Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates

Martin, Maureen V.; Mirnics, Károly; Nisenbaum, Laura; Vawter, Marquis P.

doi:10.1159/000430786

Cited by 18 publications

(16 citation statements)

References 34 publications

(32 reference statements)

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“…These results also support the recent cross-disorder analysis of gene expression where the mitochondrial and neuronal gene coexpression module was shared between BD and SZ cortical regions [49], and the shared genes were downregulated, independent of antipsychotic treatment [50]. …”

Section: Interaction Analysis Of Mitochondrial and Nuclear-encoded Genessupporting

confidence: 87%

“…In a recent cross-disorder analysis of gene expression, the mitochondrial and neuronal gene coexpression module was shared between BD and SZ cortical regions [49], and the shared genes were downregulated, independent of antipsychotic treatment [50]. Not all recent studies of mitochondrial-related pathways reported an association with SZ.…”

Section: Mitochondrial Genes In the Nuclear Genome And Szmentioning

confidence: 99%

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Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

et al. 2019

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Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ (p = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect p ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

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Section: Interaction Analysis Of Mitochondrial and Nuclear-encoded Genessupporting

confidence: 87%

Section: Mitochondrial Genes In the Nuclear Genome And Szmentioning

confidence: 99%

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

et al. 2019

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“…In these studies, APD treatment did not result in significant differences in gene expression signatures of mitochondria [97], specific RhoGTPase genes involved in dendritic spine morphogenesis [6], the immunoreactivity of MAP2 [7], or dendritic spine density in general [78]. These results were obtained from gene expression analysis of brain tissue homogenate and region-specific (but not cell-specific) imaging studies, so it is possible that APD treatment effects cannot be observed in these models without isolation or imaging co-localization of specific neuronal cell populations or subtypes.…”

Section: Resultsmentioning

confidence: 99%

Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

et al. 2015

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Genetic evidence has supported the hypothesis that schizophrenia (SZ) is a polygenic disorder caused by the disruption in function of several or many genes. The most common and reproducible cellular phenotype associated with SZ is a reduction in dendritic spines within the neocortex, suggesting alterations in dendritic architecture may cause aberrant cortical circuitry and SZ symptoms. Here, we review evidence supporting a multifactorial model of mitochondrial dysfunction in SZ etiology and discuss how these multiple paths to mitochondrial dysfunction may contribute to dendritic spine loss and/or underdevelopment in some SZ subjects. The pathophysiological role of mitochondrial dysfunction in SZ is based upon genomic analyses of both the mitochondrial genome and nuclear genes involved in mitochondrial function. Previous studies and preliminary data suggest SZ is associated with specific alleles and haplogroups of the mitochondrial genome, and also correlates with a reduction in mitochondrial copy number and an increase in synonymous and nonsynonymous substitutions of mitochondrial DNA. Mitochondrial dysfunction has also been widely implicated in SZ by genome-wide association, exome sequencing, altered gene expression, proteomics, microscopy analyses, and induced pluripotent stem cell studies. Together, these data support the hypothesis that SZ is a polygenic disorder with an enrichment of mitochondrial targets.

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“…Alternatively, it might reflect the drug effect that robustly changed the epigenomic state in SZ2 subjects 60 . To address this we showed no mix-up for the SZ2 samples that belong two independent subjects and that H3 K4me3 signal alterations overlap with genes showing change in expression under pharmacological induction and treatment of schizophrenia-like symptoms in primate-model (Supplementary Note, Supplementary Table 13) 61 .…”

Section: Discussionmentioning

confidence: 99%

Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia

et al. 2019

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Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly located HLA-DRB5 and BTNL2 genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterized LINC01115 gene and recently identified BNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia.

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Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates

Cited by 18 publications

References 34 publications

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia

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