Skip to main content

Advertisement

SpringerLink
Log in

The known and missing links between Toxoplasma gondii and schizophrenia

  • Review Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Toxoplasma gondii, an intracellular protozoan parasite, has a striking predilection for infecting the Central Nervous System and has been linked to an increased incidence of a number of psychiatric diseases. Several in vitro and in vivo studies have shown that T. gondii infection can affect the structure, bioenergetics and function of brain cells, and alters several host cell processes, including dopaminergic, tryptophan-kynurenine, GABAergic, AKT1, Jak/STAT, and vasopressinergic pathways. These mechanisms underlying the neuropathology of latent toxoplasmosis seem to operate also in schizophrenia, supporting the link between the two disorders. Better understanding of the intricate parasite-neuroglial communications holds the key to unlocking the mystery of T. gondii-mediated schizophrenia and offers substantial prospects for the development of disease-modifying therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Bentivoglio M, Mariotti R, Bertini G (2011) Neuroinflammation and brain infections: historical context and current perspectives. Brain Res Rev 66(1–2):152–173

    Article  CAS  PubMed  Google Scholar 

  • Berenreiterová M, Flegr J, Kuběna AA, Němec P (2011) The distribution of Toxoplasma gondii cysts in the brain of a mouse with latent toxoplasmosis: implications for the behavioral manipulation hypothesis. PLoS One 6, e28925

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Berk M, Dodd S, Kauer-Sant’anna M, Malhi GS, Bourin M, Kapczinski F, Norman T (2007) Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand Suppl 434:41–49

    Article  PubMed  Google Scholar 

  • Berretta S (2012) Extracellular matrix abnormalities in schizophrenia. Neuropharmacology 62:1584–1597

    Article  CAS  PubMed  Google Scholar 

  • Bhadra R, Cobb DA, Weiss LM, Khan IA (2013) Psychiatric disorders in toxoplasma seropositive patients-The CD8 connection. Schizophr Bull 39:485–489

    Article  PubMed  PubMed Central  Google Scholar 

  • Blanchard N, Dunay IR, Schluter D (2015) Persistence of Toxoplasma gondii in the central nervous system: a fine-tuned balance between the parasite, the brain and the immune system. Parasite Immunol 37:150–158

    Article  CAS  PubMed  Google Scholar 

  • Bradshaw NJ, Porteous DJ (2012) DISC1-binding proteins in neural development, signalling and schizophrenia. Neuropharmacology 62(3):1230–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brinkmann BG, Agarwal A, Sereda MW, Garratt AN, Müller T, Wende H, Stassart RM, Nawaz S, Humml C, Velanac V, Radyushkin K, Goebbels S, Fischer TM, Franklin RJ, Lai C, Ehrenreich H, Birchmeier C, Schwab MH, Nave KA (2008) Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59:581–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J, Bogerts B, Braun K, Jankowski Z, Kumaratilake J, Henneberg M, Gos T (2014) The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatr 5:47

    Google Scholar 

  • Brooks JM, Carrillo GL, Su J, Lindsay DS, Fox MA, Blader IJ (2015) Toxoplasma gondii infections alter GABAergic synapses and signaling in the central nervous system. MBio 6(6):e01428–15

    Article  PubMed  PubMed Central  Google Scholar 

  • Brown AS, Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261–280

    Article  PubMed  PubMed Central  Google Scholar 

  • Buonanno A, Kwon OB, Yan L, Gonzalez C, Longart M, Hoffman D, Vullhorst D (2008) Neuregulins and neuronal plasticity: possible relevance in schizophrenia. Novartis Found Symp 289:165–177

    Article  CAS  PubMed  Google Scholar 

  • Carter CJ (2006) Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophr Res 86:1–14

    Article  CAS  PubMed  Google Scholar 

  • Carter CJ (2007) eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? Schizophr Bull 33:1343–1353

    Article  PubMed  PubMed Central  Google Scholar 

  • Carter CJ (2009) Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. Schizophr Bull 35(6):1163–1182

