluster on chromosome 15q12 with autism in Chinese Han population.Methods:Totally 502 autism trios of Chinese Han ethnicity (including 502 autism individuals and 1004 healthy biological parents) were selected.All children met the autism diagnosis of Diagnostic and Statistical Manual of Mental Disorders,Fourth edition (DSM-Ⅳ).Genotyping for 15 selected tag SNPs in three GABAA receptor genes (GABRB3,GABRA5,and GABRG3) was performed using Agena Bioscience MassARRAY platform.The family-based association test for 15 tag SNPs was performed to compare the transmitted frequency of al leles of heterozygous genotypes from parents to offspring in autism trios.Results:The C allele of rs7180500 in GABRG3 and the A allele of rs4906902 in GABRB3 exhibited the preferential transmission from parents to affected offspring (Z =3.573,P ＜0.001;Z =3.141,P =0.002),and the association was significant after Bonferroni correction.Conclusion:It suggests that GABRG3 and GABRB3 which located in chromosome 15q12 might be susceptibility genes in Chinese Han population.

Association of AKT1 gene polymorphisms with therapeutic effects of 8-week treatment with risperidone / 中国心理卫生杂志

Objective:To investigate the association of AKT1 gene polymorphism with risperidone in the treatment of first-episode and untreated schizophrenia for 8 weeks.Methods:A total of 150 patients with Chinese schizophrenia who met DSM-Ⅳ,including 128 cases of risperidone (treatment dose 4-6 mg/d) for 8 weeks were treated with risperidone (treatment dose 4-6 mg/d).The Positive and Negative Symptom Scale (PANSS) reduction rate was used to evaluate the curative effect of drugs after 8 weeks.Using DNA sequencing,four single nucleotide polymorphisms (SNP) loci (rs1130214,rs10149779,rs1130233,rs2494732) genotype were detected in 128 Han patients with schizophrenia,and quantitative trait locus analysis (QTL) was used to explore the association between AKT1 gene polymorphisms and the efficacy of risperidone in the treatment of schizophrenia.Results:AKT1 gene rs1130233 (G ＞ A) and rs2494732(C ＞ T) were significantly associated with the increase in PANSS after 8-week risperidone treatment of schizophrenia (P ＜ 0.05).After repeated testing Bonferroni correction was still statistically significant.The correlation between rs1130214and rs10149779 in this sample was not statistically significant (P ＞0.05).Conclusion:This study suggests that polymorphisms of the AKT1 gene may be associated with the efficacy of risperidone in the treatment of schizophrenia in the Chinese Han population and is expected to provide a basis for the prediction of individual drug efficacy.

ZNF804A Variation May Affect Hippocampal-Prefrontal Resting-State Functional Connectivity in Schizophrenic and Healthy Individuals / 神经科学通报·英文版

The ZNF804A variant rs1344706 has consistently been associated with schizophrenia and plays a role in hippocampal-prefrontal functional connectivity during working memory. Whether the effect exists in the resting state and in patients with schizophrenia remains unclear. In this study, we investigated the ZNF804A polymorphism at rs1344706 in 92 schizophrenic patients and 99 healthy controls of Han Chinese descent, and used resting-state functional magnetic resonance imaging to explore the functional connectivity in the participants. We found a significant main effect of genotype on the resting-state functional connectivity (RSFC) between the hippocampus and the dorsolateral prefrontal cortex (DLPFC) in both schizophrenic patients and healthy controls. The homozygous ZNF804A rs1344706 genotype (AA) conferred a high risk of schizophrenia, and also exhibited significantly decreased resting functional coupling between the left hippocampus and right DLPFC (F(2,165) = 13.43, P < 0.001). The RSFC strength was also correlated with cognitive performance and the severity of psychosis in schizophrenia. The current findings identified the neural impact of the ZNF804A rs1344706 on hippocampal-prefrontal RSFC associated with schizophrenia.

Progressive Grey Matter Volume Changes in Patients with Schizophrenia over 6 Weeks of Antipsychotic Treatment and Their Relationship to Clinical Improvement / 神经科学通报·英文版

Cross-sectional and longitudinal studies have identified widespread and progressive grey matter volume (GMV) reductions in schizophrenia, especially in the frontal lobe. In this study, we found a progressive GMV decrease in the rostral medial frontal cortex (rMFC, including the anterior cingulate cortex) in the patient group during a 6-week follow-up of 40 patients with schizophrenia and 31 healthy controls well-matched for age, gender, and education. The higher baseline GMV in the rMFC predicted better improvement in the positive score on the Positive and Negative Syndrome Scale (PANSS), and this might be related to the improved reality-monitoring. Besides, a higher baseline GMV in the posterior rMFC predicted better remission of general symptoms, and a lesser GMV reduction in this region was correlated with better remission of negative symptoms, probably associated with ameliorated self-referential processing and social cognition. Besides, a shorter disease course and higher educational level contributed to better improvement in the general psychopathological PANSS score, and a family history was negatively associated with improvement of the negative and total PANSS scores. These phenomena might be important for understanding the neuropathological mechanisms underlying the symptoms of schizophrenia and for making clinical decisions.

