You have full text access to this OnlineOpen article
Cytokines and schizophrenia: Microglia hypothesis of schizophrenia
Article first published online: 13 APR 2009
DOI: 10.1111/j.1440-1819.2009.01945.x
© 2009 The Authors. Journal compilation © 2009 Japanese Society of Psychiatry and Neurology
Additional Information
How to Cite
Monji, A., Kato, T. and Kanba, S. (2009), Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry and Clinical Neurosciences, 63: 257–265. doi: 10.1111/j.1440-1819.2009.01945.x
Publication History
- Issue published online: 14 MAY 2009
- Article first published online: 13 APR 2009
- Accepted 27 January 2009.
REFERENCES
- 1, , , , . Addition of antipsychotics to medication regimens during schizophrenic inpatient care. Psychiatry Clin. Neurosci. 2008; 62: 56–64.
- 2, , et al. Prevalence, correlates, and disease patterns of antipsychotic use in Taiwan. Psychiatry Clin. Neurosci. 2008; 62: 677–684.
- 3, , , . The value of interleukin-12B (p40) gene promoter polymorphism in patients with schizophrenia in a region of East Turkey. Psychiatry Clin. Neurosci. 2008; 62: 307–312.
- 4, , , . Microglial control of neuronal death and synaptic properties. Glia 2007; 55: 233–238.
- 5, , et al. Localization of a novel type trypsin-like serine protease, neurosin, in brain tissues of Alzheimer's disease and Parkinson's disease. Psychiatry Clin. Neurosci. 2000; 54: 419–426.
- 6, , , , , . Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer's disease. Psychiatry Clin. Neurosci. 1997; 51: 135–138.
- 7. Microglia as a source and target of cytokines. Glia 2002; 40: 140–155.
- 8, , , , . Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol. Psychiatry 2007; 62: 711–721.
- 9, , , . Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav. Immun. 2006; 20: 532–545.
- 10, , et al. Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res. 2008; 1239: 235–248.
- 11, , , , , . Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review. Biol. Psychiatry 2008; 63: 801–808.
- 12. Immunological aetiology of major psychiatric disorders: Evidence and therapeutic implications. Drugs 2005; 65: 1493–1520.
- 13, , et al. The inflammatory response system in treatment-resistant schizophrenia: Increased serum interleukin-6. Schizophr. Res. 1998; 32: 9–15.
- 14, , , , , . Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: Relationship to outcome in schizophrenia. J. Clin. Psychiatry 2004; 65: 940–947.
- 15, , , , , . Celecoxib as adjunctive therapy in schizophrenia: A double-blind, randomized and placebo-controlled trial. Schizophr. Res. 2007; 90: 179–185.
- 16, , , . Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 2005; 255: 149–151.
- 17, , et al. Increased serum S100B in elderly, chronic schizophrenic patients: Negative correlation with deficit symptoms. Schizophr. Res. 2005; 80: 305–313.
- 18, , , , , . The role of cytokines in mediating effects of prenatal infection on the fetus: Implications for schizophrenia. Mol. Psychiatry 2006; 11: 47–55.
- 19, . Recent progress in animal modeling of immune inflammatory processes in schizophrenia: Implication of specific cytokines. Neurosci. Res. 2006; 56: 2–13.
- 20, , et al. Toll-like receptor 3 mediated hyperphosphorylation of tau in human SH-SY5Y neuroblastoma cells. Psychiatry Clin. Neurosci. 2006; 60: S27–S33.Direct Link:
- 21, . Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism. Prog. Neurobiol. 2005; 76: 77–98.
- 22. Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol. Psychiatry 1999; 46: 729–739.
- 23, , , . Possible mechanisms of neurodegeneration in schizophrenia. Neurochem. Res. 2006; 31: 1279–1294.
- 24, , , . Cerebellar toxicity of phencyclidine. J. Neurosci. 1995; 15: 2097–2108.
- 25, , , , . Haloperidol prevents ketamine- and phencyclidine-induced HSP70 protein expression but not microglial activation. Exp. Neurol. 1996; 137: 234–241.
- 26, , , . Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci. Lett. 1999; 271: 126–128.
- 27, , , . Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J. Neuropathol. Exp. Neurol. 2000; 59: 137–150.
- 28, , et al. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathol. 2006; 112: 305–316.
- 29, , et al. Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide. J. Psychiatr. Res. 2008; 42: 151–157.