    Article  CAS  PubMed  Google Scholar 

  • Clark RT, Nance JP, Noor S, Wilson EH (2011) T-cell production of matrix metalloproteinases and inhibition of parasite clearance by TIMP-1 during chronic Toxoplasma infection in the brain. ASN Neuro 3, e00049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • da Silva RC, Langoni H (2009) Toxoplasma gondii: host-parasite interaction and behavior manipulation. Parasitol Res 105(4):893–898

  • Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R (2007) C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res 93:261–265

    Article  PubMed  Google Scholar 

  • Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yang S, Yolken R (2013) C-reactive protein is elevated in schizophrenia. Schizophr Res 143:198–202

    Article  PubMed  Google Scholar 

  • Eren S, Bayam G, Ergönül O, Celikbaş A, Pazvantoğlu O, Baykam N, Dokuzoğuz B, Dilbaz N (2006) Cognitive and emotional changes in neurobrucellosis. J Infect 53(3):184–189

    Article  PubMed  Google Scholar 

  • Evans AK, Strassmann PS, Lee IP, Sapolsky RM (2014) Patterns of Toxoplasma gondii cyst distribution in the forebrain associate with individual variation in predator odor avoidance and anxiety-related behavior in male Long-Evans rats. Brain Behav Immun 37:122–133

    Article  PubMed  Google Scholar 

  • Fabiani S, Pinto B, Bonuccelli U, Bruschi F (2015) Neurobiological studies on the relationship between toxoplasmosis and neuropsychiatric diseases. J Neurol Sci 351:3–8

    Article  PubMed  Google Scholar 

  • Fekadu A, Shibre T, Cleare AJ (2010) Toxoplasmosis as a cause for behaviour disorders—overview of evidence and mechanisms. Folia Parasitol (Praha) 57(2):105–113

    Article  Google Scholar 

  • Flegr J (2007) Effects of Toxoplasma on human behavior. Schizophr Bull 33(3):757–760

    Article  PubMed  PubMed Central  Google Scholar 

  • Flegr J (2013) Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma–human model in studying the manipulation hypothesis. J Exp Biol 216:127–133

    Article  PubMed  Google Scholar 

  • Flegr J, Preiss M, Klose J, Havlícek J, Vitáková M, Kodym P (2003) Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol Psychol 63(3):253–268

    Article  PubMed  Google Scholar 

  • Flegr J, Lindova J, Kodym P (2008) Sex-dependent toxoplasmosis-associated differences in testosterone concentration in humans. Parasitology 135:427–431

    Article  CAS  PubMed  Google Scholar 

  • Flegr J, Lenochova P, Hodny Z, Vondrova M (2011) Fatal attraction phenomenon in humans: cat odour attractiveness increased for Toxoplasma-infected men while decreased for infected women. PLoS Negl Trop Dis 5, e1389

    Article  PubMed  PubMed Central  Google Scholar 

  • Flynn SW, Lang DJ, Mackay AL, Goghari V, Vavasour IM, Whittall KP, Smith GN, Arango V, Mann JJ, Dwork AJ, Falkai P, Honer WG (2003) Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Mol Psychiatry 8:811–820

    Article  CAS  PubMed  Google Scholar 

  • Fuks JM, Arrighi RBG, Weidner JM, Kumar Mendu S, Jin Z, Wallin RP, Rethi B, Birnir B, Barragan A (2012) GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS Pathog 8(12), e1003051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao HM, Zhou H, Hong JS (2014) Oxidative stress, neuroinflammation, and neurodegeneration. In Neuroinflammation and Neurodegeneration, Springer: 81–104

  • Gaskell EA, Smith JE, Pinney JW, Westhead DR, McConkey GA (2009) A unique dual activity amino acid hydroxylase in Toxoplasma gondii. PLoS One 4, e4801

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gatkowska J, Wieczorek M, Dziadek B, Dzitko K, Dlugonska H (2013) Sex-dependent neurotransmitter level changes in brains of Toxoplasma gondii infected mice. Exp Parasitol 133(1):1–7