Sleep architecture in drug naive patients with schizophrenia: A meta-analysis / 中国心理卫生杂志

Objective:To assess the characteristics change of sleep architecture in drug naive patients with schizophrenia,compared with healthy control.Methods:The key words including schizophrenia and sleep architecture (or sleep structure or sleep disturbance or polysomnogram and so on) were used to search literatures in MEDLINE,Embase,Springer,PsychINFO,google scholar,Wanfang data,published from 1980 to 2015.Fifteen studies that compared sleep architecture in drug naive patients with schizophrenia and healthy control were included.Literature quality evaluation was performed with the Newcastle-Ottawa Scale.The meta-analysis was performed by using Stata13.0 software.Results:Compared to healthy control,the total sleep time decreased (P ＜ 0.01),the sleep latency increased (P ＜ 0.01),the sleep efficiency decreased (P ＜ 0.01),and the rapid-eye-movemem (REM) sleep latency increased (P ＜ 0.01) significantly in drug naive patients with schizophrenia.The proportion of stage1 was increased,and the proportions of stage4 and slow wave sleep stage were decreased,the differences between case and control were statistically significant.Conclusion:In the control of drug effects,patients with schizophrenia may have poorer sleep quality of be poorer than healthy controls,such as the decreased total sleep time,specifically slow wave sleep,prolonged sleep latency and decreased sleep efficiency.

Association of MTHFR C677T polymorphism with weight gain induced by risperidone in schizophrenia / 中华行为医学与脑科学杂志

Objective To explore the association of methylenetetrahydrofolate reductase (MTHFR)gene C677T polymorphism with weight gain induced by risperidone.Methods 356 patients with schizophrenia according to the DSM-IV criteria in this study.The height and body weight of the patients were measured before starting risperidone treatment and 8-week later.The MTHFRC677T polymorphism was genotyped using direct DNA sequencing method.Results A significant association was found between MTHFR gene C677T and body weight mass index (BMI) change after 8-week risperidone treatment.CC-carriers experienced higher BMI gain than CT/TT-carriers (CC (4.47 ± 1.09),CT (4.54 ± 1.27),TT (2.31 ± 0.75),F =5.634,P＜0.01).The frequency of allele C in bodyweight gain (＞7％) was higher than that in non-bodyweight gain groups (48.4％ vs 32.4％,x2=11.342,P＜0.01).Conclusion MTHFRC677T polymorphism is associated with risperidone induced weight gain in Chinese Han population.

Association of MTHFR C677T polymorphism with weight gain induced by risperidone in schizophrenia / 中华行为医学与脑科学杂志

Objective To explore the association of methylenetetrahydrofolate reductase (MTHFR)gene C677T polymorphism with weight gain induced by risperidone.Methods 356 patients with schizophrenia according to the DSM-IV criteria in this study.The height and body weight of the patients were measured before starting risperidone treatment and 8-week later.The MTHFRC677T polymorphism was genotyped using direct DNA sequencing method.Results A significant association was found between MTHFR gene C677T and body weight mass index (BMI) change after 8-week risperidone treatment.CC-carriers experienced higher BMI gain than CT/TT-carriers (CC (4.47 ± 1.09),CT (4.54 ± 1.27),TT (2.31 ± 0.75),F =5.634,P＜0.01).The frequency of allele C in bodyweight gain (＞7％) was higher than that in non-bodyweight gain groups (48.4％ vs 32.4％,x2=11.342,P＜0.01).Conclusion MTHFRC677T polymorphism is associated with risperidone induced weight gain in Chinese Han population.

Karyotypes analyses in 632 autism spectrum disorder trios / 中国神经精神疾病杂志

Objective To detect chromosomal aberrations of autism spectrum disorder (ASD), we performed karyo?types analyses in 632 ASD trios and then investigated whether copy number variants and neurodevelopment related genes are present in the regions of chromosomal aberrations. Methods Karyotypes analyses were performed in 632 ASD trios (1896 individuals). In addition, we investigated whether there were pathogenic copy number variants located in the rele?vant regions of detected aberrant karyotypes by using the database of the International Standards for Cytogenomic Arrays (ISCA) and the Genomic Variation and Phenotype in Humans using Ensembl Resources (DECIPHER) for ASD patients. Results We detected aberrant results in 22 of 632 patients (3.48%) by karyotypes analyses. Of these 22 aberrant karyo?types, 5 were de novo (0.79%), including the duplication, the translocation, karyotypes of Turner syndrome and the addi?tional material with unknown origin. Seventeen children affected with autism had aberrant karyotypes inherited from one of their parents. By using the ISCA and the DECIPHER database, we found that several copy number variants with high pathogenicity were located in 1q25 and 3p24. Further, these copy number variants consisted of several genes related to neurodevelopment such as TNR, ASTN1, and NMNAT2. Conclusion There are a few de novo chromosomal aberrations in some patients affected with ASD. Copy number variants of several pathogenic neurodevelopmental related genes may exist in the regions of chromosomal aberrations. Karyotypes analyses may be applied to explore the genetic etiology in some patients affected with ASD.

