Julia Howard^*

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Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, USA.
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Abstract: There is increasing evidence for the cytokine hypothesis, which states that exposure to elevated cytokines in utero due to maternal immune activation is a major risk factor for the development of schizophrenia later in life. This is supported by numerous epidemicologic studies that connect multiple infections with schizophrenia emergence. Furthermore, cytokines are critically involved in early neurodevelopment and deviations from the norm can result in abnormal neuroanatomy and brain chemistry. Animal models of schizophrenia also support the critical role of developmental neuroinflammation in predisposing the brain to anatomical and behavioral abnormalities. Although there is strong evidence for the critical role of cytokines, they most likely work with other contributing risk factors such as genetic predisposition. New evidence indicates that cytokine exposure in utero may prime the brain and that a second stressor during adolescence, referred to as a second hit, may activate existing developmental vulnerabilities resulting in the emergence of clinical schizophrenia. Further knowledge of these pathogenic processes and risk factors could be very instrumental in reducing risk and slowing emergence of schizophrenia.

Keywords: Schizophrenia; Cytokines; Inflammation; Neurodevelopment

Cite this paper: Howard, J. (2013) The cytokine hypothesis: A neurodevelopmental explanation for the emergence of schizophrenia later in life. Advances in Bioscience and Biotechnology, 4, 81-88. doi: 10.4236/abb.2013.48A2011.

References

[1]   Bayer, T.A., Falkai, P. and Maier, W. (1999) Genetic and non-genetic vulnerability factors in schizophrenia: The basis of the “two hit hypothesis”. Journal of Psychiatric Research, 33, 543-548. doi:10.1016/S0022-3956(99)00039-4

[2]   Meyer, U., Feldon, J. and Yee, B.K. (2009) A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophrenia Bulletin, 35, 959-972. doi:10.1093/schbul/sbn022

[3]   Kinney, D.K., Hintz, K., Shearer, E.M., Barch, D.H., Riffin, C., Whitley, K. and Butler, R. (2010) A unifying hypothesis of schizophrenia: Abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction. Medical Hypotheses, 74, 555. doi:10.1016/j.mehy.2009.09.040

[4]   Buka, S.L., Cannon, T.D., Torrey, E.F. and Yolken, R.H. (2008) Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biological Psychiatry, 63, 809-815. doi:10.1016/j.biopsych.2007.09.022

[5]   Fatemi, S. H. and Folsom, T. D. (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophrenia Bulletin, 35, 528-548. doi:10.1093/schbul/sbn187

[6]   Maynard, T.M., Sikich, L., Lieberman, J.A. and LaMantia, A.S. (2001) Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia. Schizophrenia Bulletin, 27, 457-476. doi:10.1093/oxfordjournals.schbul.a006887

[7]   Meyer, U. (2011) Developmental neuroinflammation and schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 42, 20-34.

[8]   Muller, N. and Schwarz, M.J. (2004) Role of the cytokine network in major psychoses. Advances in Molecular and Cell Biology, 31, 999-1032.

[9]   Patterson, P.H. (2002) Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness. Current Opinion in Neurobiology, 12, 115-118. doi:10.1016/S0959-4388(02)00299-4

[10]   Brown, A.S. and Derkits, E.J. (2010) Prenatal infection and schizophrenia: A review of epidemiologic and translational studies. American Journal of Psychiatry, 167, 261-280. doi:10.1176/appi.ajp.2009.09030361

[11]   Na, K.S., Jung, H.Y. and Kim, Y.K. (2012) The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Progress in NeuroPsychopharmacology and Biological Psychiatry. doi:10.1016/j.pnpbp.2012.10.022

[12]   Altamura, A., Pozzoli, S., Fiorentini, A. and Dell’Osso, B. (2012) Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[13]   Meyer, U., Yee, B.K. and Feldon, J. (2007) The neurodevelopmental impact of prenatal infections at different times of pregnancy: The earlier the worse? The Neuroscientist, 13, 241-256. doi:10.1177/1073858406296401

