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Hong Xue - One of the best experts on this subject based on the ideXlab platform.
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GABRB2 in Neuropsychiatric Disorders: Genetic Associations and Functional Evidences
Current Psychopharmacology, 2019Co-Authors: Shui Y. Tsang, Ata Ullah, Hong XueAbstract:Background: The inhibitory GABAergic system has shown an association with multiple psychiatric disorders. The type A GABA receptors are an integral component of this system, and in recent years, evidence has accumulated to support an essential role in disease etiology for one of the receptor genes GABRB2 which encodes for the receptor β2 subunit. Objective: To summarize the different lines of evidence supporting the important role of GABRB2 in psychiatric disorders, with a particular focus on schizophrenia, and evaluate the recently-proposed GABRB2-origin of schizophrenia hypothesis. Results: In terms of genetics, Single Nucleotide Polymorphisms (SNPs) in GABRB2 have been associated with a number of psychiatric disorders, and some of the associations have remained significant following meta-analysis. Importantly, expression and alternative splicing of the gene was shown to be dependent on the genotypes of the associated SNPs, and receptors containing the long isoform displayed functional differences compared to those containing the short isoform. Moreover, differential epigenetic regulation and imprinting imbalance of the gene were observed in schizophrenic patients compared to healthy subjects. Finally, recent findings from a GABRB2-knockout mouse model demonstrated that knockout of the gene alone was sufficient to induce a wide range of schizophrenia- like symptoms and comorbid phenotypes. Conclusion: The different lines of evidence coalesce to strongly support the recentlyproposed GABRB2-origin of schizophrenia hypothesis, and GABRB2 may also have a potential role in cognition, the dysfunction of which is common to many psychiatric disorders.
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GABRB2 IS FUNCTIONALLY CONSERVED IN MOUSE AND MAN FOR ESSENTIAL NEURO-PSYCHOMOTOR ACTIVITIES
European Neuropsychopharmacology, 2019Co-Authors: Hong Xue, Shui Ying Tsang, Rigil K. Yeung, Zheng-hua Xiang, Pak C. Sham, Gerald StoeberAbstract:Background The type A γ-aminobutyric acid (GABAA) receptor β2 subunit gene (GABRB2) has been associated with various neuropsychiatric disorders including Schizophrenia (SCZ). However, limited examination of the phenotypical changes in GABRB2-knockout mice have been conducted. Methods Herein, GABRB2 homozygous (KO) and Heterozygous (Het) knockouts were compared with Wild-Type (WT) mice for neuropsychiatric and neurochemical alterations. Results KO exhibited increased acoustic startle, prepulse inhibition deficits, locomotor hyperactivity, behavioral stereotypy, spatial-working memory deficit and sociability impairments, establishing GABRB2-KO as SCZ-like. Moreover, reduced anxiety and depression was observed in KO, and 8-week male KO displayed compromised fertility. Het mice partially exhibited these symptoms, and the atypical antipsychotic, risperidone, partially restored these phenotypes, especially hyper-motor activity, but not sociability. Parent-of-origin effects on spontaneous motor activities were also detected. Audiogenic epilepsy was observed in KO and latency to pentylenetetrazol-induced seizure was significantly shortened, with shorter latency in female than male in both tests. The oxidation and inflammation markers, malondialdehyde, TNFα and IL6, were elevated in KO brains, and immunostaining indicated less GFAP-expressing astrocytes and DCX-expressing new-born neurons in KO hippocampus, suggesting possible involvement of oxidative stress-induced neurogenesis inhibition. Discussion Our results highlight GABRB2 being evolutionarily adapted to maintain fundamental neuro-psychomotor activities, and its dysfunction is attributable to a range of psychiatric and neurological symptoms, often comorbid in human.
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GABRB2 -knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron–astrocyte–microglia dysregulation
Translational psychiatry, 2018Co-Authors: Rigil K. Yeung, Shui Ying Tsang, Zheng-hua Xiang, Pak C. Sham, Chok-king Hui, Ming-qi Qiao, Hong XueAbstract:Intronic polymorphisms of the GABAA receptor β2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of GABRB2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by GABRB2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology.
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GABRB2 knockout mice displayed schizophrenia like and comorbid phenotypes with interneuron astrocyte microglia dysregulation
Translational Psychiatry, 2018Co-Authors: Rigil K. Yeung, Shui Ying Tsang, Hong Xue, Zheng-hua Xiang, Pak C. Sham, Chok-king Hui, Ming-qi QiaoAbstract:Intronic polymorphisms of the GABAA receptor β2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of GABRB2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by GABRB2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology.