    Article  CAS  PubMed  Google Scholar 

  • Ghosh AK, Vaughan DE (2012) PAI-1 in tissue fibrosis. J Cell Physiol 227:493–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glaser KC, Hagos B, Molestina RE (2011) Effects of Toxoplasma gondii genotype and absence of host MAL/Myd88 on the temporal regulation of gene expression in infected microglial cells. Exp Parasitol 129:409–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goff DC (2015) Drug development in schizophrenia: are glutamatergic targets still worth aiming at? Curr Opin Psychiatr 28:207–215

    Article  Google Scholar 

  • Goodwin DG, Strobl J, Mitchell SM, Zajac AM, Lindsay DS (2008) Evaluation of the mood-stabilizing agent valproic acid as a preventative for toxoplasmosis in mice and activity against tissue cysts in mice. J Parasitol 94(2):555–557

    Article  CAS  PubMed  Google Scholar 

  • Goodwin DG, Strobl JS, Lindsay DS (2011) Evaluation of five antischizophrenic agents against Toxoplasma gondii in human cell cultures. J Parasitol 97(1):148–151

    Article  PubMed  Google Scholar 

  • Guidetti P, Schwarcz R (2003) 3-Hydroxykynurenine and quinolinate: pathogenic synergism in early grade Huntington’s disease? Adv Exp Med Biol 527:137–145

    Article  CAS  PubMed  Google Scholar 

  • Guillemin GJ, Smythe G, Takikawa O, Brew BJ (2005) Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 49:15–23

    Article  PubMed  Google Scholar 

  • Guillemin GJ, Meininger V, Brew BJ (2006) Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis. Neurodegener Dis 2:166–176

    Article  CAS  Google Scholar 

  • Guo Q, Manolopoulou M, Bian Y, Schilling AB, Tang WJ (2010) Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme. J Mol Biol 395(2):430–443

    Article  CAS  PubMed  Google Scholar 

  • Gustavsson A, Svensson M, Jacobi F, Allgulander C, Alonso J, Beghi E, Dodel R, Ekman M, Faravelli C, Fratiglioni L, Gannon B, Jones DH, Jennum P, Jordanova A, Jönsson L, Karampampa K, Knapp M, Kobelt G, Kurth T, Lieb R, Linde M, Ljungcrantz C, Maercker A, Melin B, Moscarelli M, Musayev A, Norwood F, Preisig M, Pugliatti M, Rehm J, Salvador-Carulla L, Schlehofer B, Simon R, Steinhausen HC, Stovner LJ, Vallat JM, Van den Bergh P, van Os J, Vos P, Xu W, Wittchen HU, Jönsson B, Olesen J, CDBE2010Study Group (2011) Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 21:718–779

    Article  CAS  PubMed  Google Scholar 

  • Hajagos BE, Turetzky JM, Peng ED, Cheng SJ, Ryan CM, Souda P, Whitelegge JP, Lebrun M, Dubremetz JF, Bradley PJ (2012) Molecular dissection of novel trafficking and processing of the Toxoplasma gondii rhoptry metalloprotease toxolysin-1. Traffic 13(2):292–304

    Article  CAS  PubMed  Google Scholar 

  • Hans A, Bajramovic JJ, Syan S, Perret E, Dunia I, Brahic M, Gonzalez-Dunia D (2004) Persistent, noncytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis. FASEB J 18(7):863–865

    CAS  PubMed  Google Scholar 

  • Hari Dass SA, Vyas A (2014) Toxoplasma gondii infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala. Mol Ecol 23:6114–6122

    Article  CAS  PubMed  Google Scholar 

  • Haroon F, Händel U, Angenstein F, Goldschmidt J, Kreutzmann P, Lison H, Fischer KD, Scheich H, Wetzel W, Schlüter D, Budinger E (2012) Toxoplasma gondii actively inhibits neuronal function in chronically infected mice. PLoS One 7, e35516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122:593–624