[14]   Debnath, M. and Chaudhuri, T.K. (2006) The role of HLA-G in cytokine homeostasis during early pregnancy complicated with maternal infections: A novel etiopathological approach to the neurodevelopmental understanding of schizophrenia. Medical Hypotheses, 66, 286-293. doi:10.1016/j.mehy.2005.06.033

[15]   Deverman, B.E. and Patterson, P.H. (2009) Cytokines and CNS development. Neuron, 64, 61-78. doi:10.1016/j.neuron.2009.09.002

[16]   Gaughran, F. (2002) Immunity and schizophrenia: Autoimmunity, cytokines, and immune responses. International Review of Neurobiology, 52, 275-302. doi:10.1016/S0074-7742(02)52013-4

[17]   Bennett, M.R. (2011) Schizophrenia: Susceptibility genes, dendritic-spine pathology and gray matter loss. Progress in Neurobiology, 95, 275-300. doi:10.1016/j.pneurobio.2011.08.003

[18]   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

[19]   Anderson, G. and Maes, M. (2012) Schizophrenia: Linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[20]   Samuelsson, A.M., Jennische, E., Hansson, H.A. and Holmang, A. (2006) Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABAA dysregulation and impaired spatial learning. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 290, R1345-R1356. doi:10.1152/ajpregu.00268.2005

[21]   Ibi, D., Nagai, T., Kitahara, Y., Mizoguchi, H., Koike, H., Shiraki, A. and Yamada, K. (2009) Neonatal PolyI:C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. Neuroscience Research, 64, 297. doi:10.1016/j.neures.2009.03.015

[22]   Rana, S.A., Aavani, T. and Pittman, Q.J. (2012) Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life. Hormones and Behavior, 62, 228-236.

[23]   Ayhan, Y., Sawa, A., Ross, C.A. and Pletnikov, M.V. (2009) Animal models of gene-environment interactions in schizophrenia. Behavioural Brain Research, 204, 274-281. doi:10.1016/j.bbr.2009.04.010

[24]   Meyer, U., Nyffeler, M., Schwendener, S., Knuesel, I., Yee, B.K. and Feldon, J. (2008) Relative prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. Neuropsychopharmacology, 33, 441-456. doi:10.1038/sj.npp.1301413

[25]   Miller, B.J., Culpepper, N., Rapaport, M.H. and Buckley, P. (2012) Prenatal inflammation and neurodevelopment in schizophrenia: A review of human studies. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 42, 92-100.

[26]   Piontkewitz, Y., Arad, M. and Weiner, I. (2011) Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat. Biological Psychiatry, 70, 842-851. doi:10.1016/j.biopsych.2011.06.007

[27]   Kato, T., Abe, Y., Sotoyama, H., Kakita, A., Kominami, R., Hirokawa, S. and Nawa, H. (2010) Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: Implication in neurodevelopmental hypothesis for schizophrenia. Molecular Psychiatry, 16, 307-320. doi:10.1038/mp.2010.10

[28]   Erta, M., Quintana, A. and Hidalgo, J. (2012) Interleukin6, a major cytokine in the central nervous system. International Journal of Biological Sciences, 8, 1254. doi:10.7150/ijbs.4679

[29]   Weinberger, D.R. (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry, 44, 660. doi:10.1001/archpsyc.1987.01800190080012

[30]   McDade, T.W. (2003) Life history theory and the immune system: Steps toward a human ecological immunology. American Journal of Physical Anthropology, 122, 100-125. doi:10.1001/archpsyc.1987.01800190080012

[31]   Brown, A.S. (2011) The environment and susceptibility to schizophrenia. Progress in Neurobiology, 93, 23-58. doi:10.1016/j.pneurobio.2010.09.003

[32]   Giovanoli, S., Engler, H., Engler, A., Richetto, J., Voget, M., Willi, R. and Meyer, U. (2013) Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science, 339, 1095-1099. doi:10.1126/science.1228261