Top

Published in:

Open Access 01-12-2012 | Research

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model

Authors: Kristian Liaury, Tsuyoshi Miyaoka, Toshiko Tsumori, Motohide Furuya, Rei Wake, Masa Ieda, Keiko Tsuchie, Michiyo Taki, Kotomi Ishihara, Andi Jayalangkara Tanra, Jun Horiguchi

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

Schizophrenia is a debilitating and complex mental disorder whose exact etiology remains unknown. There is growing amount of evidence of a relationship between neuroinflammation, as demonstrated by microglial activation, and schizophrenia. Our previous studies have proposed that hyperbilirubinemia plays a role in the pathophysiology of schizophrenia. Furthermore, we suggested the Gunn rat, an animal model of bilirubin encephalopathy, as a possible animal model of schizophrenia. However, the effects of unconjugated bilirubin on microglia, the resident immune cell of the CNS, in Gunn rats have never been investigated. In the present study, we examined how microglial cells respond to bilirubin toxicity in adult Gunn rats.

Methods

Using immunohistochemical techniques, we compared the distribution, morphology, and ultrastructural features of microglial cells in Gunn rats with Wistar rats as a normal control. We also determined the ratio of activated and resting microglia and observed microglia-neuron interactions. We characterized the microglial cells in the hippocampal dentate gyrus.

Results

We found that microglial cells showed activated morphology in the hilus, subgranular zone, and granular layer of the Gunn rat hippocampal dentate gyrus. There was no significant difference between cell numbers between in Gunn rats and controls. However, there was significant difference in the area of CD11b expression in the hippocampal dentate gyrus. Ultrastructurally, microglial cells often contained rich enlarged rich organelles in the cytoplasm and showed some phagocytic function.

Conclusions

We propose that activation of microglia could be an important causal factor of the behavioral abnormalities and neuropathological changes in Gunn rats. These findings may provide basic information for further assessment of the Gunn rat as an animal model of schizophrenia.

Saha S, Chant D, Welham J, McGrath J: A systematic review of the prevalence of schizophrenia. PLoS Med 2005, 2:413–433.CrossRef

Monji A, Kato T, Kanba S: Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 2009, 63:257–265.CrossRefPubMed

Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, Werge T, Pietiläinen OP, Mors O, Mortensen PB, Sigurdsson E, Gustafsson O, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Suvisaari J, Lonnqvist J, Paunio T, Børglum AD, Hartmann A, Fink-Jensen A, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Böttcher Y, Olesen J, Breuer R, Möller HJ, Giegling I, et al.: Common variants conferring risk of schizophrenia. Nature 2009, 460:744–748.PubMedPubMedCentral

Miller BJ, Buckley P, Seabott W, Mellor A, Kirkpatrick B: Meta-analysis of cytokine alterations in schizophrenia: clinical studies and antipsychotic effects. Biol Psychiatry 2011, 70:663–671.CrossRefPubMedPubMedCentral

Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA: The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 2010, 10:59–76.CrossRefPubMed

Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein HG, Bogerts B: Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathol 2006, 112:305–316.CrossRefPubMed

Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG, Bogerts B: 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.CrossRefPubMed

Muller N, Myint AM, Schwarz MJ: Kynurenine pathway in schizophrenia: pathophysiological and therapeutic aspects. Curr Pharm Des 2011, 17:130–136.CrossRefPubMed

Steiner J, Bogerts B, Sarnyai Z, Walter M, Gos T, Bernstein HG, Myint AM: Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity. World J Biol Psychiatry, in press.

10.

Muller N, Schiller P, Ackenheil M: Coincidence of schizophrenia and hyperbilirubinemia. Pharmacopsychiatry 1991, 24:225–228.CrossRefPubMed

11.

Miyaoka T, Seno H, Itoga M, Iijima M, Inagaki T, Horiguchi J: Schizophrenia-associated idiopathic unconjugated bilirubinemia (Gilbert's syndrome). J Clin Psychiatry 2000, 61:868–871.CrossRefPubMed

12.