- 30, , , . In vivo evidence for microglial activation in neurodegenerative dementia. Acta Neurol. Scand. Suppl. 2006; 185: 107–114.
- 31, , et al. Microglia activation in recent-onset schizophrenia: A quantitative (R)-[11C]PK11195 positron emission tomography study. Biol. Psychiatry 2008; 64: 820–822.
- 32, . Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment. Hippocampus 2006; 16: 239–249.
- 33, , et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry 2006; 11: 514–522.
- 34, , , , , . Effects of repeated phencyclidine administration on adult hippocampal neurogenesis in the rat. Synapse 2006; 60: 56–68.Direct Link:
- 35, , et al. Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine. J. Pharmacol. Sci. 2007; 103: 299–308.
- 36, , , , . The NPAS3 gene: Emerging evidence for a role in psychiatric illness. Ann. Med. 2006; 38: 439–448.
- 37, , et al. The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proc. Natl Acad. Sci. USA 2005; 102: 14052–14057.
- 38, , et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 2007; 130: 1146–1158.
- 39, , , . Atypical neuroleptics stimulate neurogenesis in adult rat brain. J. Neurosci. Res. 2002; 69: 72–79.
- 40, , . Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol. Psychiatry 2004; 56: 570–580.
- 41, , . Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302: 1760–1765.
- 42, , , , . Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl Acad. Sci. USA 2003; 100: 13632–13637.
- 43, , . Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J. Neurosci. Res. 2005; 80: 789–797.
- 44, , et al. Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J. Neurosci. 2006; 26: 9703–9712.
- 45, , et al. Suppression of cell proliferation by interferon-alpha through interleukin-1 production in adult rat dentate gyrus. Neuropsychopharmacology 2006; 31: 2619–2626.
- 46, , et al. White matter changes in schizophrenia: Evidence for myelin-related dysfunction. Arch. Gen. Psychiatry 2003; 60: 443–456.
- 47, , et al. White matter abnormalities in early-onset schizophrenia: A voxel-based diffusion tensor imaging study. J. Am. Acad. Child Adolesc. Psychiatry 2005; 44: 934–941.
- 48, , , , . Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch. Gen. Psychiatry 2007; 64: 521–529.
- 49, . What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr. Bull. 2008; 34: 354–366.
- 50, , , . Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr. Res. 2006; 81: 47–63.
- 51, , , . Apoptotic mechanisms in the pathophysiology of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2005; 29: 846–858.
- 52, , . Antioxidants inhibit the human cortical neuron apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42. Free Radic. Res. 2002; 36: 1179–1184.
- 53, , et al. Cytokine-induced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-gamma and TNF-alpha on apoptosis. J. Neurosci. Res. 2004; 76: 834–845.
- 54, . Nitric oxide induces cultured cortical neuron apoptosis. Neurosci. Lett. 1996; 208: 1–4.
- 55, , . Cytokine-mediated neuronal apoptosis. Neurochem. Int. 1997; 30: 427–431.
- 56, , , . Nitric-oxide-directed synaptic remodeling in the adult mammal CNS. J. Neurosci. 2005; 25: 1448–1458.
- 57, . Synaptic scaling mediated by glial TNF-alpha. Nature 2006; 440: 1054–1059.
- 58, , . Synaptic differences in the postmortem striatum of subjects with schizophrenia: A stereological ultrastructural analysis. Synapse 2005; 56: 185–197.
- 59, , et al. A volumetric MRI and magnetization transfer imaging follow-up study of patients with first-episode schizophrenia. Schizophr. Res. 2006; 87: 100–108.
- 60, , et al. White matter abnormalities and brain activation in schizophrenia: A combined DTI and fMRI study. Schizophr. Res. 2007; 89: 1–11.
- 61, , , . Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: A study from the Stanley Neuropathology Consortium. Schizophr. Res. 2004; 67: 269–275.
- 62, , , , , . The role of oligodendrocyte pathology in schizophrenia. Int. J. Neuropsychopharmacol. 2007; 10: 537–545.
- 63, , , , . Effect of a functional single nucleotide polymorphism in the 2′,3′-cyclic nucleotide 3′-phosphodiesterase gene on the expression of oligodendrocyte-related genes in schizophrenia. Psychiatry Clin. Neurosci. 2008; 62: 103–108.
- 64, , et al. Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia. Schizophr. Res. 2007; 90: 15–27.
