Neurochemical Research

, Volume 22, Issue 5, pp 647–656

How a Poliovirus Might Cause Schizophrenia: A Commentary on Eagles' Hypothesis

  • R. F. Squires


John M. Eagles suggested that polioviruses might cause schizophrenia because 1) several reports of a recent decline in the incidence of schizophrenia coinciding with the introduction of polio vaccination, 2) the observed winter excesses in schizophrenic births (in temperate climates) could be explained by fetal exposure to poliovirus during the second trimester of gestation which would occur during the summer when polio epidemics are most frequent, 3) there are increased rates of schizophrenia among immigrants to the UK from regions of the world with low frequencies if immunity to polioviruses, 4) there may be genetic variants in the poliovirus receptor gene that could increase susceptibility to poliovirus infection (1). The large discordance rates for schizophrenia in monozygotic twin pairs indicate the existence of both genetic and environmental factors. Numerous genetic studies indicate an interaction of several genes in the etiology of schizophrenia. These genes may encode a family of poliovirus receptor subunits, various active combinations of which are expressed on T-immunocytes, monocytes, endothelial cells, and limited populations of (glutamatergic?) neurons. The poliovirus receptor on the T-cell may require both a specific combination of V segments of the T-cell antigen receptor, as well as a specific major histocompatibility (MHC) antigen, acting in concert to infect monocytes, the primary transporter of poliovirus from blood into the brain. The very large discordance rates for schizophrenia that probably exist for dichorionic-monozygotic twins (about 90%), as well as the much smaller discordance rates for monochorionic-monozygotic twins (about 40%), may be due to several allelic exclusion events expressed both in T-cells and possibly in certain neurons. A child who has lost some glutamatergic neurons due to viral infection during the second trimester of gestation, may be able to compensate for this deficit to a large extent by the super-abundance of excitatory synapses that exists in the brain until sexual maturity, at which time a selective loss of excitatory (mainly glutamatergic) synapses occurs together with hormonally induced changes in behavior, leading to a much increased risk of a psychotic episode.

Poliovirus schizophrenia Eagle's hypothesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Eagles, J. M. 1992. Are polioviruses a cause of schizophrenia? Br. J. Psychiat. 160:598–600.Google Scholar
  2. 2.
    Squires, R. F., and Saederup, E. 1991. A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of “functional” psychoses. Neurochem. Res. 16:1099–1111.Google Scholar
  3. 3.
    Squires, R. F., and Saederup, E. 1997. Clozapine and some other antipsychotic drugs may preferentially block the same subset of GABAA receptors. Neurochem. Res. 22:151–162.Google Scholar
  4. 4.
    Squires, R. F. 1992. Are polioviruses a cause of schizophrenia? Br. J. Psychiat. 161:427 (Letter to Editor).Google Scholar
  5. 5.
    Squires, R. F., Lajtha, A., Saederup, E., and Palkovits, M. 1993. Reduced [3H]flunitrazepam binding in cingulate cortex and hippocampus of postmortem schizophrenic brains: is selective loss of glutamatergic neurons associated with major psychoses? Neurochem. Res. 18:219–223.Google Scholar
  6. 6.
    Torrey, E. F. 1988. Stalking the schizovirus. Schizophrenia Bull. 14:223–229.Google Scholar
  7. 7.
    Torrey, E. F. 1991. A viral-anatomical explanation of schizophrenia. Schizophrenia Bull. 17:15–18.Google Scholar
  8. 8.
    Kaufmann, C. A., Weinberger, D. R., Stevens, J. R., Asher, D. M., Kleinman, J. E., Sulima, M. P., Gibbs, C. J., Jr., and Gajdusek, C. 1988. Intracerebral inoculation of experimental animals with brain tissue from patients with schizophrenia. Arch. Gen. Psychiat. 45:648–652.Google Scholar
  9. 9.