Radhakrishnan R, Kanigere M, Menon J, Calvin S, Janish A, Srinivasan K: Association between unconjugated bilirubin and schizophrenia. Psychiatry Res 2011, 189:480–482.CrossRefPubMed

13.

Miyaoka T, Yasukawa R, Mizuno S, Sukegawa T, Inagaki T, Horiguchi J, Seno H, Oda K, Kitagaki H: Proton magnetic resonance spectroscopy (1H-MRS) of hippocampus, basal ganglia, and vermis of cerebellum in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). J Psychiatr Res 2005, 39:29–34.CrossRefPubMed

14.

Yasukawa R, Miyaoka T, Mizuno S, Inagaki T, Horiguchi J, Oda K, Kitagaki H: Proton magnetic resonance spectroscopy of the anterior cingulated gyrus, insular cortex and thalamus in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). J Psychiatry Neurosci 2005, 30:416–422.PubMedPubMedCentral

15.

Miyaoka T, Yasukawa R, Mihara T, Mizuno S, Yasuda H, Sukegawa T, Hayashida M, Inagaki T, Horiguchi J: Fluid-attenuated inversion-recovery MR imaging in schizophrenia-associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). Eur Psychiatry 2005, 20:327–331.CrossRefPubMed

16.

Wake R, Miyaoka T, Tsuchie K, Kawakami K, Nishida A, Inagaki T, Horiguchi J: Abnormalities in MRI signal intensity in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia. Aus N Z J Psychiatry 2009, 43:1057–1069.CrossRef

17.

Dennery PA, Seidman DS, Stevenson DK: Neonatal hyperbilirubinemia. N Engl J Med 2001, 344:581–590.CrossRefPubMed

18.

Hansen TWR: Mechanism of bilirubin toxicity: clinical implications. Clin Perinatol 2002, 29:765–778.CrossRefPubMed

19.

Porter ML, Dennis BL: Hyperbilirubinemia in the term newborn. Am Fam Physician 2002, 65:599–606.PubMed

20.

Shapiro SM: Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). J Perinatol 2005, 25:54–59.CrossRefPubMed

21.

Dalman C, Cullberg J: Neonatal hyperbilirubinemia-vulnerability factor for mental disorder? Acta Psychiatr Scand 1999, 100:469–471.CrossRefPubMed

22.

Hayashida M, Miyaoka T, Tsuchie K, Yasuda H, Wake R, Nishida A, Inagaki T, Toga T, Hagami H, Oda T, Horiguchi J: Hyperbilirubinemia-related behavioral and neuropathological changes in rats: a possible schizophrenia animal model. Prog Neuropsychopharmacol Biol Psychiatry 2009, 33:581–588.CrossRefPubMed

23.

Gunn CK: Hereditary acholuric jaundice in the rat. Can Med Assoc J 1944, 50:230–237.PubMedPubMedCentral

24.

Silva RFM, Rodriques CM, Brites D: Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin. Pediatr Res 2002, 51:535–541.CrossRefPubMed

25.

Gordo AC, Falcão AS, Fernandes A, Brito MA, Slva RFM, Brites D: Unconjugated bilirubin activates and damages microglia. J Neurosci Res 2006, 84:194–201.CrossRefPubMed

26.

Silva SL, Vaz AR, Barateiro A, Falcão AS, Fernandes A, Brito MA, Silva RFM, Brites D: Features of bilirubin-induced reactive microglia: from phagocytosis to inflammation. Neurobiol Dis 2010, 40:663–675.CrossRefPubMed

27.

Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. 6th edition. London: Elsevier Inc; 2007.

28.

Streit WJ, Graeber MB, Kreutzberg GW: Functional plasticity of microglia: a review. Glia 1988, 1:301–307.CrossRefPubMed

29.

Nimmerjahn A, Kirchhcoff F, Helmchen F: Resting microglia cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308:1314–1318.CrossRefPubMed

30.