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Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders.
Schizophrenia Research, 2011Co-Authors: Cunyou Zhao, Feng Wang, Frank Wing Pun, Lingling Mei, Lihuan Ren, Jianhuan Chen, Shui Ying Tsang, Hong XueAbstract:Abstract Introduction To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2 , gene for the type A γ-aminobutyric acid receptor β 2 -subunit, was investigated. Methods Expression of GABRB2 , and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2 , not observable in CON, became significant in BPD. Conclusion These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders.
Cunyou Zhao - One of the best experts on this subject based on the ideXlab platform.
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DNA methylation regulates GABRB2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms.
Genes brain and behavior, 2016Co-Authors: Lijuan Wang, Wei Jiang, Qing Lin, Yiyue Zhang, Cunyou ZhaoAbstract:Single nucleotide polymorphisms (SNPs) in the human type A gamma-aminobutyric acid (GABA) receptor β2 subunit gene (GABRB2) have been associated with schizophrenia and quantitatively correlated with mRNA expression in the postmortem brain tissue of patients with schizophrenia. l-Methionine (MET) administration has been reported to cause a recrudescence of psychotic symptoms in patients with schizophrenia, and similar symptoms have been generated in MET-induced mice. In this study, a zebrafish animal model was used to evaluate the relationship between the GABRB2 mRNA expression and its promoter DNA methylation in developmental and MET-induced schizophrenia-like zebrafish. The results indicated developmental increases in global DNA methylation and decreases in GABRB2 promoter methylation in zebrafish. A significant increase in GABRB2 mRNA levels was observed after GABA was synthesized. Additionally, the MET-triggered schizophrenia-like symptoms in adult zebrafish, involving social withdrawal and cognitive dysfunction analyzed with social interaction and T-maze behavioral tests, were accompanied by significantly increased DNA methylation levels in the global genome and the GABRB2 promoter. Furthermore, the significant correlation between GABRB2 mRNA expression and GABRB2 promoter methylation observed in the developmental stages became non-significant in MET-triggered adult zebrafish. These findings demonstrate that GABRB2 mRNA expression is associated with DNA methylation varies by developmental stage and show that these epigenetic association mechanisms are disrupted in MET-triggered adult zebrafish with schizophrenia-like symptoms. In conclusion, these results provide plausible epigenetic evidence of the GABAA receptor β2 subunit involvement in the schizophrenia-like behaviors and demonstrate the potential use of zebrafish models in neuropsychiatric research.
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Association of single nucleotide polymorphisms in the promoter of GABAA receptor β2 subunit gene with schizophrenia
Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2015Co-Authors: Lin Zhou, Lu Zong, Lulu Zhang, Cong Deng, Cunyou ZhaoAbstract:OBJECTIVE To investigate the genetic association between schizophrenia and the polymorphism of GABA(A) receptor β2 subunit (GABRB2) gene. METHODS A population association analysis was performed of 5 single nucleotide polymorphisms (SNPs) in the proximal promoter of GABRB2 gene by PCR and sequencing of the genomic DNA in a cohort of 172 schizophrenics and 167 controls of Chinese Han nationality. RESULTS One out of the 5 SNPs, namely rs3811996, was found to be significantly associated with schizophrenia especially in the male cohorts, where the heterozygous genotypes (A/G) and minor allele G displayed lower frequencies in case group than in the controls. CONCLUSION We found a new risk, SNP rs3811996, for paranoia schizophrenia, which further supports the importance of genetic variations of GABRB2 in the etiology of schizophrenia.
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Social cognitive role of schizophrenia candidate gene GABRB2.
PloS one, 2013Co-Authors: Shui Ying Tsang, Cunyou Zhao, Frank Wing Pun, Lingling Mei, Jianhuan Chen, Songfa Zhong, Bing-yi Jing, Robin Chark, Jianhua GuoAbstract:The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition.
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Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders.
Schizophrenia Research, 2011Co-Authors: Cunyou Zhao, Feng Wang, Frank Wing Pun, Lingling Mei, Lihuan Ren, Jianhuan Chen, Shui Ying Tsang, Hong XueAbstract:Abstract Introduction To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2 , gene for the type A γ-aminobutyric acid receptor β 2 -subunit, was investigated. Methods Expression of GABRB2 , and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2 , not observable in CON, became significant in BPD. Conclusion These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders.
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Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders.
Schizophrenia research, 2011Co-Authors: Cunyou Zhao, Feng Wang, Frank Wing Pun, Lingling Mei, Lihuan Ren, Jianhuan Chen, Shui Ying Tsang, Hong XueAbstract:To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2, gene for the type A γ-aminobutyric acid receptor β(2)-subunit, was investigated. Expression of GABRB2, and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2, not observable in CON, became significant in BPD. These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.
