Antipsychotic-induced epigenomic reorganization in frontal cortex samples from individuals with schizophrenia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE174407 | GEO | 2021/11/05
REPOSITORIES: GEO
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Project description:Antipsychotic-induced epigenomic reorganization in frontal cortex samples from individuals with schizophrenia
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Project description:Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments showed thioridazine and olanzapine constituted a robust cluster. K-means clustering separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups. Keywords: repeat sample
2004-09-24 | GSE1501 | GEO
Project description:In pevious research we have shown that the disruption of the normal development of the ventral hippocampus in rodents leads to cellular abnormalities in the frontal cortex and behavioral deficits related to schizophenia (Neurotox Res. 2002, 4(5-6):469-475). We propose the use of gene expression analysis to investigate the molecular underpinnings of these processes which may shed light on the molecular processes relevant to human schizophrenia. In addition, we seek to characterize expression differences induced by chronic administration of antipsychotic medications, which may give insight into the molecular processes involved in ameliorating psychotic symptoms. Using both surgical and drug interventions, we aim to examine experimentally induced expression differences in the rodent brain that are relevant to human neuropsychiatric disorders. Disruption of the normal development of the vental hippocampus or chronic neuroleptic administration, will result in gene expression changes in the frontal cortex of rats. Elucidation of the molecular cascades underlying these treatments will shed light on both the pathoetiology (from the lesion experiments) and theurapeutic processes (from the antipsychotic treatment experiments) involved in human schizophrenia. We have developed 3 groups of samples:; 1] Ventral hippocampal lesion in neonatal rats (treatment and controls, total N=22); 2] Tetrodotoxin disruption of the ventral hippocampus (treatment and controls, total N=20); 3] Chronic administration of neuroleptics (multiple drugs, multiple doses, and controls, total N=63) Grand Total N=105
2008-06-12 | E-GEOD-4031 | biostudies-arrayexpress
Project description:Four sets of six microarray experiments were conducted. Six individual RTT frontal cortices were co-hybridized with six individual control frontal cortices. For example, the frontal cortex of patient RTT1 was compared with the occipital cortex of RTT1. Additionally, where the frontal cortex of a RTT sample was compared to the frontal cortex of a control sample, the comparison between the occipital cortices was conducted between the same samples. For example RTT1 frontal cortex vs. Con4 frontal cortex, RTT1 occipital cortex vs. Con4 occipital cortex. Each experiment was repeated and the fluorescent cyanine dyes were reversed.
2010-03-07 | E-MEXP-2588 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE38481: A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes [HumanRef-8 v3.0] GSE38484: A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes [HumanHT-12 V3.0] Refer to individual Series
2012-07-08 | E-GEOD-38485 | biostudies-arrayexpress
Project description:Altered Gene Expression in Antipsychotic Induced Weight Gain
| PRJEB31532 | ENA
Project description:Schizophrenia is a debilitating neurological disorder for which no cure exists. Few defining characteristics of schizophrenic neurons have been identified and the molecular mechanisms responsible for schizophrenia are not well understood, in part due to the lack of patient material for study. Human induced pluripotent stem cells (hiPSCs) offer a new strategy for studying schizophrenia. We have created the first cell-based human model of a complex genetic psychiatric disease by generating hiPSCs from schizophrenic patients and subsequently differentiating these cells to hiPSC-derived neurons in vitro. Schizophrenic hiPSC-derived neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of schizophrenic hiPSC-derived neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the schizophrenic phenotype were ameliorated following treatment of schizophrenic hiPSC-derived neurons with the antipsychotic loxapine. 3 independent differentiations (biological replicates) for each of four control and four schizophrenic patients were analyzed.
2011-05-01 | E-GEOD-25673 | biostudies-arrayexpress
Project description:Schizophrenia is a debilitating neurological disorder for which no cure exists. Few defining characteristics of schizophrenic neurons have been identified and the molecular mechanisms responsible for schizophrenia are not well understood, in part due to the lack of patient material for study. Human induced pluripotent stem cells (hiPSCs) offer a new strategy for studying schizophrenia. We have created the first cell-based human model of a complex genetic psychiatric disease by generating hiPSCs from schizophrenic patients and subsequently differentiating these cells to hiPSC-derived neurons in vitro. Schizophrenic hiPSC-derived neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of schizophrenic hiPSC-derived neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the schizophrenic phenotype were ameliorated following treatment of schizophrenic hiPSC-derived neurons with the antipsychotic loxapine.
