Generic placeholder image

Current Psychopharmacology


ISSN (Print): 2211-5560
ISSN (Online): 2211-5579

Review Article

GABRB2 in Neuropsychiatric Disorders: Genetic Associations and Functional Evidences

Author(s): Shui Y. Tsang, Ata Ullah and Hong Xue*

Volume 8 , Issue 3 , 2019

Page: [166 - 176] Pages: 11

DOI: 10.2174/2211556008666190926115813


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.

Keywords: Alternative splicing, epigenetic regulation, Gabrb2-knockout mouse, GABRB2, psychiatric disorders, single nucleotide polymorphisms.

Graphical Abstract
Kilb W. Development of the GABAergic system from birth to adolescence. Neuroscientist 2012; 18(6): 613-30.
[] [PMID: 21952258]
Fung LK, Hardan AY. Developing medications targeting glutamatergic dysfunction in autism: progress to date. CNS Drugs 2015; 29(6): 453-63.
[] [PMID: 26104862]
Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 2016; 17(8): 524-32.
[] [PMID: 27256556]
Heinz A, Beck A, Wrase J, et al. Neurotransmitter systems in alcohol dependence. Pharmacopsychiatry 2009; 42(Suppl. 1): S95-S101.
[] [PMID: 19434561]
Hirvonen J, Hietala J. Dysfunctional brain networks and genetic risk for schizophrenia: specific neurotransmitter systems. CNS Neurosci Ther 2011; 17(2): 89-96.
[] [PMID: 21199447]
Murphy DL, Moya PR, Fox MA, Rubenstein LM, Wendland JR, Timpano KR. Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity. Philos Trans R Soc Lond B Biol Sci 2013; 368(1615) 20120435
[] [PMID: 23440468]
Yang AC, Tsai SJ. New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci 2017; 18(8) E1689
[] [PMID: 28771182]
Anticevic A, Lisman J. How can global alteration of excitation/inhibition balance lead to the local dysfunctions that underlie schizophrenia? Biol Psychiatry 2017; 81(10): 818-20.
[] [PMID: 28063469]
Eichler SA, Meier JC. E-I balance and human diseases-from molecules to networking. Front Mol Neurosci 2008; 1: 2.
[] [PMID: 18946535]
Roberts E. Prospects for research on schizophrenia. An hypotheses suggesting that there is a defect in the GABA system in schizophrenia. Neurosci Res Program Bull 1972; 10(4): 468-82.
[PMID: 4663826]
Karlsgodt KH, Sun D, Cannon TD. Structural and functional brain abnormalities in schizophrenia. Curr Dir Psychol Sci 2010; 19(4): 226-31.
[] [PMID: 25414548]
Benes FM. The GABA system in schizophrenia: cells, molecules and microcircuitry. Schizophr Res 2015; 167(1-3): 1-3.
[] [PMID: 26255083]
Wassef A, Baker J, Kochan LD. GABA and schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol 2003; 23(6): 601-40.
[] [PMID: 14624191]
Belforte JE, Zsiros V, Sklar ER, et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 2010; 13(1): 76-83.
[] [PMID: 19915563]
Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry 2015; 77(12): 1031-40.
[] [PMID: 25863358]
Austin J. Schizophrenia: an update and review. J Genet Couns 2005; 14(5): 329-40.
[] [PMID: 16195940]
Karam CS, Ballon JS, Bivens NM, et al. Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci 2010; 31(8): 381-90.
[] [PMID: 20579747]
Sun J, Jia P, Fanous AH, et al. Schizophrenia gene networks and pathways and their applications for novel candidate gene selection. PLoS One 2010; 5(6)e11351
[] [PMID: 20613869]
Govindpani K, Calvo-Flores GB, Vinnakota C, Waldvogel HJ, Faull RL, Kwakowsky A. Towards a better understanding of GABAergic remodeling in Alzheimer’s disease. Int J Mol Sci 2017; 18(8) E1813
[] [PMID: 28825683]
Liu YQ, Yu F, Liu WH, He XH, Peng BW. Dysfunction of hippocampal interneurons in epilepsy. Neurosci Bull 2014; 30(6): 985-98.
[] [PMID: 25370443]
Rudolph U, Möhler H. GABAA receptor subtypes: Therapeutic potential in down syndrome, affective disorders, schizophrenia, and autism. Annu Rev Pharmacol Toxicol 2014; 54: 483-507.
[] [PMID: 24160694]
Sanacora G, Mason GF, Krystal JH. Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Crit Rev Neurobiol 2000; 14(1): 23-45.
[] [PMID: 11253954]
Schmidt MJ, Mirnics K. Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology 2015; 40(1): 190-206.
[] [PMID: 24759129]
Fritschy JM, Panzanelli P. GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system. Eur J Neurosci 2014; 39(11): 1845-65.
[] [PMID: 24628861]
Michels G, Moss SJ. GABAA receptors: properties and trafficking. Crit Rev Biochem Mol Biol 2007; 42(1): 3-14.
[] [PMID: 17364682]
Olsen RW, Sieghart W. GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 2009; 56(1): 141-8.
[] [PMID: 18760291]
Tsang SY, Ng SK, Xu Z, Xue H. The evolution of GABAA receptor-like genes. Mol Biol Evol 2007; 24(2): 599-610.
[] [PMID: 17135332]
Lo WS, Lau CF, Xuan Z, et al. Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia. Mol Psychiatry 2004; 9(6): 603-8.
[] [PMID: 14699426]
Liu J, Shi Y, Tang W, et al. Positive association of the human GABA-A-receptor beta 2 subunit gene haplotype with schizophrenia in the Chinese Han population. Biochem Biophys Res Commun 2005; 334(3): 817-23.