Shui Ying Tsang - One of the best experts on this subject based on the ideXlab platform.
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GABRB2 IS FUNCTIONALLY CONSERVED IN MOUSE AND MAN FOR ESSENTIAL NEURO-PSYCHOMOTOR ACTIVITIES
European Neuropsychopharmacology, 2019Co-Authors: Hong Xue, Shui Ying Tsang, Rigil K. Yeung, Zheng-hua Xiang, Pak C. Sham, Gerald StoeberAbstract:Background The type A γ-aminobutyric acid (GABAA) receptor β2 subunit gene (GABRB2) has been associated with various neuropsychiatric disorders including Schizophrenia (SCZ). However, limited examination of the phenotypical changes in GABRB2-knockout mice have been conducted. Methods Herein, GABRB2 homozygous (KO) and Heterozygous (Het) knockouts were compared with Wild-Type (WT) mice for neuropsychiatric and neurochemical alterations. Results KO exhibited increased acoustic startle, prepulse inhibition deficits, locomotor hyperactivity, behavioral stereotypy, spatial-working memory deficit and sociability impairments, establishing GABRB2-KO as SCZ-like. Moreover, reduced anxiety and depression was observed in KO, and 8-week male KO displayed compromised fertility. Het mice partially exhibited these symptoms, and the atypical antipsychotic, risperidone, partially restored these phenotypes, especially hyper-motor activity, but not sociability. Parent-of-origin effects on spontaneous motor activities were also detected. Audiogenic epilepsy was observed in KO and latency to pentylenetetrazol-induced seizure was significantly shortened, with shorter latency in female than male in both tests. The oxidation and inflammation markers, malondialdehyde, TNFα and IL6, were elevated in KO brains, and immunostaining indicated less GFAP-expressing astrocytes and DCX-expressing new-born neurons in KO hippocampus, suggesting possible involvement of oxidative stress-induced neurogenesis inhibition. Discussion Our results highlight GABRB2 being evolutionarily adapted to maintain fundamental neuro-psychomotor activities, and its dysfunction is attributable to a range of psychiatric and neurological symptoms, often comorbid in human.
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GABRB2 -knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron–astrocyte–microglia dysregulation
Translational psychiatry, 2018Co-Authors: Rigil K. Yeung, Shui Ying Tsang, Zheng-hua Xiang, Pak C. Sham, Chok-king Hui, Ming-qi Qiao, Hong XueAbstract:Intronic polymorphisms of the GABAA receptor β2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of GABRB2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by GABRB2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology.
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GABRB2 knockout mice displayed schizophrenia like and comorbid phenotypes with interneuron astrocyte microglia dysregulation
Translational Psychiatry, 2018Co-Authors: Rigil K. Yeung, Shui Ying Tsang, Hong Xue, Zheng-hua Xiang, Pak C. Sham, Chok-king Hui, Ming-qi QiaoAbstract:Intronic polymorphisms of the GABAA receptor β2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of GABRB2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by GABRB2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology.
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Social cognitive role of schizophrenia candidate gene GABRB2.
PloS one, 2013Co-Authors: Shui Ying Tsang, Cunyou Zhao, Frank Wing Pun, Lingling Mei, Jianhuan Chen, Songfa Zhong, Bing-yi Jing, Robin Chark, Jianhua GuoAbstract:The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition.
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Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders.
Schizophrenia Research, 2011Co-Authors: Cunyou Zhao, Feng Wang, Frank Wing Pun, Lingling Mei, Lihuan Ren, Jianhuan Chen, Shui Ying Tsang, Hong XueAbstract:Abstract Introduction To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2 , gene for the type A γ-aminobutyric acid receptor β 2 -subunit, was investigated. Methods Expression of GABRB2 , and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2 , not observable in CON, became significant in BPD. Conclusion These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders.
Frank Wing Pun - One of the best experts on this subject based on the ideXlab platform.
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Social cognitive role of schizophrenia candidate gene GABRB2.
PloS one, 2013Co-Authors: Shui Ying Tsang, Cunyou Zhao, Frank Wing Pun, Lingling Mei, Jianhuan Chen, Songfa Zhong, Bing-yi Jing, Robin Chark, Jianhua GuoAbstract:The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition.
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Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders.
Schizophrenia Research, 2011Co-Authors: Cunyou Zhao, Feng Wang, Frank Wing Pun, Lingling Mei, Lihuan Ren, Jianhuan Chen, Shui Ying Tsang, Hong XueAbstract:Abstract Introduction To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2 , gene for the type A γ-aminobutyric acid receptor β 2 -subunit, was investigated. Methods Expression of GABRB2 , and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2 , not observable in CON, became significant in BPD. Conclusion These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders.
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Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders.
Schizophrenia research, 2011Co-Authors: Cunyou Zhao, Feng Wang, Frank Wing Pun, Lingling Mei, Lihuan Ren, Jianhuan Chen, Shui Ying Tsang, Hong XueAbstract:To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2, gene for the type A γ-aminobutyric acid receptor β(2)-subunit, was investigated. Expression of GABRB2, and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2, not observable in CON, became significant in BPD. These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.
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P02-227 - Imprinting in the schizophrenia candidate gene GABRB2
European Psychiatry, 2011Co-Authors: Frank Wing Pun, Cunyou Zhao, Shui Ying Tsang, Vishwajit L. Nimgaonkar, W.s. Chung, Gabor S. Ungvari, Hong XueAbstract:Imprinting, characterized by unequal expression of the offspring's genes in a parent-of-origin dependent manner, has been functionally implicated in brain development and in psychiatric disorders. In this study, unambiguous distortion in paternal but not maternal transmission of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 (T/G) clearly indicated the presence of parent-of-origin effect (POE) in the GABA A receptor β 2 subunit gene (GABRB2). ‘Flipping' of allelic mRNA expression in heterozygotes of SNP rs2229944 (C/T) and the observed two-tiered distribution of mRNA expression levels in heterozygotes of the disease-associated SNP rs1816071 (G/A) furnished important support for the occurrence of imprinting at GABRB2. Imprinting in effect introduced heterozygotes from different parents-of-origin endowed with dissimilar mRNA expression capabilities. The deficit of upper-tiered expressions accounted for the lowered mRNA expression levels in the schizophrenic heterozygotes. This pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, allele-specific methylation was observed at the disease-associated SNPs rs6556547 and rs1816071. These findings raised the possibility that CpG methylation status of these sites could have an impact on the expression of GABRB2 and the risk of schizophrenia. Furthermore, the occurrence of imprinting and allele-specific methylation in the schizophrenia candidate gene GABRB2 was compatible with the epigenetic hypothesis for schizophrenia pathophysiology, thereby calling for the need to explore the role of epigenetic factors in mediating susceptibility to schizophrenia.
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Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA A receptor β 2 subunit
Molecular psychiatry, 2010Co-Authors: Frank Wing Pun, Cunyou Zhao, Shui Ying Tsang, Vishwajit L. Nimgaonkar, W.s. Chung, Gabor S. Ungvari, Hong XueAbstract:Schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In this study, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect strongly suggested that GABRB2 is imprinted. 'Flipping' of allelic expression in heterozygotes of SNP rs2229944 (C/T) in GABRB2 or rs2290732 (G/A) in the neighboring GABRA1 was compatible with imprinting effects on gene expression. Clustering analysis of GABRB2 mRNA expressions suggested that imprinting brought about the observed two-tiered distribution of expression levels in controls with heterozygous genotype at the disease-associated SNP rs1816071 (A/G). The deficit of upper-tiered expressions accounted for the lowered expression levels in the schizophrenic heterozygotes. The occurrence of a two-tiered distribution furnished support for imprinting, and also pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, the two schizophrenia-associated SNPs rs6556547 and rs1816071 overlapped with a CpG dinucleotide, thereby opening the possibility that CpG methylation status of these sites could have an impact on the risk of schizophrenia. Thus multiple lines of evidence pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia.
Luigina Spaccini - One of the best experts on this subject based on the ideXlab platform.
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Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes
International Journal of Molecular Sciences, 2019Co-Authors: Francesca Cogliati, Angela Peron, Valentina Giorgini, Maura Masciadri, Margherita Marchi, Irene Cracco, Davide Gentilini, Miriam Nella Savini, Maria Teresa Bonati, Luigina SpacciniAbstract:Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40–73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants—one in GABRB2 and, for first time, one in GABRG2—were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.
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pathogenic variants in stxbp1 and in genes for gabaa receptor subunities cause atypical rett rett like phenotypes
International Journal of Molecular Sciences, 2019Co-Authors: Francesca Cogliati, Angela Peron, Valentina Giorgini, Maura Masciadri, Margherita Marchi, Irene Cracco, Davide Gentilini, Miriam Nella Savini, Maria Teresa Bonati, Luigina SpacciniAbstract:Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40–73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants—one in GABRB2 and, for first time, one in GABRG2—were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.