    Taller, A. M., Asher, D. M., Pomeroy, K. L., Eldadah, B. A., Godec, M. S., Falkai, P. G., Bogert, B., Kleinman, J. E., Stevens, J. R., and Torrey, E. F. 1996. Search for viral nucleic acid sequences in brain tissues of patients with schizophrenia using nested polymerase chain reaction. Arch. Gen. Psychiat. 53:32–40.Google Scholar
  10. 10.
    Torrey, E. F., Rawlings, R., and Waldman, I. N. 1988. Schizophrenia births and viral diseases in two states. Schizo. Res. 1:73–77.Google Scholar
  11. 11.
    Bodian, D. 1947. Poliomyelitis. Neuropathologic observations in relation to motor symptoms. J. Amer. Med. Assoc. 134:1149–1154.Google Scholar
  12. 12.
    Johnson, R. T. 1985. Acute anterior poliomyelitis. In: Wyngaarden, J. B., Smith, L. H. Jr. (Eds), Cecil Textbook of Medicine. W. B. Saunders, 2130–2132.Google Scholar
  13. 13.
    Ren, R., and Racaniello, V. R. 1992. Human poliovirus receptor gene expression and poliovirus tissue tropism in transgenic mice. J. Virol. 66:296–304.Google Scholar
  14. 14.
    Brown, R. H., Jr., Johnson, D., Ogonowski, M., and Weiner, H. L. 1987. Type I human poliovirus binds to human synaptosomes. Ann. Neurol. 21:64–70.Google Scholar
  15. 15.
    Pritchett, D. B., Sontheimer, H., Shivers, B. D., Ymer, S., Kettenmann, H., Schofield, P. R., and Seeburg, P. H. 1989. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 338:582–585.Google Scholar
  16. 16.
    Pritchett, D. B., Lüddens, H., and Seeburg, P. H. 1989. Type I and Type II GABAA benzodiazepine receptors produced in transfected cells. Science 245:1389–1392.Google Scholar
  17. 17.
    Deng, H., Liu, R., Ellmeir, W., Choe, S., Unutmaz, D., Burkhart, M., Di Marzio, P., Marmon, S., Sutton, R. E., Hill, C. M., Davis, C. B., Peiper, S. C., Schall, T. J., Littman, D. R., and Landau, N. R. 1996. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666.Google Scholar
  18. 18.
    Dragic, T., Litwin, V., Allaway, G. P., Martin, S. R., Huang, Y., Nagashima, K. A., Cayanan, C., Maddon, P. J., Koup, R. A., Moore, J. P., and Paxton, W. A. 1996. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381:667–673.Google Scholar
  19. 19.
    Morris, P. J. and Pietsch, M. C. 1973. A possible association between paralytic poliomyelitis and multiple sclerosis. Lancet II:847.Google Scholar
  20. 20.
    Pietsch, M. C., and Morris, P. J. 1974. An association of HL-A3 and HL-A7 with paralytic poliomyelitis. Tissue Antigen 4:50–55.Google Scholar
  21. 21.
    Steigman, A. J. 1973. HL-A types and paralytic poliomyelitis. Lancet II:1383.Google Scholar
  22. 22.
    Torrey, E. F., Bowler, A. E., Taylor, E. H., and Gottesman, I.I. 1994. Schizophrenia and Manic-Depressive Disorder, Basic Books, New York, N.Y.Google Scholar
  23. 23.
    Gregersen, P. K. 1993. Discordance for autoimmunity in monozygotic twins. Are “identical” twins really identical? Arthritis Rheum. 36:1185–1192.Google Scholar
  24. 24.
    Ivanyi, P., Droes, J., Schreuder, G. M. Th., D'Amaro, J., and van Rood, J. J. 1983. A search for association of HLA antigens with paranoid schizophrenia. Tissue Antigen 22:186–193.Google Scholar
  25. 25.
    Miyanaga, K., Machiyama, Y., and Juji, T. 1984. Schizophrenic disorders and HLA-DR antigens. Biol. Psychiat. 19:121–129.Google Scholar
  26. 26.
