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Supportive evidence for reduced expression of GNB1L in schizophrenia.

ABSTRACT: BACKGROUND: Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. METHODS: Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. RESULTS: Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene region did not confirm excess homozygosity in 1918 Japanese schizophrenia cases and 1909 Japanese controls. Haloperidol treatment for 50 weeks increased Gnb1l gene expression in prefrontal cortex of mice. CONCLUSIONS: Taken together with the impaired prepulse inhibition observed in heterozygous Gnb1l knockout mice reported by the previous study, the present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia.

SUBMITTER: Ishiguro H

PROVIDER: S-EPMC2894596 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Supportive evidence for reduced expression of GNB1L in schizophrenia.

Ishiguro Hiroki H Koga Minori M Horiuchi Yasue Y Noguchi Emiko E Morikawa Miyuki M Suzuki Yoshimi Y Arai Makoto M Niizato Kazuhiro K Iritani Shyuji S Itokawa Masanari M Inada Toshiya T Iwata Nakao N Ozaki Norio N Ujike Hiroshi H Kunugi Hiroshi H Sasaki Tsukasa T Takahashi Makoto M Watanabe Yuichiro Y Someya Toshiyuki T Kakita Akiyoshi A Takahashi Hitoshi H Nawa Hiroyuki H Arinami Tadao T

Schizophrenia bulletin 20081114 4

<h4>Background</h4>Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia t ...[more]

PMID: 19011233

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Project description:BackgroundSupportive therapy is often used in everyday clinical care and in evaluative studies of other treatments.ObjectivesTo review the effects of supportive therapy compared with standard care, or other treatments in addition to standard care for people with schizophrenia.Search methodsFor this update, we searched the Cochrane Schizophrenia Group's register of trials (November 2012).Selection criteriaAll randomised trials involving people with schizophrenia and comparing supportive therapy with any other treatment or standard care.Data collection and analysisWe reliably selected studies, quality rated these and extracted data. For dichotomous data, we estimated the risk ratio (RR) using a fixed-effect model with 95% confidence intervals (CIs). Where possible, we undertook intention-to-treat analyses. For continuous data, we estimated the mean difference (MD) fixed-effect with 95% CIs. We estimated heterogeneity (I(2) technique) and publication bias. We used GRADE to rate quality of evidence.Main resultsFour new trials were added after the 2012 search. The review now includes 24 relevant studies, with 2126 participants. Overall, the evidence was very low quality.We found no significant differences in the primary outcomes of relapse, hospitalisation and general functioning between supportive therapy and standard care.There were, however, significant differences favouring other psychological or psychosocial treatments over supportive therapy. These included hospitalisation rates (4 RCTs, n = 306, RR 1.82 CI 1.11 to 2.99, very low quality of evidence), clinical improvement in mental state (3 RCTs, n = 194, RR 1.27 CI 1.04 to 1.54, very low quality of evidence) and satisfaction of treatment for the recipient of care (1 RCT, n = 45, RR 3.19 CI 1.01 to 10.7, very low quality of evidence). For this comparison, we found no evidence of significant differences for rate of relapse, leaving the study early and quality of life.When we compared supportive therapy to cognitive behavioural therapy CBT), we again found no significant differences in primary outcomes. There were very limited data to compare supportive therapy with family therapy and psychoeducation, and no studies provided data regarding clinically important change in general functioning, one of our primary outcomes of interest.Authors' conclusionsThere are insufficient data to identify a difference in outcome between supportive therapy and standard care. There are several outcomes, including hospitalisation and general mental state, indicating advantages for other psychological therapies over supportive therapy but these findings are based on a few small studies where we graded the evidence as very low quality. Future research would benefit from larger trials that use supportive therapy as the main treatment arm rather than the comparator.

Project description:ContextCannabis use is associated with both impaired cognitive functions, including working memory, and an increased risk of schizophrenia. Schizophrenia is characterized by impairments in working memory that are associated with reduced gamma-aminobutyric acid (GABA) neurotransmission in the dorsolateral prefrontal cortex. The cannabinoid 1 receptor (CB1R) is highly expressed in the dorsolateral prefrontal cortex, is contained in the axon terminals of a subpopulation of perisomatic-targeting GABA neurons, and, when activated, suppresses the release of GABA.ObjectiveTo determine the potential relationship between CB1R signaling and altered GABA neurotransmission in schizophrenia by evaluating CB1R messenger RNA (mRNA) and protein expression in the dorsolateral prefrontal cortex.DesignIn situ hybridization and immunocytochemistry techniques were used to examine the cortical levels of CB1R mRNA and protein, respectively.SettingBrain specimens were obtained from autopsies conducted at the Allegheny County Medical Examiner's Office, Pittsburgh, Pennsylvania.ParticipantsPostmortem brain specimens from 23 pairs of subjects with schizophrenia and age-, sex-, and postmortem interval-matched comparison subjects, as well as brain specimens from 18 macaque monkeys with long-term exposure to haloperidol, olanzapine, or placebo.Main outcome measuresOptical density measures of CB1R mRNA expression and protein levels and correlations with previously reported glutamic acid decarboxylase 67 and cholecystokinin mRNA measures.ResultsLevels of CB1R mRNA were significantly lower by 14.8% in the subjects with schizophrenia. Similarly, CB1R protein levels, assessed by radioimmunocytochemistry and standard immunocytochemistry, were significantly decreased by 11.6% and 13.9%, respectively. Group differences in CB1R mRNA levels were significantly correlated with those in glutamic acid decarboxylase 67 and cholecystokinin mRNA levels. Expression of CB1R mRNA was not changed in antipsychotic-exposed monkeys, and neither CB1R mRNA levels nor protein levels were affected by potential confounding factors in the subjects with schizophrenia.ConclusionsThis combination of findings suggests the testable hypothesis that reduced CB1R mRNA and protein levels in schizophrenia represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting cholecystokinin interneurons with impaired GABA synthesis.

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Supportive evidence for reduced expression of GNB1L in schizophrenia.

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Supportive evidence for reduced expression of GNB1L in schizophrenia.

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