    Article  PubMed  Google Scholar 

  • Hinze-Selch D, Däubener W, Eggert L, Erdag S, Stoltenberg R, Wilms S (2007) A controlled prospective study of toxoplasma gondii infection in individuals with schizophrenia: beyond seroprevalence. Schizophr Bull 33:782–788

    Article  PubMed  PubMed Central  Google Scholar 

  • Holub D, Flegr J, Dragomirecká E, Rodriguez M, Preiss M, Novák T, Čermák J, Horáček J, Kodym P, Libiger J, Höschl C, Motlová LB (2013) Differences in onset of disease and severity of psychopathology between toxoplasmosis-related and toxoplasmosis-unrelated schizophrenia. Acta Psychiatr Scand 127:227–238

    Article  CAS  PubMed  Google Scholar 

  • Horacek J, Flegr J, Tintera J, Verebova K, Spaniel F, Novak T, Brunovsky M, Bubenikova-Valesova V, Holub D, Palenicek T, Höschl C (2012) Latent toxoplasmosis reduces gray matter density in schizophrenia but not in controls: voxel-based-morphometry (VBM) study. World J Biol Psychiatry 13:501–509

    Article  PubMed  Google Scholar 

  • Howes O, McCutcheon R, Stone J (2015) Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol 29:97–115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hunter CA, Sibley LD (2012) Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nat Rev Microbiol 10:766–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ingram WM, Goodrich LM, Robey EA, Eisen MB (2013) Mice infected with low-virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance. PLoS One 8, e75246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones MR, Quinton LJ, Simms BT, Lupa MM, Kogan MS, Mizgerd JP (2006) Roles of interleukin-6 in activation of STAT proteins and recruitment of neutrophils during Escherichia coli pneumonia. J Infect Dis 193(3):360–369

    Article  CAS  PubMed  Google Scholar 

  • Jones-Brando L, Torrey EF, Yolken R (2003) Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res 62(3):237–244

    Article  PubMed  Google Scholar 

  • Jung BK, Pyo KH, Shin KY, Hwang YS, Lim H, Lee SJ, Moon JH, Lee SH, Suh YH, Chai JY, Shin EH (2012) Toxoplasma gondii infection in the brain inhibits neuronal degeneration and learning and memory impairments in a murine model of Alzheimer’s disease. PLoS ONE 7(3), e33312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalichman SC, Heckman T, Kochman A, Sikkema K, Bergholte J (2000) Depression and thoughts of suicide among middle-aged and older persons living with HIV-AIDS. Psychiatr Serv 51(7):903–907

    Article  CAS  PubMed  Google Scholar 

  • Kegel ME, Bhat M, Skogh E, Samuelsson M, Lundberg K, Dahl ML, Sellgren C, Schwieler L, Engberg G, Schuppe-Koistinen I, Erhardt S (2014) Imbalanced kynurenine pathway in schizophrenia. Int J Tryptophan Res 7:15–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kendler KS, Diehl SR (1993) The genetics of schizophrenia: a current, genetic-epidemiologic perspective. Schizophr Bull 19:261–284

    Article  CAS  PubMed  Google Scholar 

  • Kim CH, Koo MS, Cheon KA, Ryu YH, Lee JD, Lee HS (2003) Dopamine transporter density of basal ganglia assessed with [123I] IPT SPET in obsessive–compulsive disorder. Eur J Nucl Med Mol Imaging 30:1637–1643

    Article  CAS  PubMed  Google Scholar 

  • Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S (2011) Could Toxoplasma gondii have any role in Alzheimer disease? Alzheimer Dis Assoc Disord 25:1–3

    Article  PubMed  Google Scholar 

  • Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36(2):764–785

    Article  CAS  PubMed  Google Scholar 

  • Li H, Gang Z, Yuling H, Luokun X, Jie X, Hao L et al (2006) Different neurotropic pathogens elicit neurotoxic CCR9- or neurosupportive CXCR3-expressing microglia. J Immunol 177(6):3644–3656

    Article  CAS  PubMed  Google Scholar 

  • Lim A, Kumar V, Hari Dass SA, Vyas A (2013) Toxoplasma gondii infection enhances testicular steroidogenesis in rats. Mol Ecol 22:102–110