    Cazzullo, C. L., Smeraldi, E., and Penati, G. 1974. The leukocyte antigenic system HL-A as a possible genetic marker of schizophrenia. Brit. J. Psychiat. 125:25–27.Google Scholar
  27. 27.
    Gattaz, W. F., Beckmann, H., and Mendlewicz, J. 1981. HLA antigens and schizophrenia: a pool of two studies. Psychiat. Res. 5:123–128.Google Scholar
  28. 28.
    McGuffin, P., Farmer, A. E., and Yonace, A. H. 1981. HLA antigens and subtypes of schizophrenia. Psychiat. Res. 5:115–122.Google Scholar
  29. 29.
    Crowe, R. R., Thompson, J. S., Flink, R., and Weinberger, B. 1979. HLA antigens and schizophrenia. Arch. Gen. Psychiat. 36:231–233.Google Scholar
  30. 30.
    Özcan, M. E., Taskin, R., Banoglu, R., Babacan, M., and Tuncer, E. 1996. HLA antigens in schizophrenia and mood disorders. Biol. Psychiat. 39:891–895.Google Scholar
  31. 31.
    Nimgaonkar, V. L., Rudert, W. A., Zhang, X. R., Tsoi, W-F., Trucco, M., and Saha, N. 1995. Further evidence for an association between schizophrenia and the HLA DQB1 gene locus. Schizophr. Res. 18:43–49.Google Scholar
  32. 32.
    Eaton, W. W., Hayward, C., and Ram, R. 1992. Schizophrenia and rheumatoid arthritis: a review. Schizophr. Res. 6:181–192.Google Scholar
  33. 33.
    Feldmann, M., Brennan, F. M., and Maini, R. N. 1996. Rheumatoid arthritis. Cell 85:307–310.Google Scholar
  34. 34.
    Wright, P., Sham, P. C., Gilvarry, C. M., Jones, P. B., Cannon, M., Sharma, T., and Murray, R. M. 1996. Autoimmune diseases in the pedigrees of schizophrenic and control subjects. Schizophr. Res. 20:261–267.Google Scholar
  35. 35.
    Wright, P., Donaldson, P. T., Underhill, J. A., Choudhuri, K., Doherty, D. G., and Murray, R. M. 1996. Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia. Amer. J. Psychit. 153:1530–1533.Google Scholar
  36. 36.
    Straub, R. E., MacLean, C. J., O'Neill, F. A., Burke, J., Murphy, B., Duke, F., Shinkwin, R., Webb, B. T., Zhang, J., Walsh, D., and Kendler, K. S. 1995. A potential vulnerability locus for schizophrenia on chromosome 6p24–22 evidence for genetic heterogeneity. Nat. Genet. 11:287–293.Google Scholar
  37. 37.
    Schwab, S. G., Albus, M., Hallmayer, J., Hönig, S., Borrmann, M., Lichtermann, D., Ebstein, R. P., Ackenheil, M., Lerer, B., Risch, N., Maier, W., and Wildenauer, D. B. 1995. Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nat. Genet. 11:325–327.Google Scholar
  38. 38.
    Moises, H. W., Yang, L., Kristbjarnarson, H., Wiese, C., Byerley, W., Macciardi, F., Arolt, V., Blackwood, D., Liu, X., Sjögren, B., Aschauer, H. N., Hwu, H.-G., Jang, K., Livesley, W. J., Kennedy, J. L., Zoega, T., Ivarsson, O., Bui, M.-T., Yu, M.-H., Havsteen, B., Commenges, D., Weissenbach, J., Schwinger, E., Gottesman, I. I., Pakstis, A. J., Wetterberg, L., Kidd, K. K., and Helgason, T. 1995. An international two-stage genome-wide search for schizophrenia susceptibility genes. Nat. Genet. 11:321–324.Google Scholar
  39. 39.
