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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    • "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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    • "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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