Shapiro LA, Perez ZD, Foresti ML, Arisi GM, Ribak CE: Morphological and ultrastructural features of Iba1-immunolabeled microglial cells in the hippocampal dentate gyrus. Brain Res 2009, 1266:29–36.CrossRefPubMedPubMedCentral

31.

Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M: Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 2010, 7:483–495.CrossRefPubMedPubMedCentral

32.

Rossum VD, Hanisch UK: Microglia. Metab Brain Dis 2004, 19:393–411.CrossRefPubMed

33.

Hanisch UK, Kettenmann H: Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10:1387–1394.CrossRefPubMed

34.

Graeber MB: Changing face of microglia. Science 2010, 330:783–788.CrossRefPubMed

35.

Streit WJ, Walter SA, Pennel NA: Reactive microgliosis. Prog Neurobiol 1999, 57:563–581.CrossRefPubMed

36.

Bessis A, Béchade C, Bernard D, Roumier A: Microglial control of neuronal death and synaptic properties. Glia 2007, 55:233–238.CrossRefPubMed

37.

Ladeby R, Wirenfeldt M, Garcia-Overejo D, Fenger C, Dissing Olsen L, Dalmau I, Finsen B: Microglial cell population dynamics in the injured adult central nervous system. Brain Res Rev 2005, 48:196–206.CrossRefPubMed

38.

Hailer NP, Grampp A, Nitsch R: Proliferation of microglia and astrocytes in the dentate gyrus following entohirnal cortex lesion: a quantitative bromodeoxyuridine-labelling study. Eur J Neurosci 1999, 11:3359–3364.CrossRefPubMed

39.

Ahdab-Barmada M, Moossy J: The neuropathology of kernicterus in the premature neonate: diagnostic problems. J Neuropathol Exp Neurol 1984, 43:45–52.CrossRefPubMed

40.

Johnson L, Sarmiento F, Blanc WA, Day R: Kernicterus in rats with inherited deficiency of glucuronyl transferase. AMA J Dis Child 1959, 97:591–608.PubMed

41.

McDonald JW, Shapiro SM, Silverstein FS, Johnston MV: Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model. Exp Neurol 1998, 150:21–29.CrossRefPubMed

42.

Ekdahl CT, Kokaia Z, Lindvall O: Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 2009, 158:1021–1029.CrossRefPubMed

43.

Doorduin J, de Vries EFJ, Willemsen ATM, de Groot JC, Dierckx RA, Klein HC: Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 2009, 50:1801–1807.CrossRefPubMed

44.

Lin A, Kenis G, Bignotti S, Tura GJ, de Jong R, Bosmans E, Pioli R, Altamura C, Scharpé S, Maes M: The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res 1998, 32:9–15.CrossRefPubMed

45.

Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC: 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.CrossRefPubMed

46.

Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B: Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized, and placebo-controlled trial. Schizophr Res 2007, 90:179–185.CrossRefPubMed

47.

Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J: Minocycline as adjunctive therapy for schizophrenia: an open-label study. Clin Neuropharmacol 2008, 315:287–292.CrossRef

48.

Kato T, Monji A, Hashioka S, Kanba S: Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr Res 2007, 92:108–115.CrossRefPubMed

49.

Bian Q, Kato T, Monji A, Hashioka S, Mizoguchi Y, Horikawa H, Kanba S: The effect of atypical antipsychotics, perospirone, ziprasidone, and quetiapine on microglial activation induced by interferon-gamma. Prog Neuropsychopharmacol Biol Psychiatry 2008, 32:42–48.CrossRefPubMed

Title: Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model
Authors: Kristian Liaury
Tsuyoshi Miyaoka
Toshiko Tsumori
Motohide Furuya
Rei Wake
Masa Ieda
Keiko Tsuchie
Michiyo Taki
Kotomi Ishihara
Andi Jayalangkara Tanra
Jun Horiguchi
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-56

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis

Vitamin D mitigates age-related cognitive decline through the modulation of pro-inflammatory state and decrease in amyloid burden

Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation

HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia

CC chemokine ligand 2 upregulates the current density and expression of TRPV1 channels and Nav1.8 sodium channels in dorsal root ganglion neurons