    Article  CAS  PubMed  Google Scholar 

  • Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33(2):177–182

    Article  CAS  PubMed  Google Scholar 

  • Miller CL, Llenos IC, Dulay JR, Barillo MM, Yolken RH, Weis S (2004) Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Dis 15:618–629

    Article  CAS  PubMed  Google Scholar 

  • Miller CM, Boulter NR, Ikin RJ, Smith NC (2009) The immunobiology of the innate response to Toxoplasma gondii. Int J Parasitol 39:23–39

    Article  CAS  PubMed  Google Scholar 

  • Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 70:663–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miman O, Kusbeci OY, Aktepe OC, Cetinkaya Z (2010) The probable relation between Toxoplasma gondii and Parkinson’s disease. Neurosci Lett 475:129–131

    Article  CAS  PubMed  Google Scholar 

  • Mitra R, Sapolsky RM, Vyas A (2013) Toxoplasma gondii infection induces dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion. Dis Model Mech 6:516–520

    Article  CAS  PubMed  Google Scholar 

  • Montoya JG, Liesenfeld O (2004) Toxoplasmosis. Lancet 363:1965–1976

    Article  CAS  PubMed  Google Scholar 

  • Mortensen PB, Nørgaard-Pedersen B, Waltoft BL, Sørensen TL, Hougaard D, Yolken RH (2007) Early infections of Toxoplasma gondii and the later development of schizophrenia. Schizophr Bull 33(3):741–744

    Article  PubMed  PubMed Central  Google Scholar 

  • Mou X, Peterson CB, Prosser RA (2009) Tissue-type plasminogen activator-plasmin-BDNF modulate glutamate-induced phase-shifts of the mouse suprachiasmatic circadian clock in vitro. Eur J Neurosci 30:1451–1460

    Article  PubMed  Google Scholar 

  • Notarangelo FM, Wilson EH, Horning KJ, Thomas MA, Harris TH, Fang Q, Hunter CA, Schwarcz R (2014) Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: implications for schizophrenia. Schizophr Res 152:261–267

  • Ogden KK, Traynelis SF (2011) New advances in NMDA receptor pharmacology. Trends Pharmacol Sci 32:726–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okulski P, Jay TM, Jaworski J, Duniec K, Dzwonek J, Konopacki FA, Wilczynski GM, Sánchez-Capelo A, Mallet J, Kaczmarek L (2007) TIMP-1 abolishes MMP-9-dependent long-lasting long-term potentiation in the prefrontal cortex. Biol Psychiatry 62:359–362

    Article  CAS  PubMed  Google Scholar 

  • Okusaga O, Duncan E, Langenberg P, Brundin L, Fuchs D, Groer MW, Giegling I, Stearns-Yoder KA, Hartmann AM, Konte B, Friedl M, Brenner LA, Lowry CA, Rujescu D, Postolache TT (2016) Combined Toxoplasma gondii seropositivity and high blood kynurenine - Linked with nonfatal suicidal self-directed violence in patients with schizophrenia. J Psychiatr Res 72:74–81

    Article  PubMed  Google Scholar 

  • Parlog A, Schlüter D, Dunay IR (2015) Toxoplasma gondii-induced neuronal alterations. Parasite Immunol 37(3):159–710

    Article  CAS  PubMed  Google Scholar 

  • Poirotte C, Kappeler PM, Ngoubangoye B, Bourgeois S, Moussodji M, Charpentier MJ (2016) Morbid attraction to leopard urine in Toxoplasma-infected chimpanzees. Curr Biol 26(3):R98–9

    Article  CAS  PubMed  Google Scholar 

  • Prandota J (2010) Neuropathological changes and clinical features of autism spectrum disorder participants are similar to that reported in congenital and chronic cerebral toxoplasmosis in humans and mice. Res Autism Spect Disord 4:103–118