[] [PMID: 16023997]
Lo WS, Xu Z, Yu Z, et al. Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene. PLoS One 2007; 2(5) e462
[] [PMID: 17520021]
Petryshen TL, Middleton FA, Tahl AR, et al. Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. Mol Psychiatry 2005; 10(12): 1074-88.
Yu Z, Chen J, Shi H, Stoeber G, Tsang SY, Xue H. Analysis of GABRB2 association with schizophrenia in German population with DNA sequencing and one-label extension method for SNP genotyping. Clin Biochem 2006; 39(3): 210-8.
[] [PMID: 16472798]
Zhao X, Qin S, Shi Y, et al. Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABA(B) receptor 1 gene and GABA(A) receptor subunit beta2 gene, with schizophrenia using a universal DNA microarray. Schizophr Res 2007; 93(1-3): 374-84.
[] [PMID: 17412563]
Ikeda M, Iwata N, Suzuki T, et al. Association analysis of chromosome 5 GABAA receptor cluster in Japanese schizophrenia patients. Biol Psychiatry 2005; 58(6): 440-5.
[] [PMID: 15993854]
Jamra RA, Becker T, Klopp N, et al. No evidence for an association between variants at the gamma-amino-n-butyric acid type A receptor beta2 locus and schizophrenia. Psychiatr Genet 2007; 17(1): 43-5.
[] [PMID: 17167345]
Allen NC, Bagade S, McQueen MB, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008; 40(7): 827-34.
[] [PMID: 18583979]
Shi J, Gershon ES, Liu C. Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. Schizophr Res 2008; 104(1-3): 96-107.
[] [PMID: 18715757]
Zhao C, Xu Z, Chen J, et al. Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: differential expression and genotypical correlations in schizophrenia. Mol Psychiatry 2006; 11(12): 1092-105.
[] [PMID: 16983389]
Zhao C, Xu Z, Wang F, et al. Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders. PLoS One 2009; 4(9)e6977
[] [PMID: 19763268]
Ng SK, Lo WS, Pun FW, et al. A recombination hotspot in a schizophrenia-associated region of GABRB2. PLoS One 2010; 5(3) e9547
[] [PMID: 20221451]
Pun FW, Zhao C, Lo WS, et al. Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit. Mol Psychiatry 2011; 16(5): 557-68.
[] [PMID: 20404824]
Schwab SG, Knapp M, Mondabon S, et al. Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Am J Hum Genet 2003; 72(1): 185-90.
[] [PMID: 12474144]
Schiffer HH, Heinemann SF. Association of the human kainate receptor GluR7 gene (GRIK3) with recurrent major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144B(1): 20-6.
[] [PMID: 16958029]
Crespi B. Genomic imprinting in the development and evolution of psychotic spectrum conditions. Biol Rev Camb Philos Soc 2008; 83(4): 441-93.
[] [PMID: 18783362]
Wang L, Jiang W, Lin Q, Zhang Y, Zhao C. DNA methylation regulates gabrb2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms. Genes Brain Behav 2016; 15(8): 702-10.
[] [PMID: 27509263]
Chen J, Tsang SY, Zhao CY, et al. GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations. Biochem Soc Trans 2009; 37(Pt 6): 1415-8.
[] [PMID: 19909288]
Zhao J, Bao AM, Qi XR, et al. Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients. J Affect Disord 2012; 138(3): 494-502.
[] [PMID: 22357337]
Kim YS, Yang M, Mat WK, et al. GABRB2 haplotype association with heroin dependence in Chinese population. PLoS One 2015; 10(11) e0142049
[] [PMID: 26561861]
Radel M, Vallejo RL, Iwata N, et al. Haplotype-based localization of an alcohol dependence gene to the 5q34 gamma-aminobutyric acid type A gene cluster. Arch Gen Psychiatry 2005; 62(1): 47-55.
[] [PMID: 15630072]
Tsang SY, Zhong S, Mei L, et al. Social cognitive role of schizophrenia candidate gene GABRB2. PLoS One 2013; 8(4) e62322
[] [PMID: 23638040]
Yuan H, Low CM, Moody OA, Jenkins A, Traynelis SF. Ionotropic GABA and glutamate receptor mutations and human neurologic diseases. Mol Pharmacol 2015; 88(1): 203-17.
[] [PMID: 25904555]
Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharmacol 2011; 164(4): 1162-94.
[] [PMID: 21449915]
Spielewoy C, Roubert C, Hamon M, Nosten-Bertrand M, Betancur C, Giros B. Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav Pharmacol 2000; 11(3-4): 279-90.
[] [PMID: 11103882]
Kalueff AV, Bergner CL. Transgenic and mutant tools to model brain disorders. New York: Human Press 2010.
Collinson N, Kuenzi FM, Jarolimek W, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 2002; 22(13): 5572-80.
[] [PMID: 12097508]
Duncan GE, Moy SS, Perez A, et al. Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 2004; 153(2): 507-19.
[] [PMID: 15265649]
Nakazawa K, Zsiros V, Jiang Z, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 2012; 62(3): 1574-83.
[] [PMID: 21277876]
Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995; 52(12): 998-1007.
[] [PMID: 7492260]
Yeung RK, Xiang ZH, Tsang SY, et al. Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation. Transl Psychiatry 2018; 8(1): 128.
[] [PMID: 30013074]

© 2022 Bentham Science Publishers | Privacy Policy