- 65, , , , . Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc. Natl Acad. Sci. USA 2005; 102: 9936–9941.
- 66, , , , . Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 1993; 151: 2132–2141.
- 67, . Maturation of oligodendrocytes is more sensitive to TNF alpha than is survival of precursors and immature oligodendrocytes. J. Neuroimmunol. 1999; 97: 37–42.
- 68, , , . Effects of interferon-gamma and tumor necrosis factor-alpha on survival and differentiation of oligodendrocyte progenitors. J. Soc. Gynecol. Invest. 2004; 11: 89–96.
- 69, , et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch. Gen. Psychiatry 2005; 62: 361–370.
- 70, , et al. Duration of illness and treatment effects on hippocampal volume in male patients with schizophrenia. Br. J. Psychiatry 2005; 186: 26–31.
- 71, , et al. Volume changes in gray matter in first-episode neuroleptic-naive schizophrenic patients treated with risperidone. J. Clin. Psychopharmacol. 2005; 25: 111–117.
- 72, , , , , . Risperidone in first-episode psychosis: A longitudinal, exploratory voxel-based morphometric study. Schizophr. Res. 2006; 82: 89–94.
- 73, , , , , . Effect of clozapine and risperidone on serum cytokine levels in patients with first-episode paranoid schizophrenia. Academic journal of the first medical college of PLA. Di Yi Jun Yi Da Xue Xue Bao 2004; 24: 1251–1254 (in Chinese).
- 74, , , , , . Possible antipsychotic effects of minocycline in patients with schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2007; 31: 304–307.
- 75, , , , , . Minocycline as adjunctive therapy for schizophrenia: An open-label study. Clin. Neuropharmacol. 2008; 31: 287–292.
- 76, , . Flupentixol and trifluperidol reduce secretion of tumor necrosis factor-alpha and nitric oxide by rat microglial cells. Neurochem. Int. 2003; 43: 173–178.
- 77, , . Flupentixol and trifluperidol reduce interleukin-1 beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Pol. J. Pharmacol. 2004; 56: 563–570.
- 78, , , . Chlorpromazine and loxapine reduce interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Eur. Neuropsychopharmacol. 2005; 15: 23–30.
- 79, , et al. Effects of clozapine, olanzapine and haloperidol on nitric oxide production by lipopolysaccharide-activated N9 cells. Prog. Neuropsychopharmacol. Biol. Psychiatry 2006; 30: 1523–1528.
- 80, , , . Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr. Res. 2007; 92: 108–115.
- 81, , et al. The effect of atypical antipsychotics, perospirone, ziprasidone and quetiapine on microglial activation induced by interferon-gamma. Prog. Neuropsychopharmacol. Biol. Psychiatry 2008; 32: 42–48.
- 82, , et al. Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro. J. Neurochem. 2008; 106: 815–825.
- 83, , , , , . The antipsychotic spiperone attenuates inflammatory response in cultured microglia via the reduction of proinflammatory cytokine expression and nitric oxide production. J. Neurochem. 2008; 107: 1225–1235.
- 84, , , . The Th2-hypothesis of schizophrenia: A strategy to identify a subgroup of schizophrenia caused by immune mechanisms. Med. Hypotheses 2001; 56: 483–486.
- 85, , . Review of immunological and immunopathological findings in schizophrenia. Brain Behav. Immun. 2001; 15: 319–339.
- 86, , et al. Cytokine profiles in drug-naive schizophrenic patients. Schizophr. Res. 2001; 47: 293–298.
- 87, . Neurotransmitter receptors on microglia. Trends Neurosci. 2007; 30: 527–535.
- 88, . Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J. Mol. Neurosci. 2005; 27: 43–64.
- 89, , et al. Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J. Neurosci. Res. 2006; 83: 1461–1470.
- 90, , . Cholinergic agonists as novel treatments for schizophrenia: The promise of rational drug development for psychiatry. Am. J. Psychiatry 2008; 165: 931–936.
- 91, , . Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol. 2006; 27: 24–31.
- 92, , et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Double-blind placebo-controlled randomised phase III trial. Lancet 2006; 367: 29–35.
- 93, , , . Rationale for a trial of immunosuppressive therapy in acute schizophrenia. Mol. Psychiatry 2007; 12: 424–431.

1440-1819/asset/olbannerleft.gif?v=1&s=53aa57299a73f1cea88ed36d923a25e042c23538)
