[en] Inflammatory and immunological processes interfering with brain development are discussed as one cause of schizophrenia. Various signs of overactivation of the immune system were often found in this disease. Based on post-mortem analysis showing an increased number of activated microglial cells in patients with schizophrenia, it can be hypothesized that these cells contribute to disease pathogenesis and may actively be involved in gray matter loss observed in such patients. In the present study, PolyI:C incubation of pregnant dams was used as animal model of schizophrenia, and the number and shape of microglia were assessed in the offspring in the early phase of this disease, using fluorescence immunostaining (Iba1). Descendants of mice exposed to PolyI:C at embryonic day 9 showed higher number of microglial cells in the hippocampus and striatum, but not in the frontal cortex at postnatal day 30, which is similarly to adolescence in man, as compared to those exposed to saline. Furthermore, offspring microglia from PolyI:C treated mothers were morphologically characterized by a reduced arborization indicative for a status of higher activation compared to the offspring microglia from vehicle treated mice. This study supports the hypothesis that maternal infection during embryogenesis contributes to microglial activation in the offspring, which may therefore represent a contributing factor to the pathogenesis of schizophrenia and underlines the need for new pharmacological treatment options in this regard.
Disciplines :
Neurology
Author, co-author :
Juckel, Georg; Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Germany. georg.juckel@wkp-lwl.org
Manitz, Marie Pierre; Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Germany
Brüne, Martin; Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Germany
Friebe, Astrid; Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Germany
HENEKA, Michael ; Department of Clinical Neuroscience, University of Bonn, Germany
Wolf, Rainer J; Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Germany
External co-authors :
yes
Language :
English
Title :
Microglial activation in a neuroinflammational animal model of schizophrenia--a pilot study.
Bayer T.A., Buslei R., Havas L., Falkai P. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci. Lett. 1999, 271(2):126-128.
Brown A.S., Begg M.D., Gravenstein S., Schaefer C.A., Wyatt R.J., Bresnahan M., Babulas V.P., Susser E.S. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch. Gen. Psychiatry 2004, 61(8):774-780.
Fatemi S.H., Emamian E.S., Sidwell R.W., Kist D.A., Stary J.M., Earle J.A., Thuras P. Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice. Mol. Psychiatry 2002, 7(6):633-640.
Fatemi S.H., Reutiman T.J., Folsom T.D., Huang H., Oishi K., Mori S., Smee D.F., Pearce D.A., 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. Schizophr. Res. 2008, 99(1-3):56-70.
Fuster J. The Prefrontal Cortex 2008, New York. 4th ed.
Imai Y., Ibata I., Ito D., Ohsawa K., Kohsaka S. A novel gene in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem. Biophys. Res. Commun. 1996, 224(3):855-862.
Juckel G., Heinz A., Sass L. Anhedonia, self-experience in schizophrenia, and implications for treatment. Pharmacopsychiatry 2003, 36(Suppl 3):176-180.
Manitz M.P., Horst B., Seeliger S., Strey A., Skryabin B.V., Gunzer M., Frings W., Schönlau F., Roth J., Sorg C., Nacken W. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol. Cell. Biol. 2003, 23(3):1034-1043.
Meyer U., Feldon J. Neural basis of psychosis-related behaviour in the infection model of schizophrenia. Behav. Brain Res. 2009, 204(2):322-334.
Müller N., Riedel M., Scheppach C., Brandstatter B., Sokullu S., Krampe K., Ulmschneider M., Engel R.R., Möller H.J., Schwarz M.J. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am. J. Psychiatry 2002, 159(6):1029-1034.
Ohsawa K., Imai Y., Kanasawa H., Sasaki Y., Kohsaka S. Involvement of Iba1 in membrane ruffing and phagocytosis of macrophages/microglia. J. Cell Sci. 2000, 113(Pt 17):3073-3084.
Paxinos G., Franklin K.B.J. The Mouse Brain in Stereotaxic Coordinates 2001, Deluxe Second Edition, New York.
Preuss T.M. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered. J. Cogn. Neurosci. 1995, 7(1):1-24.
Radewicz K., Garey L.J., Gentleman S.M., Reynolds R. Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J. Neuropathol. Exp. Neurol. 2000, 59(2):137-150.
Schofield C.M., Hsu R., Barker A.J., Gertz C.C., Blelloch R., Ullian E.M. Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortex. Neural Dev. 2011, 6:11-21.
Shapiro L.A., Perez Z.D., Foresti M.L., Arisi G.M., Ribak C.E. Morphological and ultrastructural features of Iba1-immunolabeled microglial cells in the hippocampal dentate gyrus. Brain Res. 2009, 1266:29-36.
Shi L., Fatemi S.H., Sidwell R.W., Patterson P.H. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 2003, 23(1):297-302.
Stehen R.G., Mull C., McClure R., Hamer R.M., Lieberman J.A. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br. J. Psychiatry 2006, 188(6):510-518.
Stence N., Waite M., Dailey M.E. Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 2001, 33(3):256-266.
Winter C., Djodari-Irani A., Sohr R., Morgenstern R., Feldon J., Juckel G., Meyer U. 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(4):513-524.
Witthaus H., Kaufmann C., Bohner G., Özgürdal S., Gudlowski Y., Gallinat J., Ruhrmann S., Brüne M., Heinz A., Klingebiel R., Juckel G. Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls. Psychiatry Res. Neuroimaging 2009, 173(3):163-169.