    Alexander, R. C., Coggiano, M., Daniel, D. C., and Wyatt, R. J. 1990. HLA antigens in schizophrenia. Psychiat. Res. 31:221–233.Google Scholar
  40. 40.
    Campion, D., Leboyer, M., Hillaire, D., Halle, L., Gorwood, P., Cavelier, B., Soufflet, M. F., D'Amato, T., Muller, B., Kaplan, C., Jay, M., and Clerget-Darpoux, F. 1992. Relationship of HLA to schizophrenia not supported in multiplex families. Psychiat. Res. 41:99–105.Google Scholar
  41. 41.
    Wekerle, H., Linington, C., Lassmann, H., and Meyermann, R. 1986. Cellular immune reactivity within the CNS. TINS 9:271–277.Google Scholar
  42. 42.
    Luber-Narod, J., and Rogers, J. 1988. Immune system associated antigens expressed by cells of the human central nervous system. Neurosci. Lett. 94:17–22.Google Scholar
  43. 43.
    Aldrich, M. S. 1992. Narcolepsy. Neurology 42:34–43.Google Scholar
  44. 44.
    Douglass, A. B., Harris, L., and Pazderka, F. 1989. Monozygotic twins concordant for the narcoleptic syndrome. Neurology 39:140–141.Google Scholar
  45. 45.
    Montplaisir, J., and Poirier, G. 1987. Narcolepsy in monozygotic twins. Neurology 37:1089.Google Scholar
  46. 46.
    Billiard, M., and Seignalet, J. 1985. Extraordinary association between HLA-DR2 and narcolepsy. Lancet I:226–227.Google Scholar
  47. 47.
    Marcadet, A., Gebuhrer, L., Betuel, H., Seignalet, J., Freidel, A. C., Confavreux, C., Billiard, M., Dausett, J., and Cohen, D. 1985. DNA polymorphism related to HLA-DR2 Dw2 in patients with narcolepsy. Immunogenetics 22:679–683.Google Scholar
  48. 48.
    Douglass, A. B., Hays, P., Pazderka, F., and Russell, J. M. 1991. Florid refractory schizophrenias that turn out to be treatable variants of HLA-associated narcolepsy. J. Nerv. Ment. Dis. 179:12–17.Google Scholar
  49. 49.
    Roy, A. 1976. Psychiatric aspects of narcolepsy. Brit. J. Psychiat. 128:562–565.Google Scholar
  50. 50.
    Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., Brown, C. J., Willard, H. F., Lawrence, C., Persico, M. G., Camerino, G., and Ballabio, A. 1991. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353:529–536.Google Scholar
  51. 51.
    Legouis, R., Hardelin, J.-P., Levilliers, J., Claverie, J.-M., Compain, S., Wunderle, V., Millasseau, P., Le Paslier, D., Cohen, D., Caterina, D., Bougueleret L., Delemarre-Van de Waal, H., Lutfalla, G., Weissenbach, J., and Petit, C. 1991. The candidate gene for the x-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67:423–435.Google Scholar
  52. 52.
    Cowen, M. A., and Green, M. 1993. The Kallmann's syndrome variant (KSV) model of the schizophrenias. Schizo. Res. 9:1–10.Google Scholar
  53. 53.
    Crow, T. J. 1993. Sexual selection, Machiavellian intelligence, and the origins of psychosis. Lancet 342:594–598.Google Scholar
  54. 54.
    Benes, F. M., Davidson, J., and Bird, E. D. 1986. Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch. Gen. Psychiat. 43:31–35.Google Scholar
  55. 55.
    Meltzer, H. Y., and Crayton, J. W. 1974. Subterminal motor nerve abnormalities in psychotic patients. Nature 249:373–375.Google Scholar
  56. 56.
    Crayton, J. W., and Meltzer, H. Y. 1979. Degeneration and regeneration of motor neurons in psychotic patients. Biol. Psychiat. 14:803–819.Google Scholar
  57. 57.