2011-05-01 | GSE25673 | GEO
Project description:Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments showed thioridazine and olanzapine constituted a robust cluster. K-means clustering separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups. Experiment Overall Design: Male 13-week-old ddY mice (Japan SLC Co., Hamamatsu, Japan) weighing 38-43 g were used. Animals were housed with free access to standard food in an air-conditioned room under a constant dark-and-light cycle (light: 7:00 a.m. to 7:00 p.m.) at a temperature of 22 to 24°C and 60 to 70% relative humidity. Ether was used for anesthesia during decapitation. All efforts were made to minimize animal suffering and to reduce the number of animals used. The present experiments were carried out after obtaining permission from the Committee of Animal Experimentation of the Graduate School of Medical and Dental Sciences at Kagoshima University. Experiment Overall Design: Doses of 25 mg/kg chlorpromazine HCl (Sigma-Aldrich Co., St. Louis, MO), 25 mg/kg thioridazine HCl (Sigma-Aldrich Co.), 1.25 mg/kg olanzapine (gift from Eli Lilly and Company, Indianapolis, IN) and 18.75 mg/kg quetiapine fumarate (gift from AstraZeneca, Macclesfield, UK) were used in the study. The dosages for these drugs were determined from therapeutically equivalent doses previously reported (Lehman et al, 2003; Woods, 2003). The drugs were dissolved in acetic anhydride and diluted with 0.9% saline, resulting in a final concentration of acetic acid of 0.5%. The drugs were injected intraperitoneally once daily for 28 consecutive days in a volume of 0.1 ml/10 g body weight. Experiment Overall Design: Microarray experiments were performed using an Agilent G4121A Mouse Oligo Microarray Kit (Agilent Technologies, Palo Alto, CA) as per the manufacturerâ??s instructions. The frontal cortex was immediately removed and the RNA was stabilized in RNAlater RNA Stabilization Reagent (Qiagen, Valencia, CA) and stored at -80°C until use. Total RNA was extracted using the RNeasy Mini Kit (Qiagen). The RNA was amplified and labeled by the Low RNA Input Fluorescent Linear Amplification Kit (Agilent). To synthesize cDNA, 200 ng total RNA was used. Vehicle-injected controls were labeled by cyanine 3 (PerkinElmer Life Sciences, Inc., Boston, MA) and drug-injected mice were labeled by cyanine 5 (PerkinElmer Life Sciences, Inc.). Hybridizations to the microarray were performed using the In situ Hybridization Kit Plus (Agilent). Doses of 750 ng cyanine 3-labeled cRNA, 750 ng cyanine 5-labeled cRNA, and control targets were mixed and fragmented in the kitâ??s fragmentation buffer, and then hybridized to the microarrays for 17 hours at 60°C in a hybridization rotator (Agilent) set to rotate at 4 rpm. Microarrays were washed in 6Ã?SSC with 0.005% Triton X-102 at RT for 10 min, followed by 0.1Ã?SSC with 0.005% Triton X-102 at 4°C for 5 min. The slides were dried, and then scanned by the Agilent G2565BA Microarray Scanner System. Data were analyzed using the Agilent Feature Extraction Software version 7.1. A rank consistency filter and LOWESS were used for dye normalization. Control mice and drug-injected mice were processed in parallel. The data discussed in this publication are presented in accordance with the MIAME guidelines (http://www.mged.org/Workgroups/MIAME/miame.html) and were deposited in NCBIs Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/). They can be accessed using the GEO series accession number GSE1501. Experiment Overall Design: Cluster analysis was performed using free software written by M. Eisen (http://rana.lbl.gov/EisenSoftware.htm). The cclust package in the â??Râ?? statistical software system (www.cran.r-project.org) was used to find the most appropriate number of clusters (i.e. â??kâ?? in the k-means clustering).
2008-06-12 | E-GEOD-1501 | biostudies-arrayexpress
Project description:Multiple studies have shown that brain gene expression is disturbed in subjects suffering from schizophrenia. However, disentangling disease effects from alterations caused by neuroleptics is a challenging task. <br> To address the issues of disease heterogeneity and the effect of antipsychotic medication, we use a large collection of 110 brain autopsy samples, subdivided according to the type of antipsychotic medication received. We use global and high-resolution mRNA quantification techniques to analyse gene expression in brain tissues. We also analyse transcription in-vitro, in cell lines before and after treatment with cytokines.<br> Results. We show that inflammation-related genes are up regulated in all groups of patients, including those not treated at the time of death. In particular, four co-expressed genes that are inducible by inflammatory cytokines showed increased mRNA levels, namely IFITM2, IFITM3, SERPINA3, and GBP1 (p-values from qPCR ? 0.01). We also show that these genes are expressed in oligodendrocyte and endothelial cell lines, and transcription is inducible by inflammatory cytokines in both cell lines. Our results give molecular support to the inflammatory theory of schizophrenia and suggest that inflammatory cytokines may stimulate transcription in endothelial brain cells during schizophrenia progression. Unexpectedly, inflammation-related genes may also have a role in myelin producing cells, since they are also inducible by cytokines in oligodendrocyte cell lines. Our findings encourage future research to explore whether anti-inflammatory agents can be used in combination with traditional antipsychotics for a more efficient treatment of schizophrenia.
2007-12-06 | E-MEXP-857 | biostudies-arrayexpress