Abstract
We investigated the role of maternal exposure to human influenza virus (H1N1) in C57BL/6 mice on Day 9 of pregnancy on pyramidal and nonpyramidal cell density, pyramidal nuclear area, and overall brain size in Day 0 neonates and 14-week-old progeny and compared them to sham-infected cohorts. Pyramidal cell density increased significantly (p < 0.0038) by 170% in Day 0 infected mice vs. controls. Nonpyramidal cell density decreased by 33% in Day 0 infected progeny vs. controls albeit, nonsignificantly. Pyramidal cell nuclear size decreased significantly (p < 0.0465) by 29% in exposed newborn mice vs. controls. Fourteen-week-old exposed mice continued to show significant increases in both pyramidal and nonpyramidal cell density values vs. controls respectively (p < 0.0085 E1 (exposed group 1), p < 0.0279 E2 (exposed group 2) pyramidal cell density; p < 0.0092 E1, p < 0.0252 E2, nonpyramidal cell density). By the same token, pyramidal cell nuclear size exhibited 37–43% reductions when compared to control values; these were statistically significant vs. controls (p < 0.04 E1, p < 0.0259 E2). Brain and ventricular area measurements in adult exposed mice also showed significant increases and decreases respectively vs. controls. Ventricular brain ratios exhibited 38–50% decreases in exposed mice vs. controls. While the rate of pyramidal cell proliferation per unit area decreased from birth to adulthood in both control and exposed groups, nonpyramidal cell growth rate increased only in the exposed adult mice. These data show for the first time that prenatal exposure of pregnant mice on Day 9 of pregnancy to a sublethal intranasal administration of influenza virus has both short-term and long-lasting deleterious effects on developing brain structure in the progeny as evident by altered pyramidal and nonpyramidal cell density values; atrophy of pyramidal cells despite normal cell proliferation rate and final enlargement of brain. Moreover, abnormal corticogenesis is associated with development of abnormal behavior in the exposed adult mice.
Similar content being viewed by others
REFERENCES
Barak, Y., Kimhi. R., Stien, D., Gutman, J., and Weizinan, A. (1998). Autistic subjects with comorbid epilepsy: A possible association with viral infections. Child Psych. Human Dev. 29:245–251.
Buxhoeveden, D., Roy, E., Switala, A., and Casanova, M. F. (2000). Reduced interneuronal space in schizophrenia. Biol. Psychiatry 47(7):681–683.
Chess, S. (1977). Follow-up report on autism in congenital rubella. J. Autism Child Schizophr. 7:68–81.
Connolly, A. M., Chez, M. G., Pestronk, A., Arnold, S. T., Shobhna, M., and Deuel, K. (1999). Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J. Pediatrics 134(5):607–613.
Desmond, M. M., Wilson, G. S., Melnick, J. L., Singer, D. B., and Zion, T. E. (1967). Congenital rubella encephalitis. Course and early sequelae. J. Pediatrics 71:311–331.
Fatemi, S. H. (2001). Reelin mutations in mouse and man: From reeler mouse to schizophrenia, mood disorders, autism and lissencephaly. Mol. Psychiatry 6:129–133.
Fatemi, S. H., Cuadra, A., El-Fakahany, E., Sidwell, R.W., and Thuras, P. (2000a). Prenatal viral infection causes alterations in nNOS expression in developing mouse brains. Neuro. Report 11:1493–1496.
Fatemi, S. H., Earle, J., and McMenomy, T. (2000b). Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol. Psychiatry 5:654–663.
Fatemi, S. H., Emamian, E. S., Kist, D., Sidwell, R.W., Nakajima, K., Akhter, P., Shier, A., Sheikh, S., and Bailey, K. (1999). Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol. Psychiatry 4:145–154.
Fatemi, S. H., Emamian, E. S., Sidwell, R. W., Stary, J., Earle, J., and Thuras, P. (2002). Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice. Mol. Psychiatry.
Fatemi, S. H., Sidwell, R., Akhter. P., Sedgwick, J., Thuras, P., Bailey, K., and Kist, D. (1998a). Human influenza viral infection in utero increases nNOS expression in hippocampi of neonatal mice. Synapse 29:84–88.