    Howland, R. H. 1990. Schizophrenia and amyotrophic lateral sclerosis. Compr. Psychiat. 31:327–336.Google Scholar
  58. 58.
    Karson, C. N., Casanova, M. F., Kleinman, J. E., and Griffin, W. S. T. 1993. Choline acetyltransferase in schizophrenia. Amer. J. Psychiat. 150:454–459.Google Scholar
  59. 59.
    Mednick, S. A., Machon, R. A., Huttunen, M. O., and Bonett, D. 1988. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch. Gen. Psychiat. 45:189–192.Google Scholar
  60. 60.
    Barr, C. E., Mednick, S. A., and Munk-Jorgensen, P. 1990. Exposure to influenza epidemics during gestation and adult schizophrenia. Arch. Gen. Psychiat. 47:869–874.Google Scholar
  61. 61.
    O'Callaghan, E., Sham, P., Takei, N., Glover, G., and Murray, R. M. 1991. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet 337:1248–1250.Google Scholar
  62. 62.
    Sham, P. C., O'Callaghan, E., Takei, N., Murray, G. K., Hare, E. H., and Murray, R. M. 1992. Schizophrenia following prenatal exposure to influenza epidemics between 1939 and 1960. Brit. J. Psychiat. 160:461–466.Google Scholar
  63. 63.
    Kendell, R. E., and Kemp, I. W. 1989. Maternal influenza in the etiology of schizophrenia. Arch. Gen. Psychiat. 46:878–882.Google Scholar
  64. 64.
    Crow, T. J., and Done, D. J. 1992. Prenatal exposure to influenza does not cause schizophrenia. Brit. J. Psychiat. 161:390–393.Google Scholar
  65. 65.
    Crow, T. J. 1994. Prenatal exposure to influenza as a cause of schizophrenia. Brit. J. Psychiat. 164:588–592.Google Scholar
  66. 66.
    Selten, J.-P. C. J., and Slaets, J. P. J. 1994. Evidence against maternal influenza as a risk factor for schizophrenia. Brit. J. Psychiat. 164:674–676.Google Scholar
  67. 67.
    Susser, E., Lin, S. P., Brown, A. S., Lumey, L. H., and Erlenmeyer-Kimling, L. 1994. No relation between risk of schizophrenia and prenatal exposure to influenza in Holland. Amer. J. Psychiat. 151:922–924.Google Scholar
  68. 68.
    Douglas, R. G., Jr. 1985. Influenza. In: J. B. Wyngaarden, J. B. Smith, L. H., Jr. (Eds). Cecil Textbook of Medicine. W. B. Saunders, pp. 1700–1705.Google Scholar
  69. 69.
    Menninger, K. A. 1926. Influenza and schizophrenia. Amer. J. Psychiat. V:469–529.Google Scholar
  70. 70.
    Paul, J. R. 1971. A History of Poliomyelitis, Yale University Press, New Haven and London.Google Scholar
  71. 71.
    Parish, J. G. 1978. Early outbreaks of ‘epidemic neuromyasthenia.’ Postgrad. Med. J. 54:711–717.Google Scholar
  72. 72.
    Gow, J. W., Behan, W. M. H., Clements, G. B., Woodall, C., Riding, M., and Behan, P. O. 1991. Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome. BMJ 302:692–696.Google Scholar
  73. 73.
    Davis, J. O., and Phelps, J. A. 1995. Twins with schizophrenia: genes or germs? Schizophrenia Bull. 21:13–18.Google Scholar
  74. 74.
    Davis, J. O., Phelps, A., and Bracha, H. S. 1995. Prenatal development of monozygotic twins and concordance for schizophrenia. Schizophrenia Bull. 21:357–366.Google Scholar
  75. 75.
    Zhang, L., van Rood, J. J., and Claas, F. H. J. 1991. The T-cell repertoire is not dictated by self antigens alone. Res. Immunol. 142:441–445.Google Scholar
  76. 76.
