GAD67 regulation involves a network of genes implicated in schizophrenia and bipolar disorder. We have studied the copy number intensities of these genes in specific hippocampal subregions to clarify whether abnormalities of genomic integrity covary with gene expression in a circuitry-based manner.
To compare the copy number intensities of genes associated with GAD67 regulation in the stratum oriens of sectors CA3/2 and CA1 in patients with schizophrenia, patients with bipolar disorder, and healthy controls.
Samples of sectors CA3/2 and CA1 were obtained from patients with schizophrenia, patients with bipolar disorder, and healthy controls. Genomic integrity was analyzed using microarrays, and the copy number intensities identified were correlated with the gene expression profile from a subset of these cases previously reported.
Harvard Brain Tissue Resource Center at McLean Hospital, Belmont, Massachusetts.
A total of 15 patients with schizophrenia, 15 patients with bipolar disorder, and 15 healthy controls.
The copy number intensities for 28 target genes were individually examined using single-nucleotide polymorphism microarrays and correlated with homologous messenger RNA (mRNA) fold changes.
The copy number intensities examined using both microarrays and quantitative real-time polymerase chain reaction for the GAD67 gene were significantly decreased in sector CA3/2 of patients with schizophrenia and patients with bipolar disorder. Other genes associated with GAD67 regulation also showed changes in copy number intensities, and these changes were similar in magnitude and direction to those previously reported for mRNA fold changes in sector CA3/2 but not sector CA1. Moreover, the copy number intensities and mRNA fold changes were significantly correlated for both patients with schizophrenia (r=0.649; P=.0003) and patients with bipolar disorder (r=0.772; P=.0002) in sector CA3/2 but not in sector CA1.
Insertions and deletions of genomic DNA in γ-aminobutyric acid cells at a key locus of the hippocampal circuit are reflected in transcriptional changes in GAD67 regulation that are circuitry-based and diagnosis-specific.
"GAD1 (GAD67) accounts for 80–90% of overall brain GABA, while 10–20% reflects the activity of a related gene, GAD2 (GAD65) (Asada et al., 1997; Condie et al., 1997). To date, there are at least 20 reports in the literature, conducted by multiple groups of investigators on postmortem tissues collected in the U.S., Europe and Australia, reporting downregulated RNA and protein expression specifically of GAD1 in multiple brain regions of SCZ subjects, including the prefrontal, medial temporal and occipital cortex and cerebellar cortex and basal ganglia (Akbarian et al., 1995; Impagnatiello et al., 1998; Guidotti et al., 2000; Mirnics et al., 2000; Volk et al., 2000, 2012; Hashimoto et al., 2003, 2008a,b; Fatemi et al., 2005; Torrey et al., 2005; Veldic et al., 2005, 2007; Benes et al., 2007; Huang et al., 2007; Bullock et al., 2008; Curley et al., 2011; Thompson Ray et al., 2011; Gilabert-Juan et al., 2012; Sheng et al., 2012). Furthermore, in a postmortem cohort comprised of elderly subjects, increased GAD1 expression in the SCZ brain has been reported (Dracheva et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20 years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5′ end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia.
Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.10.020 · 3.92 Impact Factor
"Left hemisphere Ammon's horn neuronal loss without gliosis, entorhinal cortex neuronal loss, and reduced density of interneurons have been described in postmortem brains of patients with schizophrenia, with pyramidal cell loss being more noticeable in patients with paranoid schizophrenia than in patients with catatonic schizophrenia  . Other findings include nonpyramidal cell loss in CA2  and decreased glutamic acid decarboxylase (GAD) expression in the Ammon's horn and dentate gyrus    but increased in the subiculum and parahippocampal gyrus . Microtubule-associated protein type 2 (MAP2) was found increased in the Ammon's horn and subiculum , while overall loss of somatostatin-and parvalbuminpositive interneurons has been reported  . "
[Show abstract][Hide abstract] ABSTRACT: Temporal lobe epilepsy (TLE) and psychosis coexist more frequently than chance would predict. In this short review, clinical and neuropathological findings of schizophrenia, TLE, and psychosis of epilepsy are described to enhance our understanding of the noncoincidental association between these conditions. In addition, psychosis of epilepsy was included for the first time in the Diagnostic and Statistical Manual of Mental Disorders (DSM), in the recently launched 5th edition, and improvement in diagnostic criteria was highlighted. Since the hippocampus has long been considered an anatomical area involved in the pathophysiology of TLE and schizophrenia, neuropathological studies of psychoses of epilepsy may contribute to our understanding of the pathophysiology of psychosis in general. The discovery of shared mechanisms and/or affected neurochemicals in TLE and schizophrenia might disclose important clues on the vulnerability of patients with TLE to psychotic symptoms and be an opportunity for new treatment development.
This article is part of a Special Issue entitled “NEWroscience 2013”.
[Show abstract][Hide abstract] ABSTRACT: Understanding the origins of normal and pathological behavior is one of the most exciting opportunities in contemporary biomedical research. There is increasing evidence that, in addition to DNA sequence and the environment, epigenetic modifications of DNA and histone proteins may contribute to complex phenotypes. Inherited and/or acquired epigenetic factors are partially stable and have regulatory roles in numerous genomic activities, thus making epigenetics a promising research path in etiological studies of psychiatric disease. In this article, we review recent epigenetic studies examining the brain and other tissues, including those from individuals with schizophrenia (SCZ) and bipolar disorder (BPD). We also highlight heuristic aspects of the epigenetic theory of psychiatric disease and discuss the future directions of psychiatric epigenetics.
Trends in Genetics 05/2012; 28(9):427-35. DOI:10.1016/j.tig.2012.04.002 · 9.92 Impact Factor
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