Molecular Evidence for Increased Expression of Genes Related to Immune and Chaperone Function in the Prefrontal Cortex in Schizophrenia

BACKGROUND Schizophrenia is characterized by complex gene expression changes. The transcriptome alterations in the prefrontal cortex have been the subject of several recent postmortem studies that yielded both convergent and divergent findings. METHODS To increase measurement precision, we used a custom-designed DNA microarray platform with long oligonucleotides and multiple probes with replicates. The platform was designed to assess the expression of > 1800 genes specifically chosen because of their hypothesized roles in the pathophysiology of schizophrenia. The gene expression differences in dorsolateral prefrontal cortex samples from 14 matched pairs of schizophrenia and control subjects were analyzed with two technical replicates and four data mining approaches. RESULTS In addition to replicating many expression changes in synaptic, oligodendrocyte, and signal transduction genes, we uncovered and validated a robust immune/chaperone transcript upregulation in the schizophrenia samples. CONCLUSIONS We speculate that the overexpression of SERPINA3, IFITM1, IFITM2, IFITM3, CHI3L1, MT2A, CD14, HSPB1, HSPA1B, and HSPA1A in schizophrenia subjects represents a long-lasting and correlated signature of an early environmental insult during development that actively contributes to the pathophysiology of prefrontal dysfunction.

[1]  Pat Levitt,et al.  Molecular Characterization of Schizophrenia Viewed by Microarray Analysis of Gene Expression in Prefrontal Cortex , 2000, Neuron.

[2]  H. Cohen,et al.  Cytokines and Cognition—The Case for A Head‐to‐Toe Inflammatory Paradigm , 2002, Journal of the American Geriatrics Society.

[3]  M. Schwarz,et al.  The Immune System and Schizophrenia: An Integrative View , 2000, Annals of the New York Academy of Sciences.

[4]  S. J. Lee,et al.  Identification of antibodies to heat shock proteins 90 kDa and 70 kDa in patients with schizophrenia , 2001, Schizophrenia Research.

[5]  K. Hashimoto,et al.  Immune Activation During Pregnancy in Mice Leads to Dopaminergic Hyperfunction and Cognitive Impairment in the Offspring: A Neurodevelopmental Animal Model of Schizophrenia , 2006, Biological Psychiatry.

[6]  P. Patterson,et al.  Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness , 2002, Current Opinion in Neurobiology.

[7]  Urs Meyer,et al.  The Time of Prenatal Immune Challenge Determines the Specificity of Inflammation-Mediated Brain and Behavioral Pathology , 2006, The Journal of Neuroscience.

[8]  H. Potter,et al.  The inflammation-induced pathological chaperones ACT and apo-E are necessary catalysts of Alzheimer amyloid formation , 2001, Neurobiology of Aging.

[9]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[10]  D. Mousseau,et al.  PILRα, a Novel Immunoreceptor Tyrosine-based Inhibitory Motif-bearing Protein, Recruits SHP-1 upon Tyrosine Phosphorylation and Is Paired with the Truncated Counterpart PILRβ* , 2000, The Journal of Biological Chemistry.

[11]  J. Weis,et al.  Expression of the mouse fragilis gene products in immune cells and association with receptor signaling complexes , 2006, Genes and Immunity.

[12]  Gustavo Stolovitzky,et al.  Genes@Work: an efficient algorithm for pattern discovery and multivariate feature selection in gene expression data , 2004, Bioinform..

[13]  Urs Meyer,et al.  Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia , 2005, Neuroscience & Biobehavioral Reviews.

[14]  G. Stark,et al.  Molecular analysis of a human interferon-inducible gene family. , 1991, European journal of biochemistry.

[15]  A. Sampson,et al.  Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. , 2000, Archives of general psychiatry.

[16]  I. Weiner,et al.  Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. , 2005, Journal of psychiatric research.

[17]  Melinda Fitzgerald,et al.  Immunol. Cell Biol. , 1995 .

