Differences in the Circuitry-Based Association of Copy Numbers and Gene Expression Between the Hippocampi of Patients With Schizophrenia and the Hippocampi of Patients With Bipolar Disorder

Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, Harvard Medical School, Boston, MA 02478, USA.
Archives of general psychiatry (Impact Factor: 14.48). 02/2012; 69(6):550-61. DOI: 10.1001/archgenpsychiatry.2011.1882
Source: PubMed


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.

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    • "In the overall patient group more severe negative symptoms were associated with smaller subfield volumes. The affected hippocampal subfields in this patient group are similar to those reported in postmortem studies to have neurochemical and synaptic changes associated with schizophre- nia[2,45632,33]. The relative predominance of findings on the left side, and the sparing of the CA1 region was also consistent with postmortem studies of the hippocampus in schizophrenia[5]. "
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    ABSTRACT: Reduced hippocampal volume in schizophrenia is a well-replicated finding. New imaging techniques allow delineation of hippocampal subfield volumes. Studies including predominantly chronic patients demonstrate differences between subfields in sensitivity to illness, and in associations with clinical features. We carried out a cross-sectional and longitudinal study of first episode, sub-chronic, and chronic patients, using an imaging strategy that allows for the assessment of multiple hippocampal subfields. Hippocampal subfield volumes were measured in 34 patients with schizophrenia (19 first episode, 6 sub-chronic, 9 chronic) and 15 healthy comparison participants. A subset of 10 first episode and 12 healthy participants were rescanned after six months. Total left hippocampal volume was smaller in sub-chronic (p = 0.04, effect size 1.12) and chronic (p = 0.009, effect size 1.42) patients compared with healthy volunteers. The CA2-3 subfield volume of chronic patients was significantly decreased (p = 0.009, effect size 1.42) compared to healthy volunteers. The CA4-DG volume was significantly reduced in all three patient groups compared to healthy group (all p < 0.005). The two affected subfield volumes were inversely correlated with severity of negative symptoms (p < 0.05). There was a small, but statistically significant decline in left CA4-DG volume over the first six months of illness (p = 0.01). Imaging strategies defining the subfields of the hippocampus may be informative in linking symptoms and structural abnormalities, and in understanding more about progression during the early phases of illness in schizophrenia.
    Full-text · Article · Feb 2015 · PLoS ONE
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    • "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). "
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    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.
    Full-text · Article · Oct 2014 · Schizophrenia Research
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    • "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 [68] [70]. Other findings include nonpyramidal cell loss in CA2 [71] and decreased glutamic acid decarboxylase (GAD) expression in the Ammon's horn and dentate gyrus [72] [73] [74] but increased in the subiculum and parahippocampal gyrus [75]. Microtubule-associated protein type 2 (MAP2) was found increased in the Ammon's horn and subiculum [76], while overall loss of somatostatin-and parvalbuminpositive interneurons has been reported [74] [77]. "
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    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”.
    Full-text · Article · Sep 2014 · Epilepsy & Behavior
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