Variations in differential gene expression patterns across multiple brain regions in schizophrenia

Katsel, Pavel; Davis, Kenneth L.; Gorman, Jack M.; Haroutunian, Vahram

doi:10.1016/j.schres.2005.03.020

Cited by 127 publications

(125 citation statements)

References 84 publications

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“…Numerous reports have implicated the ACC in schizophrenia. The ACC had the second most abnormally expressed genes in a study using microarray analyses that examined 15 discrete brain regions [28]. Several other postmortem studies have found changes in the number of neurons and glia in this region [29][30][31].…”

Section: Discussionmentioning

confidence: 95%

Altered Vesicular Glutamate Transporter Expression in the Anterior Cingulate Cortex in Schizophrenia

Oni-Orisan

Kristiansen

Haroutunian

et al. 2008

Biological Psychiatry

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Background-Schizophrenia is a chronic, severe mental illness with profound emotional and economic burdens for those afflicted and their families. An increasing number of studies have found that schizophrenia is marked by dysregulation of glutamatergic neurotransmission. While numerous studies have found alterations of postsynaptic molecules in schizophrenia, a growing body of evidence implicates presynaptic factors. Vesicular glutamate transporters (VGLUTs) have been identified and are known to package glutamate into vesicles in the presynaptic terminal for subsequent release into the synaptic cleft. Recent studies have shown that VGLUTs regulate synaptic activity via the amount of glutamate released. Accordingly, we hypothesized that VGLUTs are altered in schizophrenia, contributing to dysfunction of presynaptic activity.

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Section: Discussionmentioning

confidence: 95%

Altered Vesicular Glutamate Transporter Expression in the Anterior Cingulate Cortex in Schizophrenia

Oni-Orisan

Kristiansen

Haroutunian

et al. 2008

Biological Psychiatry

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“…36,37,58,59 Few studies have explored global expression changes between groups of suicides and psychiatrically normal controls, some have however focused on a particular psychiatric diagnosis, such as bipolar disorder or schizophrenia, and included within these groups subjects that died by suicide. [60][61][62][63][64][65][66][67] Sibille et al 51 recently compared expression patterns in BA9 and BA47 of depressed suicides versus psychiatrically normal controls matched on the basis of sex, age, DAVID genes correspond to the total number of unique DAVID annotated genes. The percentage represents the number of differentially expressed genes belonging to a given category over the total number of DAVID annotated genes.…”

Section: Discussionmentioning

confidence: 99%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

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The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides = 18, non depressed suicides = 8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.

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“…The SMRI Consortium Collection was used, an established collection of 60 well-diagnosed postmortem cases (Torrey et al, 2000) that has been validated frequently and used to investigate chronic psychiatric disease-associated proteins (for publication overview, see http://www.stanleyresearch.org/publications/consortiumall.asp). Frozen brain pieces from cingulum cortex (BA23), a brain region that is considered an anatomical region associated with psychiatric disease pathology (Hulshoff Pol et al, 2001;Katsel et al, 2005;Narr et al, 2005), were used. Lack of protein degradation in these samples was confirmed by intactness of degradation-sensitive marker dihydropyrimidinase-related protein-2 (supplemental Fig.…”

Section: Purifying the Insoluble Proteomementioning

confidence: 99%

Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease

Leliveld¹,

Bader²,

Hendriks³

et al. 2008

J. Neurosci.

119

174

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Disrupted-in-schizophrenia 1 (DISC1) and other genes have been identified recently as potential molecular players in chronic psychiatric diseases such as affective disorders and schizophrenia. A molecular mechanism of how these genes may be linked to the majority of sporadic cases of these diseases remains unclear. The chronic nature and irreversibility of clinical symptoms in a subgroup of these diseases prompted us to investigate whether proteins corresponding to candidate genes displayed subtle features of protein aggregation. Here, we show that in postmortem brain samples of a distinct group of patients with phenotypes of affective disorders or schizophrenia, but not healthy controls, significant fractions of DISC1 could be identified as cold Sarkosyl-insoluble protein aggregates. A loss-offunction phenotype could be demonstrated for insoluble DISC1 through abolished binding to a key DISC1 ligand, nuclear distribution element 1 (NDEL1): in human neuroblastoma cells, DISC1 formed expression-dependent, detergent-resistant aggregates that failed to interact with endogenous NDEL1. Recombinant (r) NDEL1 expressed in Escherichia coli selectively bound an octamer of an rDISC1 fragment but not dimers or high molecular weight multimers, suggesting an oligomerization optimum for molecular interactions of DISC1 with NDEL1. For DISC1-related sporadic psychiatric disease, we propose a mechanism whereby impaired cellular control over self-association of DISC1 leads to excessive multimerization and subsequent formation of detergent-resistant aggregates, culminating in loss of ligand binding, here exemplified by NDEL1. We conclude that the absence of oligomer-dependent ligand interactions of DISC1 can be associated with sporadic mental disease of mixed phenotypes.

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Variations in differential gene expression patterns across multiple brain regions in schizophrenia

Cited by 127 publications

References 84 publications

Altered Vesicular Glutamate Transporter Expression in the Anterior Cingulate Cortex in Schizophrenia

Altered Vesicular Glutamate Transporter Expression in the Anterior Cingulate Cortex in Schizophrenia

Patterns of gene expression in the limbic system of suicides with and without major depression

Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease

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