    Birnbaum, G., Kotilinek, L., Schwartz, M., and Sternad, M. 1986. Disparate responses of lymphocyte clones to cells of monozygotic twins discordant for multiple sclerosis. J. Neuroimmunol. 11:237–243.Google Scholar
  77. 77.
    Utz, U., Biddlson, W. E., McFarland, H. F., McFarlin, D. E., Flerlage, M., and Martin, R. 1993. Skewed T-cell receptor repertoire in genetically identical twins correlates with multiple sclerosis. Nature 364:243–247.Google Scholar
  78. 78.
    Oettinger, M. A., Schatz, D. G., Gorka, C., and Baltimore, D. 1990. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248:1517–1523.Google Scholar
  79. 79.
    Chun, M. J. M., Schatz, D. G., Oettinger, M. A., Jaenisch, R., and Baltimore, D. 1991. The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system. Cell 64:189–200.Google Scholar
  80. 80.
    Matsuoka, M., Nagawa, F., Okazaki, K., Kingsbury, L., Yoshida, K., Müller, U., Larue, D. T., Winer, J. A., and Sakano, H. 1991. Detection of somatic DNA recombination in the transgenic mouse brain. Science 254:81–86.Google Scholar
  81. 81.
    Singer-Sam, J. 1991. An epigenetic role in schizophrenia. Schizophrenia Bull. 17:365.Google Scholar
  82. 82.
    Huttenlocher, P. R. 1979. Synaptic density in human frontal cortex — developmental changes and effects of aging. Brain Res. 163:195–205.Google Scholar
  83. 83.
    Zecevic, N., Bourgeois, J.-P., and Rakic, P. 1989. Changes in synaptic density in motor cortex of rhesus monkey during fetal and postnatal life. Develop. Brain Res. 50:11–32.Google Scholar
  84. 84.
    Bourgeois, J.-P., and Rakic, P. 1993. Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage. J. Neurosci. 13:2801–2820.Google Scholar
  85. 85.
    Feinberg, I. 1982–83. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J. Psychiat. Res. 17:319–334.Google Scholar
  86. 86.
    Keshavan, M. S., Anderson, S., and Pettegrew, J. W. 1994. Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. J. Psychiat. Res. 28:239–265.Google Scholar
  87. 87.
    Weinberger, D. R. 1987. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiat. 44:660–669.Google Scholar
  88. 88.
    Fañanas, L., van Os, J., Hoyos, C., McGrath, J., Mellor, C. S., and Murray, R. 1996. Dermatoglyphic a-b ridge count as a possible marker for developmental disturbance in schizophrenia: replication in two samples. Schizophr. Res. 20:307–314.Google Scholar
  89. 89.
    Davis, J. O., and Bracha, H. S. 1996. Prenatal growth markers in schizophrenia. A monozygotic co-twin control study. Amer. J. Psychiat. 153:1166–1172.Google Scholar
  90. 90.
    Eberle, K. E., Nguyen, V. T., and Freistadt, M. S. 1995. Low levels of poliovirus replication in primary human monocytes: possible interactions with lymphocytes. Arch. Virol. 140:2135–2150.Google Scholar
  91. 91.
    Freistadt, M. S., and Eberle, K. E. 1996. Correlation between poliovirus type 1 mahoney replication in blood cells and neurovirulence. J. Virol. 70:6486–6492.Google Scholar
  92. 92.
    Blinzinger, K., Simon, J., Magrath, D., and Boulger, L. 1969. Poliovirus crystals within the endoplasmic reticulum of endothelial and mononuclear cells in the monkey spinal cord. Science 163:1336–1337.Google Scholar
  93. 93.
    Kowall, N. W., and Beal, M. F. 1991. Glutamate-, glutaminase-, and taurine-immunoreactive neurons develop neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 29:162–167.Google Scholar

Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  • R. F. Squires
    • 1
  1. 1.Nathan S. Kline Institute for Psychiatric ResearchOrangeburg

Personalised recommendations