[18]  T. Huizinga,et al.  Functional regulatory immune responses against human cartilage glycoprotein-39 in health vs. proinflammatory responses in rheumatoid arthritis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  T. Nagasu,et al.  Reduced neuropeptide Y mRNA levels in the frontal cortex of people with schizophrenia and bipolar disorder. , 2001, Brain research. Gene expression patterns.

[20]  T. Foster,et al.  Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment , 2003, The Journal of Neuroscience.

[21]  D. Frechilla,et al.  Reduced basal and phencyclidine-induced expression of heat shock protein-70 in rat prefrontal cortex by the atypical antipsychotic abaperidone , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[22]  I. Weiner,et al.  Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia , 2003, Neuropsychopharmacology.

[23]  A. Serretti,et al.  Polymorphisms of heat shock protein 70 gene (HSPA1A, HSPA1B and HSPA1L) and schizophrenia , 2005, Neuroscience Research.

[24]  H. Nawa,et al.  Recent progress in animal modeling of immune inflammatory processes in schizophrenia: Implication of specific cytokines , 2006, Neuroscience Research.

[25]  K. Iwamoto,et al.  Gene Expression Profiling in Schizophrenia and Related Mental Disorders , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[26]  Kazuya Iwamoto,et al.  Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. , 2005, Human molecular genetics.

[27]  T. Bayer,et al.  Review of Immunological and Immunopathological Findings in Schizophrenia , 2001, Brain, Behavior, and Immunity.

[28]  J. Pierri,et al.  Gene Expression Profiling Reveals Alterations of Specific Metabolic Pathways in Schizophrenia , 2002, The Journal of Neuroscience.

[29]  W H Wong,et al.  Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  I. Gottesman,et al.  Theories of schizophrenia: a genetic-inflammatory-vascular synthesis , 2005, BMC Medical Genetics.

[31]  A. Kakita,et al.  Perinatal inflammatory cytokine challenge results in distinct neurobehavioral alterations in rats: implication in psychiatric disorders of developmental origin , 2004, Neuroscience Research.

[32]  Yaniv Ziv,et al.  Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood , 2006, Nature Neuroscience.

[33]  R. Morimoto,et al.  The Chaperone Function of hsp70 Is Required for Protection against Stress-Induced Apoptosis , 2000, Molecular and Cellular Biology.

[34]  D. Shucard,et al.  The immune system can affect learning: chronic immune complex disease in a rat model , 1998, Journal of Neuroimmunology.

[35]  Gavin Giovannoni,et al.  Inflammatory disorders of the central nervous system. , 2003, Current opinion in neurology.

[36]  Daniel R Weinberger,et al.  Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study , 2002, Schizophrenia Research.

[37]  A. Jablensky.  Epidemiology of schizophrenia: the global burden of disease and disability , 2000, European Archives of Psychiatry and Clinical Neuroscience.

[38]  K. Mirnics,et al.  Platform influence on DNA microarray data in postmortem brain research , 2005, Neurobiology of Disease.

[39]  M. Cannon,et al.  Risk for schizophrenia — broadening the concepts, pushing back the boundaries , 2005, Schizophrenia Research.

[40]  M. Mimmack,et al.  Quantitative polymerase chain reaction: validation of microarray results from postmortem brain studies , 2004, Biological Psychiatry.

[41]  Peter B. Jones,et al.  Oligodendrocyte dysfunction in schizophrenia and bipolar disorder , 2003, The Lancet.

[42]  Simon C Watkins,et al.  Alterations in inducible 72‐kDa heat shock protein and the chaperone cofactor BAG‐1 in human brain after head injury , 2003, Journal of neurochemistry.

[43]  J. Hidalgo,et al.  Metallothionein Treatment Reduces Proinflammatory Cytokines IL-6 and TNF-α and Apoptotic Cell Death during Experimental Autoimmune Encephalomyelitis (EAE) , 2001, Experimental Neurology.

