Molecular mechanisms and timing of cortical immune activation in schizophrenia.

OBJECTIVE Immune-related abnormalities are commonly reported in schizophrenia, including higher mRNA levels for the viral restriction factor interferon-induced transmembrane protein (IFITM) in the prefrontal cortex. The authors sought to clarify whether higher IFITM mRNA levels and other immune-related disturbances in the prefrontal cortex are the consequence of an ongoing molecular cascade contributing to immune activation or the reflection of a long-lasting maladaptive response to an in utero immune-related insult. METHOD Quantitative polymerase chain reaction was employed to measure mRNA levels for immune-related cytokines and transcriptional regulators, including those reported to regulate IFITM expression, in the prefrontal cortex from 62 schizophrenia and 62 healthy subjects and from adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant poly(I:C). RESULTS Schizophrenia subjects had markedly higher mRNA levels for interleukin 6 (IL-6) (+379%) and interferon-β (+29%), which induce IFITM expression; lower mRNA levels for Schnurri-2 (-10%), a transcriptional inhibitor that lowers IFITM expression; and higher mRNA levels for nuclear factor-κB (+86%), a critical transcription factor that mediates cytokine regulation of immune-related gene expression. In adult mice that received daily poly(I:C) injections, but not in offspring with prenatal exposure to maternal immune activation, frontal cortex mRNA levels were also markedly elevated for IFITM (+304%), multiple cytokines including IL-6 (+493%), and nuclear factor-κB (+151%). CONCLUSIONS These data suggest that higher prefrontal cortex IFITM mRNA levels in schizophrenia may be attributable to adult, but not prenatal, activation of multiple immune markers and encourage further investigation into the potential role of these and other immune markers as therapeutic targets in schizophrenia.

[1]  D. Volk,et al.  Chemokine receptors and cortical interneuron dysfunction in schizophrenia , 2015, Schizophrenia Research.

[2]  I. McKeague,et al.  Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. , 2014, The American journal of psychiatry.

[3]  D. Volk,et al.  Cortical inhibitory neuron disturbances in schizophrenia: role of the ontogenetic transcription factor Lhx6. , 2014, Schizophrenia bulletin.

[4]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[5]  D. Volk,et al.  Elevated Viral Restriction Factor Levels in Cortical Blood Vessels in Schizophrenia , 2014, Biological Psychiatry.

[6]  M. Riva,et al.  Prenatal immune activation induces maturation-dependent alterations in the prefrontal GABAergic transcriptome. , 2014, Schizophrenia bulletin.

[7]  P. Mortensen,et al.  The Epidemiologic Evidence Linking Autoimmune Diseases and Psychosis , 2014, Biological Psychiatry.

[8]  M. Webster,et al.  Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder , 2014, Translational Psychiatry.

[9]  P. Mortensen,et al.  A nationwide study on the risk of autoimmune diseases in individuals with a personal or a family history of schizophrenia and related psychosis. , 2014, The American journal of psychiatry.

[10]  J. Schmid,et al.  The complexity of NF-κB signaling in inflammation and cancer , 2013, Molecular Cancer.

[11]  P. Patterson,et al.  Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development , 2013, Brain, Behavior, and Immunity.

[12]  R. Murray,et al.  Serum and gene expression profile of cytokines in first-episode psychosis , 2013, Brain, Behavior, and Immunity.

[13]  D. Volk,et al.  Endocannabinoid metabolism in the prefrontal cortex in schizophrenia , 2013, Schizophrenia Research.

[14]  Ryan J Kast,et al.  Epigenetic changes at gene promoters in response to immune activation in utero , 2013, Brain, Behavior, and Immunity.

[15]  J. Roder,et al.  Maternal Immune Activation during Gestation Interacts with Disc1 Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice , 2013, The Journal of Neuroscience.

[16]  D. Kelly,et al.  A review of anti-inflammatory agents for symptoms of schizophrenia , 2013, Journal of psychopharmacology.

[17]  J. Feldon,et al.  Stress in Puberty Unmasks Latent Neuropathological Consequences of Prenatal Immune Activation in Mice , 2013, Science.

