Article

Prefrontal GABAA receptor a-subunit expression in normal postnatal human development and schizophrenia

Schizophrenia Research Institute, Sydney 2021, Australia.
Journal of Psychiatric Research (Impact Factor: 3.96). 07/2010; 44(10):673-81. DOI: 10.1016/j.jpsychires.2009.12.007
Source: PubMed

ABSTRACT

Cortical GABA deficits that are consistently reported in schizophrenia may reflect an etiology of failed normal postnatal neurotransmitter maturation. Previous studies have found prefrontal cortical GABA(A) receptor alpha subunit alterations in schizophrenia, yet their relationship to normal developmental expression profiles in the human cortex has not been determined. The aim of this study was to quantify GABA(A) receptor alpha-subunit mRNA expression patterns in human dorsolateral prefrontal cortex (DLPFC) during normal postnatal development and in schizophrenia cases compared to controls. Transcript levels of GABA(A) receptor alpha subunits were measured using microarray and qPCR analysis of 60 normal individuals aged 6weeks to 49years and in 37 patients with schizophrenia/schizoaffective disorder and 37 matched controls. We detected robust opposing changes in cortical GABA(A) receptor alpha1 and alpha5 subunits during the first few years of postnatal development, with a 60% decrease in alpha5 mRNA expression and a doubling of alpha1 mRNA expression with increasing age. In our Australian schizophrenia cohort we detected decreased GAD67 mRNA expression (p=0.0012) and decreased alpha5 mRNA expression (p=0.038) in the DLPFC with no significant change of other alpha subunits. Our findings confirm that GABA deficits (reduced GAD67) are a consistent feature of schizophrenia postmortem brain studies. Our study does not confirm alterations in cortical alpha1 or alpha2 mRNA levels in the schizophrenic DLPFC, as seen in previous studies, but instead we report a novel down-regulation of alpha5 subunit mRNA suggesting that post-synaptic alterations of inhibitory receptors are an important feature of schizophrenia but may vary between cohorts.

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    • "Interneuron health is compromised in schizophrenia as evidenced by reduced gene expression and protein levels of glutamic acid decarboxylase (GAD67), an enzyme that synthesizes GABA, in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (Akbarian et al., 1995; Woo et al., 1998; Guidotti et al., 2000; Lewis et al., 2004b; Thompson et al., 2009; Duncan et al., 2010). These cortical GABAergic inhibitory interneurons are a heterogeneous population of neurons that vary based on morphology, electrophysiological properties, laminar distribution, innervation of pyramidal neurons and expression of neuropeptides and calcium binding proteins (Markram et al., 2004; Petilla Interneuron Nomenclature GROUP, 2008). "
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    ABSTRACT: Late adolescence in males is a period of increased susceptibility for the onset of schizophrenia, coinciding with increased circulating testosterone. The cognitive deficits prevalent in schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions of depleted (monkey and rat) and replaced (rat) testosterone over adolescence, changes in gene expression of cortical BDNF and TrkB transcripts and interneuron markers and the relationships between these mRNAs and circulating testosterone. Testosterone removal by gonadectomy reduced gene expression of some BDNF transcripts in monkey and rat frontal cortices and the BDNF mRNA reduction was prevented by testosterone replacement. In rat, testosterone replacement increased the potential for classical TrkB signalling by increasing the full length to truncated TrkB mRNA ratio, whereas in the monkey cortex, circulating testosterone was negatively correlated with the TrkB full length/truncated mRNA ratio. We did not identify changes in interneuron gene expression in monkey frontal cortex in response to gonadectomy, and in rat, we showed that only somatostatin mRNA was decreased by gonadectomy but not restored by testosterone replacement. We identified complex and possibly species-specific, relationships between BDNF/TrkB gene expression and interneuron marker gene expression that appear to be dependent on the presence of testosterone at adolescence in rat and monkey frontal cortices. Taken together, our findings suggest there are dynamic relationships between BDNF/TrkB and interneuron markers that are dependent on the presence of testosterone but that this may not be a straightforward increase in testosterone leading to changes in BDNF/TrkB that contributes to interneuron health. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · Schizophrenia Research
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    • "Therefore, our GABA-Aα5 and GABA-Aε findings lend further support to the notion that altered tonic inhibition by GABA may contribute to the pathophysiology of schizophrenia (Maldonado-Aviles et al., 2009). Reduced GAD67 expression is a consistent finding in schizophrenia (Akbarian et al., 1995; Guidotti et al., 2000; Volk et al., 2000; Woo et al., 2004; Hashimoto et al., 2005, 2008a,b; Thompson et al., 2009; Duncan et al., 2010; Curley et al., 2011; Kimoto et al., 2014); however, we observed increased GAD67 expression in the ACC of the female schizophrenia group. It is possible that this difference may be due to medication because we observed that the expression of GAD67 was significantly higher in patients who were on medication compared with those who were off medication (Fig. 2; Table 3). "
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    ABSTRACT: GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n=21) and a comparison group of individuals without a history of psychiatric illness (n=18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Aε. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression of GABA-Aα1-3, GABA-Aβ2, GABA-Aγ2, and GAD67 in the medicated group compared to the unmedicated group. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Feb 2015 · Schizophrenia Research
    • "Maldonado-Avilés et al. (2009) No change in mRNA in DLPFC Duncan et al. (2010) GABRα5 ↓ protein in BA9 and BA40; no change in Cer Fatemi et al. (2010b) ↓ mRNA in BA9; ↑ mRNA in Cer; no change in BA40 Fatemi et al. (2010b) No change in mRNA or protein in Cer No change in mRNA or protein in Cer No change in mRNA or protein in Cer Fatemi et al. (2013b) ↓ mRNA in DLPFC Beneyto et al., 2011, Duncan et al., 2010 No change in mRNA in PFC Akbarian et al. (1995) GABRα6 ↓ protein in BA9; no change in BA40 or Cer ↑ protein in Cer Fatemi et al. (2013b, 2014) "
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    ABSTRACT: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic receptor abnormalities have been documented in several major psychiatric disorders including schizophrenia, mood disorders, and autism. Abnormal expression of mRNA and protein for multiple GABA receptors has also been observed in multiple brain regions leading to alterations in the balance between excitatory/inhibitory signaling in the brain with potential profound consequences for normal cognition and maintenance of mood and perception. Altered expression of GABAA receptor subunits has been documented in fragile X mental retardation 1 (FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem studies from our laboratory have shown reduced expression of FMRP in the brains of subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP acts as a translational repressor and, under normal conditions, inhibits metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5 signaling, ultimately resulting in the behavioral and intellectual impairments associated with this disorder. Our laboratory has identified changes in mGluR5 expression in autism, schizophrenia, and mood disorders. In the current review article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels and compare our results with other laboratories. Finally, we discuss the interactions between these molecules and the potential for new therapeutic interventions that target these interconnected signaling systems. Copyright © 2014 Elsevier B.V. All rights reserved.
    No preview · Article · Nov 2014 · Schizophrenia Research
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