Prefrontal GABAA receptor a-subunit expression in normal postnatal human development and schizophrenia
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). "
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.Schizophrenia Research 06/2015; 85. DOI:10.1016/j.schres.2015.05.040 · 3.92 Impact Factor
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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). "
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.Schizophrenia Research 02/2015; DOI:10.1016/j.schres.2015.01.025 · 3.92 Impact Factor
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- "For example, in prenatal and early infantile life GABA serves as an excitatory neurotransmitter and this is mediated primarily by the structure and fuction of GABA receptors (Ben-Ari et al., 1994; Leinekugel et al., 1999; Rakhade and Jensen, 2009). It is thought that density of GABAA receptors decreases from childhood to adulthood (Chugani et al., 2001) and that the subunit composition of GABAA receptors varies substantially during development (Duncan et al., 2010). Lower cortical inhibition early in life may reflect increased plasticity and optimum conditions for learning and development (Mall et al., 2004). "
ABSTRACT: Objectives: The objective of this post-hoc exploratory analysis was to examine the relationship between age and measures of cortical excitability and inhibition. Methods: Forty-six participants (24 with major depressive disorder and 22 healthy controls) completed MT, SICI, ICF, and CSP testing in a cross-sectional protocol. Of these 46 participants, 33 completed LICI testing. Multiple linear robust regression and Spearman partial correlation coefficient were used to examine the relationship between age and the TMS measures. Results: In the overall sample of 46 participants, age had a significant negative relationship with motor threshold (MT) in both the right (rs = −0.49, adjusted p = 0.007; β = −0.08, adjusted p = 0.001) and left (rs = −0.42, adjusted p = 0.029; β = −0.05, adjusted p = 0.004) hemispheres. This significant negative relationship of age with MT was also observed in the sample of depressed youth in both the right (rs = −0.70, adjusted p = 0.002; β = −0.09, adjusted p = 0.001) and left (rs = −0.54, adjusted p = 0.034; β = −0.05, adjusted p = 0.017) hemispheres, but not in healthy controls. In the sample of the 33 participants who completed LICI testing, age had a significant negative relationship with LICI (200 ms interval) in both the right (rs = −0.48, adjusted p = 0.05; β = −0.24, adjusted p = 0.007) and left (rs = −0.64, adjusted p = 0.002; β = −0.23, adjusted p = 0.001) hemispheres. This negative relationship between age and LICI (200 ms interval) was also observed in depressed youth in both the right (rs = −0.76, adjusted p = 0.034; β = −0.35, adjusted p = 0.004) and left (rs = −0.92, adjusted p = 0.002; β = −0.25, adjusted p = 0.001) hemispheres. Conclusion: These findings suggest that younger children have higher MTs. This is more pronounced in depressed youth than healthy controls. LICI inhibition may also increase with age in youth.Frontiers in Human Neuroscience 09/2014; 8:669. DOI:10.3389/fnhum.2014.00669 · 2.99 Impact Factor