[44]  Y. Shoenfeld,et al.  Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. , 2006, Journal of autoimmunity.

[45]  David A Lewis,et al.  Schizophrenia as a disorder of neurodevelopment. , 2002, Annual review of neuroscience.

[46]  V. Berezin,et al.  The role of metallothionein II in neuronal differentiation and survival , 2003, Brain Research.

[47]  P. Levitt,et al.  Critical Appraisal of DNA Microarrays in Psychiatric Genomics , 2006, Biological Psychiatry.

[48]  D. Lewis,et al.  Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia , 2001, Molecular Psychiatry.

[49]  N. Rothwell,et al.  Cytokines and the nervous system II: actions and mechanisms of action , 1995, Trends in Neurosciences.

[50]  C. Aston,et al.  Microarray analysis of postmortem temporal cortex from patients with schizophrenia , 2004, Journal of neuroscience research.

[51]  L. Lanier,et al.  Activation of Natural Killer Cells and Dendritic Cells upon Recognition of a Novel CD99-like Ligand by Paired Immunoglobulin-like Type 2 Receptor , 2004, The Journal of experimental medicine.

[52]  M. Schwarz,et al.  Neuroimmune–endocrine crosstalk in schizophrenia and mood disorders , 2006, Expert review of neurotherapeutics.

[53]  Philip Seeman,et al.  Schizophrenia hippocampus has elevated expression of chondrex glycoprotein gene , 2003, Synapse.

[54]  Andrew L. Lemire,et al.  Deficient Hippocampal Neuron Expression of Proteasome, Ubiquitin, and Mitochondrial Genes in Multiple Schizophrenia Cohorts , 2005, Biological Psychiatry.

[55]  K. Yamagata,et al.  Differential expression of the CD14/TLR4 complex and inflammatory signaling molecules following i.c.v. administration of LPS , 2006, Brain Research.

[56]  R. Yolken,et al.  Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress , 2004, Molecular Psychiatry.

[57]  P. Adlard,et al.  Neuron‐glia communication: metallothionein expression is specifically up‐regulated by astrocytes in response to neuronal injury , 2003, Journal of neurochemistry.

[58]  H. Saito,et al.  A Family of Stress-Inducible GADD45-like Proteins Mediate Activation of the Stress-Responsive MTK1/MEKK4 MAPKKK , 1998, Cell.

[59]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[60]  A. Sampson,et al.  Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia , 2003, The Journal of Neuroscience.

[61]  C. Heyser,et al.  Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[62]  J. Vickers,et al.  Metallothionein-IIA Promotes Initial Neurite Elongation and Postinjury Reactive Neurite Growth and Facilitates Healing after Focal Cortical Brain Injury , 2003, The Journal of Neuroscience.

[63]  L. Rensing,et al.  Induction of Hsp68 by oxidative stress involves the lipoxygenase pathway in C6 rat glioma cells , 2000, Brain Research.

[64]  N. Rothwell,et al.  Cytokines and their receptors in the central nervous system: physiology, pharmacology, and pathology. , 1996, Pharmacology & therapeutics.

[65]  M. Pender,et al.  Immune dysregulation and self‐reactivity in schizophrenia: Do some cases of schizophrenia have an autoimmune basis? , 2005, Immunology and cell biology.

[66]  F. Middleton,et al.  Altered Expression of 14-3-3 Genes in the Prefrontal Cortex of Subjects with Schizophrenia , 2005, Neuropsychopharmacology.

[67]  H. M. Morris,et al.  Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia , 2008, Molecular Psychiatry.

[68]  F. Middleton,et al.  Gene Expression Profiling with DNA Microarrays: Advancing Our Understanding of Psychiatric Disorders , 2002, Neurochemical Research.

[69]  S. Poole,et al.  The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia , 2006, Molecular Psychiatry.