    Article  Google Scholar 

  • Prandovszky E, Gaskell E, Martin H, Dubey JP, Webster JP, McConkey GA (2011) The neurotropic parasite Toxoplasma gondii increases dopamine metabolism. PLoS One 6(9), e23866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rozenfeld C, Martinez R, Seabra S, Sant’anna C, Gonçalves JG, Bozza M, Moura-Neto V, De Souza W (2005) Toxoplasma gondii prevents neuron degeneration by interferon-gamma-activated microglia in a mechanism involving inhibition of inducible nitric oxide synthase and transforming growth factor-beta1 production by infected microglia. Am J Pathol 167:1021–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saeij JP, Boyle JP, Coller S, Taylor S, Sibley LD, Brooke-Powell ET, Ajioka JW, Boothroyd JC (2006) Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science 314(5806):1780–1783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwarcz R, Hunter CA (2007) Toxoplasma gondii and schizophrenia: linkage through astrocyte-derived kynurenic acid? Schizophr Bull 33:652–653

    Article  PubMed  PubMed Central  Google Scholar 

  • Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303:1–10

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50:521–530

    Article  CAS  PubMed  Google Scholar 

  • Semiz UB, Turhan V, Basoglu C, Oner O, Ebrinc S, Cetin M (2005) Leptospirosis presenting with mania and psychosis: four consecutive cases seen in a military hospital in Turkey. Int J Psychiatry Med 35(3):299–305

    Article  PubMed  Google Scholar 

  • Skallová A, Kodym P, Frynta D, Flegr J (2006) The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an ethological and ethopharmacological study. Parasitology 133(Pt 5):525–535

    Article  PubMed  CAS  Google Scholar 

  • Stibbs HH (1985) Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice. Ann Trop Med Parasitol 79(2):153–157

    CAS  PubMed  Google Scholar 

  • Strobl JS, Goodwin DG, Rzigalinski BA, Lindsay DS (2012) Dopamine stimulates propagation of Toxoplasma gondii tachyzoites in human fibroblast and primary neonatal rat astrocyte cell cultures. J Parasitol 98(6):1296–1299

    Article  PubMed  Google Scholar 

  • Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60:1187–1192

    Article  PubMed  Google Scholar 

  • Sun GY, Horrocks LA, Farooqui AA (2007) The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J Neurochem 103(1):1–16

    CAS  PubMed  Google Scholar 

  • Sutterland AL, Fond G, Kuin A, Koeter MWJ, Lutter R, vanGool T, Yolken R, Szoke A, Leboyer M, deHaan L (2015) Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis. Acta Psychiatr Scand 132(3):161–79

    Article  CAS  PubMed  Google Scholar 

  • Suvisaari J, Loo BM, Saarni SE, Haukka J, Perälä J, Saarni SI, Viertiö S, Partti K, Lönnqvist J, Jula A (2011) Inflammation in psychotic disorders: a population-based study. Psychiatry Res 189:305–311

    Article  PubMed  Google Scholar 

  • Suzuki Y, Claflin J, Wang X, Lengi A, Kikuchi T (2005) Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii. Int J Parasitol 35:83–90

    Article  CAS  PubMed  Google Scholar 

  • Swedo SE, Leonard HL, Rapoport JL (2004) The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. Pediatrics 113:907–111

    Article  PubMed  Google Scholar 

  • Taboas W, McKay D, Taylor S (2012) Does Toxoplasma gondii play a role in obsessive-compulsive disorder? Psychiatry Res 198(1):176–177

    Article  PubMed  Google Scholar 

  • Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, Kolachana BS, Straub RE, Meyer-Lindenberg A, Sei Y, Mattay VS, Callicott JH, Weinberger DR (2008) Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest 118:2200–2208

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tomasik J, Schultz TL, Kluge W, Yolken RH, Bahn S, Carruthers VB (2015) Shared immune and repair markers during experimental Toxoplasma chronic brain infection and schizophrenia. Schizophr Bull

  • Van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS (2008) Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 64:820–822

