| 1 | Pharmacogenet. Genomics 2008 Apr 18: 317-23 |
|---|---|
| PMID | 18334916 |
| Title | Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. |
| Abstract | Neuroleptic-induced tardive dyskinesia (TD) is an involuntary movement disorder that develops in patients who have undergone long-term treatment with antipsychotic medications, and its etiology is unclear. In this study, a genome-wide association screening was done to identify the pathway(s) in which genetic variations influence susceptibility to neuroleptic-induced TD. Screening with Sentrix Human-1 Genotyping BeadChip (Illumina, San Diego, California, USA) was done for 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD. A total of 40 573 single nucleotide polymorphisms that were not in linkage disequilibrium with each other and were located in the exonic and intronic regions of 13 307 genes were analyzed. After gene-based corrections, P values for allelic associations were subjected to canonical pathway-based analyses with Ingenuity Pathway Analysis software (Ingenuity Systems, Inc., Redwood City, California, USA). Eight genes (ABAT, ALDH9A1, GABRA3, GABRA4, GABRB2, GABRAG3, GPHN, and SLC6A11) contained polymorphisms with gene-based corrected allelic P values of less than 0.05. They were aggregated significantly in 33 genes belonging to the gamma-aminobutyric acid (GABA) receptor signaling pathway (P=0.00007, corrected P=0.01). Associations were replicated in an independent sample of 36 patients with TD and 136 patients without TD for polymorphisms in SLC6A11 (GABA transporter 3) (P=0.0004 in the total sample), GABRB2 (beta-2 subunit of GABA-A receptor) (P=0.00007 in the total sample), and GABRG3 (gamma-3 subunit of GABA-A receptor) (P=0.0006 in the total sample). The results suggest that the GABA receptor signaling pathway may be involved in genetic susceptibility to treatment-resistant TD, at least in a subgroup of Japanese patients with schizophrenia. The present results suggest that benzodiazepines may be considered as possible treatment option for TD. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1521-6 |
| PMID | 18565636 |
| Title | Sensitization to nicotine significantly decreases expression of GABA transporter GAT-1 in the medial prefrontal cortex. |
| Abstract | This study investigated GABA signaling following induction of behavioural sensitization to nicotine. Rats were repeatedly injected with saline, nicotine or hexamethonium for 18 days and gene expression was measured with qPCR. Nicotine upregulated GABAA alpha1 subunit expression in the nucleus accumbens (p<0.05) while no changes were observed for GABAA alpha3, alpha4 or alpha5. In the medial prefrontal cortex, no change in expression of the GABAA subunits was observed. We found that nicotine significantly decreased expression of the transporter GAT-1/SLC6A1 (p<0.05) in the medial prefrontal cortex while the expression of the GAT-3/SLC6A11 (p<0.05) transporter was increased in the nucleus accumbens. This provides the first evidence of neuroadaptive changes in the GABA system after nicotine sensitization and the first demonstration of an effect on GAT-1 or GAT-3 transporters in the addiction field. The GAT-1 findings also provide evidence for an alternative theory of why most schizophrenic individuals also use tobacco products. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Psychiatry Res 2011 Oct 189: 478-9 |
| PMID | 21367462 |
| Title | Association between the SLC6A12 gene and negative symptoms of schizophrenia in a Korean population. |
| Abstract | We investigated the association of single nucleotide polymorphisms of solute carrier family 6 member 11 (SLC6A11) (rs2304725, rs2272400, and rs2245532), SLC6A12 (rs216250 and rs557881) and SLC6A13 (rs2289954) with schizophrenia and its clinical symptoms. We found that rs216250 of SLC6A12 was correlated with the Scale for the Assessment of Negative Symptoms (SANS) scores. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Eur Arch Psychiatry Clin Neurosci 2013 Jun 263: 285-97 |
| PMID | 22968646 |
| Title | Aripiprazole differentially regulates the expression of Gad67 and ?-aminobutyric acid transporters in rat brain. |
| Abstract | The molecular etiology of schizophrenia comprises abnormal neurotransmission of the amino acid GABA (?-aminobutyric acid). Neuropathological studies convincingly revealed reduced expression of glutamic acid decarboxylase (Gad67) in GABAergic interneurons. Several antipsychotics influence the expression of GABAergic genes, but aripiprazole (APZ), a partial dopaminergic and serotonergic receptor agonist, has not been involved into these studies so far. We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ suspended in drinking water and doses of 10 and 40 mg per kg body weight. Gene expression of Gad67, the vesicular GABA transporter Slc32a1 (solute carrier family, Vgat), the transmembrane transporters Slc6a1 (Gat1) and SLC6A11 (Gat3) was assessed by semiquantitative radioactive in situ hybridization. APZ treatment resulted in time- and dose-dependent effects with qualitative differences between brain regions. In the 10-mg group, Slc6a1 was strongly induced after 4 weeks in the hippocampus, amygdala, and cerebral cortex, followed by an induction of Gad67 in the same regions after 4 months, while frontocortical regions as well as basal ganglia showed dose-dependent reductions of Gad67 expression after 4 months. In several frontocortical and subcortical regions, we observed a decrease of Slc32a1 and an increase of SLC6A11 expression. In conclusion, APZ modulates gene expression of GABAergic marker genes involved into pathogenetic theories of schizophrenia. APZ only partially mirrors the effects of other antipsychotics with some important differences regarding brain regions. The findings might be explained by regulatory connections between serotonergic, GABAergic, and dopaminergic neurotransmission and should be validated in behavioral animal models of psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Nord J Psychiatry 2014 Feb 68: 123-8 |
| PMID | 23795861 |
| Title | Gaba transporter SLC6A11 gene polymorphism associated with tardive dyskinesia. |
| Abstract | Gamma-aminobutyric acid (GABA) insufficiency has been reported to be related to the tardive dyskinesia (TD) susceptibility. Inada et al. (Pharmacogenet Genomics 2008;18:317-23) identified eight genes belonging to GABA receptor signaling pathway that may be involved in TD susceptibility by genome-wide screening and they replicated associations in an independent sample for polymorphisms in SLC6A11 (GABA transporter 3), GABRG3 (c-3 subunit of GABA-A receptor) and GABRB2 (?-2 subunit of GABA-A receptor). In this study, we tried to replicate their finding in a larger Korean sample and find if any of the genes was associated with the susceptibility to TD. We selected three polymorphisms in SLC6A11 (rs4684742), GABRG3 (rs2061051) and GABRB2 (rs918528) from the previous study. We carried out a case-control study (105 TD and 175 non-TD schizophrenic patients) to identify the association between the three candidate polymorphisms and susceptibility to TD and their epistatic interactions by using the multifactor dimensionality reduction (MDR) algorithm. Among the three variants, SCL6A11 genotypes distribution showed a significant difference between the TD and non-TD patients (P = 0.049). However, GABRG3 and GABRB2 genotype distributions were not associated with TD (P = 0.268 and P = 0.976, respectively). Further, our analyses provided significant evidence for gene-gene interactions (SCL6A11, GABRG3 and GABRB2) in the development of TD. The odds ratio increased to 2.53 (CI = 1.515-4.217, P = 0.0003) when the genetic susceptibility to TD was analyzed with the three genes considered altogether through MDR approach. These results suggest that GABA receptor signaling pathway was associated with the increased susceptibility to TD in Korean schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic |