Mikroglia bei Schizophrenie

Zusammenfassung

In der Pathophysiologie der Schizophrenie spielen die Mikrogliazellen eventuell die entscheidende Rolle. Frühe Reize in der Embryonalzeit und degenerative Veränderungen führen zu einer Mikrogliaaktivierung, die durch die neurotoxischen Eigenschaften zu einer Rarifizierung der synaptischen Verbindungen frontotemporal und zur Neuropilreduktion führen könnte. In dem inflammatorischen PolyI:C-Tiermodell der Schizophrenie konnte diese Mikrogliaaktivierung gut nachvollzogen werden, mit einem zeitlichen Höhepunkt in der späten Jugendzeit bzw. im jungen Erwachsenenalter. Wie genau die Mikrogliaaktivierung zur Neurodegeneration führt, muss weiter vertiefend untersucht werden. Das Forschungsfeld zur Rolle der Mikroglia bei der Schizophrenie ist noch jung. Die wenigen wissenschaftlichen und klinischen Arbeiten deuten darauf hin, dass die Aktivierung der Mikroglia eine Schlüsselrolle in der Pathogenese der Schizophrenie einnehmen könnten. Ziel dieses Übersichtsartikels ist es, diese Zusammenhänge und die entsprechenden Tiermodelle bei der Schizophrenie und ihre wesentlichen Befunde zusammenfassend darzustellen.

Summary

Within the pathophysiology of schizophrenia, microglial cells seem to play the most important role. Early signals within the embryonal phase and neurodegenerative changes lead to activation of microglia cells, which – via the neurotoxic activities of these cells – induces a rarification of synaptic connections in frontal and temporal brain regions, i. e. reduction of the neuropil. This microglial activation could be well modelled within the inflammational PolyI:C animal model of schizophrenia, having a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then trigger neurodegeneration, must be investigated further on in broad detail. The research field concerning the role of microglia in patients with schizophrenia is still young. The few basic scientific and clinical studies suggest that activation of microglia cells plays a key role within the pathogenesis of schizophrenia. Aim of this review article is to present this theoretical framework as well as the respective animal models of schizophrenia and their findings in a summary manner.

Schlüsselwörter

Mikroglia - Schizophrenie - Neurodegeneration - Tiermodell - post mortem - Suizidalität