Fatemi, S. H., Sidwell, R., Kist, D., Akhter, P., Meltzer, H. Y., Bailey, K., and Sedgwick, J. (1998b). Differential expression of synaptosome-associated protein 25 kDa [SNAP-25] in hippocampi of neonatal mice following exposure to human influenza virus in utero. Brain Res. 800:1–9.
Fatemi, S. H., Stary, J., Halt, A., and Realmuto, G. R. (2001). Dysregulation of Reelin and Bcl2 proteins in autistic cerebellum. J. Autism Dev. Dis. 31:529–535.
Franklin, K., and Paxinos, G. (1997). The Mouse Brain in Sterotaxic Coordinates, Academic Press, San Diego, CA.
Geyer, M. A., and Braff, D. L. (1987). Startle habituation and sensorimotor gating in schizophrenia and related animal models. Schizophr. Bull. 13:643–668.
Guidotti, A. R., Auta, J., Davis, J., DiGiorgi Gerevini, V., Dwivedi, Y., Grayson, D. R., Impagnatiello, F., Pandey,G., Pesold, C., Sharma, R., Uzunov, D., and Costa, E. (2000). Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: A postmortem brain study. Arch. Gen. Psychiatry 57:1061–1069.
Lotspiech, L. J., and Ciaranello, R. D. (1993). The neurobiology and genetics of infantile autism. Int. Rev. Neurobiol. 87–129.
Mednick, S. A., Machon, R. A., Huttunen, M. D., and Bonnet, D. (1988). Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch. Gen. Psychiatry 45:189–192.
Miles, J. H., Hadden, L. L., Takahashi, T. N., and Hillman, R. E. (2000). Head circumference is an independent clinical finding associated with autism. Am. J. Med. Genetics 95:339–350.
Rajkowska, G., Miguel-Hidalgo, J. J., Wei, J., Dilley, G., Pittman, S. D., Meltzer, H. Y., Overholser, J. C., Roth, B. L., and Stockmeier, C. A. (1999). Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol. Psychiatry 45:1085–1098.
Rajkowska,G., Selemon, L., and Goldman-Rakic, P. (1998). Neuronal and glial somal size in the prefrontal cortex: A postmortem morphometric study of schizophrenia and Huntington disease. Arch. Gen. Psychiatry 55:215–224.
Reed, L. S., and Muench, H. (1938). A simple method of estimating 50 percent end points. Am. J. Hyg. 27:493–498.
Rutter, M., and Bartok, L. (1971). Causes of infantile autism: Some considerations from recent research. J. Autism Child Schizophr. 1:20–32.
Schambra, U. B., Lauder, J. M., and Silver, J. (1992). Atlas of the Prenatal Mouse Brain, Academic Press, San Diego, CA, p. 327.
Shi, L., Fatemi, S. H., Sidwell, R.W., and Patterson, P. H. (2001).Aschizophrenia model: Maternal influenza infection alters brain development. In Proceedings of IV International Symposium on Respiratory Viral Infections. Cura¸cao, Netherlands Antilles, 2001.
Singh, V. K., Warren, R., Averette, H. R., and Ghaziuddin, M. (1997). Circulating autoantibodies to neuronal and glial filament proteins in autism. Ped. Neurol. 17:88–90.
Stubbs, E. G., Ash, E. S., and Williams, C. P. (1984). Autism and congenital cytomegalovirus. J. Autism Dev. Dis. 14:183–189.
Susser, E. S., Brown, A. S., and Gorman, J.M.(eds.) (1999). Prenatal Exposures in Schizophrenia, American Psychiatric Press, Washington, DC, pp. 1–275.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fatemi, S.H., Earle, J., Kanodia, R. et al. Prenatal Viral Infection Leads to Pyramidal Cell Atrophy and Macrocephaly in Adulthood: Implications for Genesis of Autism and Schizophrenia. Cell Mol Neurobiol 22, 25–33 (2002). https://doi.org/10.1023/A:1015337611258
Issue Date:
DOI: https://doi.org/10.1023/A:1015337611258