[18]  Hironori K. Nakamura,et al.  Deficiency of Schnurri-2, an MHC Enhancer Binding Protein, Induces Mild Chronic Inflammation in the Brain and Confers Molecular, Neuronal, and Behavioral Phenotypes Related to Schizophrenia , 2013, Neuropsychopharmacology.

[19]  M. Cairns,et al.  Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia , 2013, Molecular Psychiatry.

[20]  M. Diamond,et al.  The broad-spectrum antiviral functions of IFIT and IFITM proteins , 2012, Nature Reviews Immunology.

[21]  A. Thotakura,et al.  The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. , 2012, Trends in cell biology.

[22]  Danko D. Georgiev,et al.  Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia. , 2012, The American journal of psychiatry.

[23]  M. Farzan,et al.  Ifitm3 Limits the Severity of Acute Influenza in Mice , 2012, PLoS pathogens.

[24]  Erin Walker,et al.  Cortical opioid markers in schizophrenia and across postnatal development. , 2012, Cerebral cortex.

[25]  B. Kirkpatrick,et al.  Meta-Analysis of Cytokine Alterations in Schizophrenia: Clinical Status and Antipsychotic Effects , 2011, Biological Psychiatry.

[26]  M. Swami.  New from NPG: Genome-wide association study identifies five new schizophrenia loci , 2011, Nature Medicine.

[27]  A. Sampson,et al.  Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. , 2011, The American journal of psychiatry.

[28]  P. Patterson,et al.  Activation of the maternal immune system induces endocrine changes in the placenta via IL-6 , 2011, Brain, Behavior, and Immunity.

[29]  A. Brass,et al.  Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus , 2011, PLoS pathogens.

[30]  D. Volk,et al.  Alterations in metabotropic glutamate receptor 1α and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. , 2010, The American journal of psychiatry.

[31]  Peilin Jia,et al.  Common variants conferring risk of schizophrenia: A pathway analysis of GWAS data , 2010, Schizophrenia Research.

[32]  Alan S. Brown,et al.  Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. , 2010, The American journal of psychiatry.

[33]  Rudi A. Dierckx,et al.  Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study , 2009, Journal of Nuclear Medicine.

[34]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[35]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[36]  Jianxin Shi,et al.  Common variants on chromosome 6p22.1 are associated with schizophrenia , 2009, Nature.

[37]  R. Boellaard,et al.  Microglia Activation in Recent-Onset Schizophrenia: A Quantitative (R)-[11C]PK11195 Positron Emission Tomography Study , 2008, Biological Psychiatry.

[38]  Urs Meyer,et al.  Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice , 2008, Brain, Behavior, and Immunity.

[39]  Emmanuel Stip,et al.  Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review , 2008, Biological Psychiatry.

[40]  David A Lewis,et al.  Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. , 2008, The American journal of psychiatry.

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

[42]  K. Mirnics,et al.  Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6 , 2007, The Journal of Neuroscience.

[43]  Pat Levitt,et al.  Molecular Evidence for Increased Expression of Genes Related to Immune and Chaperone Function in the Prefrontal Cortex in Schizophrenia , 2007, Biological Psychiatry.

[44]  Colm Cunningham,et al.  The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C) , 2007, Brain, Behavior, and Immunity.

[45]  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.

[46]  Zhuoxin Sun,et al.  The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys , 2005, Neuropsychopharmacology.

[47]  E. Lewandowska,et al.  Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics. , 2005, Folia neuropathologica.

[48]  Charles P Quesenberry,et al.  Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. , 2005, The American journal of psychiatry.

[49]  E. Susser,et al.  Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. , 2004 .

[50]  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.

[51]  E. Susser,et al.  Serologic evidence for prenatal influenza in the etiology of schizophrenia , 2003, Schizophrenia Research.

[52]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[53]  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.

[54]  L. Garey,et al.  Increase in HLA‐DR Immunoreactive Microglia in Frontal and Temporal Cortex of Chronic Schizophrenics , 2000, Journal of neuropathology and experimental neurology.

[55]  E. Jazin,et al.  BMC Psychiatry BioMed Central Research article Inflammation-related genes up-regulated in schizophrenia brains , 2007 .