Keywords

Mikroglial cells - schizophrenia - animal model - neurodegeneration

• Literatur

• 1 Juckel G. et al. Ventricle size and P300 in schizophrenia. Eur Arch Psychiatry Clin Neurosci 1994; 243 (06) 352-354.
• 2 Juckel G. et al. Residual symptoms and P300 in schizophrenic outpatients. Psychiatry Res 1996; 65 (01) 23-32.
• 3 Juckel G, Sass L, Heinz A. Anhedonia, self-experience in schizophrenia, and implications for treatment. Pharmacopsychiatry 2003; 36 (Suppl. 03) S176-180.
• 4 Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995; 346 8974 552-557.
• 5 Heinz A. et al. Striatal dopamine receptors and transporters in monkeys with neonatal temporal limbic damage. Synapse 1999; 32 (02) 71-79.
• 6 Falkai P. et al. Influence of genetic loading, obstetric complications and premorbid adjustment on brain morphology in schizophrenia: a MRI study. Eur Arch Psychiatry Clin Neurosci 2003; 253 (02) 92-99.
• 7 Heinz A, Weinberger D. Schizophrenie: Die neurobiologische Entwicklungshypothese. In: Helmchen et al. (eds.) Psychiatrie der Gegenwart 5. Berlin: Springer; 2000
• 8 Heinz A. et al. Molecular brain imaging and the neurobiology and genetics of schizophrenia. Pharmacopsychiatry 2003; 36 (Suppl. 03) S152-157.
• 9 Mathalon DH. et al. Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2001; 58 (02) 148-157.
• 10 Cahn W. et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002; 59 (11) 1002-1010.
• 11 Pantelis C. et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003; 361 9354 281-288.
• 12 Scherk H, Vogeley K, Falkai P. [The importance of interneurons in schizophrenic and affective disorders]. Fortschr Neurol Psychiatr 2003; 01 (Suppl. 01) S27-32.
• 13 Mednick SA. et al. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988; 45 (02) 189-192.
• 14 Takei N. et al. Prenatal exposure to influenza and increased cerebrospinal fluid spaces in schizophrenia. Schizophr Bull 1996; 22 (03) 521-534.
• 15 Munk-Jørgensen P, Ewald H. Epidemiology in neurobiological research: exemplified by the influenza-schizophrenia theory. Br J Psychiatry 2001; (Suppl. 40) s30-32.
• 16 Limosin F. et al. Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psychiatr Scand 2003; 107 (05) 331-5.
• 17 Brown AS. et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004; 61 (08) 774-780.
• 18 Müller N, Dobmeier P, Empl M, Riedel M, Schwarz M, Ackenheil M. Soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients. Eur Psychiatry 1997; 12 (06) 294-9.
• 19 Müller N. et al. Increased frequency of CD8 positive gamma/delta T-lymphocytes (CD8+ gamma/ delta+) in unmedicated schizophrenic patients: relation to impairment of the blood-brain barrier and HLA-DPA*02011. Schizopr Res 1998; 32 (01) 69-71.
• 20 Gaughran F. Immunity and schizophrenia: auto-immunity, cytokines, and immune responses. Int Rev Neurobiol 2002; 52: 275-302.
• 21 Müller M, Ackenheim M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22 (01) 1-33.
• 22 Rothermundt M, Arolt V, Bayer TA. Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun 2001; 15 (04) 319-39.
• 23 Müller J. et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 2002; 159 (06) 1029-34.
• 24 Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19 (08) 312-8.
• 25 Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry and Clinical Neurosciences 2009; 03: 257-265.
• 26 Bayer TA, Buslei R, Havas L, Falkai P. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett 1999; 271 (02) 126-8.
• 27 Radewicz K. et al. Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol 2000; 59 (02) 137-150.
• 28 Munn N. Microglia dysfunction in schizophrenia: an integrative theory. Med Hypotheses 2000; 54 (02) 198-202.
• 29 van Berckel BN. et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008; 64 (09) 820-2.
• 30 Doorduin J. et al. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 2009; 50 (11) 1801-1807.
• 31 Fatemi SH. et al. Human influenza viral infection in utero increases nNOS expression in hippocampi of neonatal mice. Synapse 1998; 29 (01) 84-8.
• 32 Fatemi SH. et al. Differential expression of synaptosome-associated protein 25 kDa [SNAP-25] in hippocampi of neonatal mice following exposure to human influenza virus in utero. Brain Res 1998; 800 (01) 1-9.
• 33 Fatemi SH. et al. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry 1999; 04 (02) 145-154.
• 34 Fatemi SH. et al. Prenatal viral infection causes alteratios in nNOS expression in developing mouse brains. Neuroreport 2000; 11 (07) 1493-1496.
• 35 Shi L. et al. A mouse model of mental illness: maternal influenza infection causes behavioural and pharmacological abnormalities in the offspring. J Neurosci 2002; 23 (01) 297-302.
• 36 Meyer U, Feldon J. Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol 2002; 90 (03) 285-326.
• 37 Winter C. et al. Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: Implications for brain disorders of neurodevelopmental origin such as schizophrenia. Int J Neuropsychopharmacol 2009; 12 (04) 513-524.
• 38 Meyer U. Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry 20014; 75 (04) 307-15.
• 39 Meyer U. et al. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci 2006; 26 (18) 4752-4762.
• 40 Winter C. et al. Dopamine and serotonin levels following prenatal viral infection in mouse-implications for psychiatric disorders such as schizophrenia and autism. Eur Neuropsychopharmacol 2008; 18 (10) 712-716.
• 41 Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, Smee DF, Pearce DA, Winter C, Sohr R, Juckel G. Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: Implications for genesis of neurodevelopmental disorders. Schizophrenia Research 2008; 99 (1–3) 56-70.
• 42 Winter C. et al. Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: Implications for brain disorders of neurodevelopmental origin such as schizophrenia. Int J Neuropsychopharmacol 2008; 12 (04) 513-524.
• 43 Juckel G. et al. Microglial activation in a neuroinflammational animal model of schizophrenia – a pilot study. Schizophrenia Research 2011; 131: 96-100.
• 44 Shapiro LA. et al. Morphological and ultrastructural features of Iba1-immunolabeled microglial cells in the hippocampaldentate gyrus. Brain Res 2009; 1266: 29-36.
• 45 Stence N, Waite M, Dailey ME. Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 2001; 33 (03) 256-266.
• 46 Stehen RG. et al. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry 2006; 188 (06) 510-518.
• 47 Witthaus H. et al. Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients. Psychiatry Res 2006; 173 (03) 163-9.
• 48 Manitz MP. et al. The role of microglia during life span in neuropsychiatric disease – an animal study. Schizophr Res 2013; 143 (01) 221-222.
• 49 Howes et al. From the prodrome to chronic schizophrenia: the neurobiology underlying psychotic symptoms and cognitive impairments. Curr Pharm Des 2012; 18: 459-465.
• 50 Ye SM, Johnson RW. Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 1999; 93 (1–2) 139-148.