Detection of differentially expressed miRNAs in serum of patients with schizophrenia by RT-PCR / 中国心理卫生杂志

Objective:To detect differentiallyexpressed microRNAs (miRNAs)in plasma of schizophrenia and explore biomarker for diagnosis of schizophrenia.Methods:The discovery cohort tincluded 6 patients with schizophrenia meeting diagnostic criteria of schizophrenia of the Diagnostic and Statistical Manual of Mental Disor-der,Fourth Edition (DSM-IV),as well as 6 healthy control subjects,whose age and gender were matched to pa-tients.The expression of 754 miRNAs (Sanger human miRBase v14)in the discovery cohort was investigated by Taqman Array (Human MicroRNA A +B Cards Set v3.0).Then the quantitative reverse-transcription polymor-phism chain reaction (qRT-PCR)assay was conducted to validate differentially expressed miRNAs in an independ-ent replication cohort,which included 25 schizophrenia patients and 18 healthy control subjects.The student's t-tests were used to analyze the differential expression of miRNA between schizophrenia patients and controls.All analyses were performed in Significance Analysis of Microarrays (SAM)software.Results:Twenty down-regulated miRNAs were observed in discovery cohort.Four miRNAs,hsa-miR-15b-5p were down-regulated in both discovery and rep-licated cohorts.Conclusion:The present study suggests that aberrant expression of miRNA might be of potential im-portance as biomarkers in the diagnosis of schizophrenia.

The association study of Ghrelin gene polymorphisms with the susceptivity of schizophrenia in Chinese Han population / 中华行为医学与脑科学杂志

Objective To investigate the potential association of Ghrelin(GHRL)gene polymorphisms susceptible to schizophrenia by case-control study.Methods Six hundred and thirty-four patients,six hundred and six healthy control subjects were recruited.Four SNPs rs696217,rs26802,rs27647 and rs26311 were detected by the polymerase chain reaction-based-restriction fragment length polymorphism analysis.Results No significant differences in genotype or allele frequencies of the four SNPs were observed between schizophrenic patients and healthy controls (Pvalues of genotype frequencies were 0.649,0.944,0.410,0.826;P values of allele frequencies were 0.773,0.992,0.301,0.723).However,seven haplotypes(GAAG,GAGC,GAGG,GCGC,GCGG,TAGC,TAGG)showed significant differences in frequency between schizophrenic and control groups(P values were 0.011,0.001,1.76×10-6,9.84×10-10,1.38×10-9,2.12×10-5,2.57×10-6).Conclusion These data suggest that the GHRL gene may not be associated with susceptibility to schizophrenia in the Chinese Han population.However,the haplotype of GA may be the susceptive factor of schizophrenia.

Association Study of the Disrupted in Schizophrenia 1(DISC1)Gene Polymorphisms with Schizophrenia / 中国心理卫生杂志

T,P=0.008; Genotype:P=0.031)of DISC1 gene were significantly associated with schizophrenia.The haplotypes constructed by these two markers were significantly associated with schizophrenia,such as AT(?2=7.065,P=0.008,OR=1.42,95%CI=1.10~1.83)and GA(?2=6.009,P=0.014,OR=0.80,95%CI=0.68~0.96).When the subjects examined with the positive and negative syndrome scale(PANSS),the risk haplotype AT was not significantly correlated with positive,negative,excitement,depression and cognitive impairment factors of PANSS. Conclusion:These findings provide further evidence for DISC1 as a predisposing gene involved in schizophrenia in the Chinese Han Population.However,no positive association is found between DISC1 polymorphisms with schizophrenia clinical symptoms.

Depression and Anxiety in Patients with Sleep Apnea-hypopnea Syndrome / 中国临床心理学杂志

Objective: To evaluate the depression and anxiety in patients with sleep apnea-hypopnea syndrome (SAHS). Methods: Fifty patients with SAHS were diagnosed with polysomnography (PSG) and 30 healthy controls underwent whole-night PSG monitory and evaluated by Zung Self-rating Depression Scale (SDS) and Zung Self-rating Anxiety Scale (SAS). Results: The total scores of SAS and SDS in SAHS group were significantly higher than those in control group ( P