    Article  PubMed  Google Scholar 

  • Van Os J, Kapur S (2009) Schizophrenia. Lancet 374:635–645

    Article  PubMed  CAS  Google Scholar 

  • Vasconcelos AR, Yshii LM, Viel TA, Buck HS, Mattson MP, Scavone C, Kawamoto EM (2014) Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment. J Neuroinflammation 11:85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vega P, Sweetland A, Acha J, Castillo H, Guerra D, Smith Fawzi MC, Shin S (2004) Psychiatric issues in the management of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 8(6):749–759

    CAS  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Tomasi D, Baler RD (2013) Obesity and addiction: neurobiological overlaps. Obes Rev 14:2–18

    Article  CAS  PubMed  Google Scholar 

  • Vyas A, Kim KS, Giacomini N, Boothroyd JC, Sapolsky RM (2007) Behvioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc Natl Acad Sci U S A 104:6442–6447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Michie SA, Xu B, Suzuki Y (2007) Importance of IFN-gamma-mediated expression of endothelial VCAM-1 on recruitment of CD8+ T cells into the brain during chronic infection with Toxoplasma gondii. J Interferon Cytokine Res 27:329–338

    Article  PubMed  CAS  Google Scholar 

  • Webster JP, Lamberton PH, Donnelly CA, Torrey EF (2006) Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii’s ability to alter host behaviour. Proc Biol Sci 273(1589):1023–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Widner B, Fuchs D, Leblhuber F, Sperner-Unterweger B (2001) Does disturbed homocysteine and folate metabolism in depression result from enhanced oxidative stress? J Neurol Neurosurg Psychiatry 70:419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson EH, Harris TH, Mrass P, John B, Tait ED, Wu GF, Pepper M, Wherry EJ, Dzierzinski F, Roos D, Haydon PG, Laufer TM, Weninger W, Hunter CA (2009) Behavior of parasite-specific effector CD8+ T cells in the brain and visualization of a kinesis-associated system of reticular fibers. Immunity 30:300–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao J, Li Y, Jones-Brando L, Yolken RH (2013) Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains. J Neural Transm (Vienna) 120(12):1631–1639

    Article  CAS  Google Scholar 

  • Zghair KH, AL-Qadhi BN, Mahmood SH (2015) The effect of toxoplasmosis on the level of some sex hormones in males blood donors in Baghdad. J Parasit Dis 39(3):393–400

    Article  PubMed  Google Scholar 

  • Zhou CX, Zhou DH, Elsheikha HM, Liu GX, Suo X, Zhu XQ (2015) Global metabolomic profiling of mice brains following experimental infection with the cyst-forming Toxoplasma gondii. PLoS One 10(10), e0139635

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou CX, Zhou DH, Elsheikha HM, Zhao Y, Suo X, Zhu XQ (2016) Metabolomic profiling of mice serum during toxoplasmosis progression using liquid chromatography-mass spectrometry. Sci Rep 6:19557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zindler E, Zipp F (2010) Neuronal injury in chronic CNS inflammation. Best Pract Res Clin Anaesthesiol 24:551–562

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We apologize to colleagues whose work we were unable to adequately cite due to space limitation. We thank Dr Carl Stevenson from the University of Nottingham for comments on the manuscript. XQZ is supported by the National Natural Science Foundation of China (Grant No. 31230073).

Author information

Authors and Affiliations

  1. Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Leicestershire, LE12 5RD, UK

    Hany M. Elsheikha

  2. Weill Cornell Medical College in Qatar, Qatar Foundation - Education City, P.O. Box: 24144, Doha, Qatar

    Dietrich Büsselberg

  3. State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, 730046, People’s Republic of China

    Xing-Quan Zhu

Authors
  1. Hany M. Elsheikha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dietrich Büsselberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xing-Quan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hany M. Elsheikha.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Elsheikha, H.M., Büsselberg, D. & Zhu, XQ. The known and missing links between Toxoplasma gondii and schizophrenia. Metab Brain Dis 31, 749–759 (2016). https://doi.org/10.1007/s11011-016-9822-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-016-9822-1

Keywords

Search

Navigation