Login | Register

Prenatal Immune Challenge Induces Developmental Changes in the Morphology of Pyramidal Neurons of the Prefrontal Cortex and Hippocampus in Rats


Prenatal Immune Challenge Induces Developmental Changes in the Morphology of Pyramidal Neurons of the Prefrontal Cortex and Hippocampus in Rats

Baharnoori, Moogeh, Brake, Wayne G. and Srivastava, Lalit (2009) Prenatal Immune Challenge Induces Developmental Changes in the Morphology of Pyramidal Neurons of the Prefrontal Cortex and Hippocampus in Rats. Schizophrenia Research, 107 (1). pp. 99-109. ISSN 0920-9964

Text (Post-print: final draft post-refereeing) (application/pdf)

Official URL: http://dx.doi.org/10.1016/j.schres.2008.10.003


Background -- The neural mechanisms by which maternal infections increase the risk for schizophrenia are poorly understood; however, animal models using maternal administration of immune activators suggest a role for cytokine imbalance in maternal/fetal compartments. As cytokines can potentially affect multiple aspects of neuronal development and the neuropathology of schizophrenia is believed to involve subtle temporo-limbic neurodevelopmental alterations, we investigated morphological development of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus in rats that were prenatally challenged with the immune activator lipopolysaccharide (LPS).
Methods -- Pregnant Sprague-Dawley rat dams were administered with LPS (100μg/kg, at E15 and E16) or saline. The brains of offspring were processed for Golgi-Cox staining at postnatal days (PD) 10, 35 and 56. Dendritic length, branching, spine density and structure were quantified using Neurolucida software.
Results -- At all ages, dendritic arbor was significantly reduced in mPFC and CA1 neurons of LPS-treated animals. Dendritic length was significantly reduced in the mPFC neurons of LPS group at PD10 and 35 but returned to control values at PD60. Opposite pattern was observed in CA1 region of LPS animals (normal values at PD10 and 35, but a reduction at PD60). LPS treatment significantly altered the structure of CA1 dendritic spines at PD10. Spine density was found to be significantly lower only in layer V mPFC of PD60 LPS rats.
Conclusion -- The study provides the first evidence that prenatal exposure to an immunogen dynamically affects spatio-temporal development of mPFC and hippocampal neurons that can potentially lead to aberrant neuronal connectivity and functions of these structures.

Divisions:Concordia University > Faculty of Arts and Science > Psychology
Item Type:Article
Authors:Baharnoori, Moogeh and Brake, Wayne G. and Srivastava, Lalit
Journal or Publication:Schizophrenia Research
Date:January 2009
Digital Object Identifier (DOI):10.1016/j.schres.2008.10.003
Keywords:schizophrenia, neurodevelopment, prenatal infection, dendrite arbor, spine plasticity
ID Code:6330
Deposited On:09 Sep 2009 19:38
Last Modified:18 Jan 2018 17:28
Related URLs:


1. Agnello D, Villa P, Ghezzi P (2000) Increased tumor necrosis factor and interleukin-6 production in the central nervous system of interleukin-10-deficient mice. Brain Res 869:241-243.

2. Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN (2006) The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. Mol Psychiatry 11:47-55.

3. Ashdown H, Poole S, Boksa P, Luheshi GN (2007) Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats. Am J Physiol Regul Integr Comp Physiol 292:R1667-R1674.

4. bdul-Monim Z, Neill JC, Reynolds GP (2007) Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat. J Psychopharmacol 21:198-205.

5. Beasley CL, Reynolds GP (1997) Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schizophr Res 24:349-355.

6. Beloosesky R, Gayle DA, Ross MG (2006) Maternal N-acetylcysteine suppresses fetal inflammatory cytokine responses to maternal lipopolysaccharide. American Journal of Obstetrics and Gynecology 195:1053-1057.

7. Black JE, Kodish IM, Grossman AW, Klintsova AY, Orlovskaya D, Vostrikov V, Uranova N, Greenough WT (2004) Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia. Am J Psychiatry 161:742-744.

8. Blatteis CM, Sehic E (1998) Cytokines and fever. Ann N Y Acad Sci 840:608-618.

9. Boksa P, El-Khodor BF (2003) Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: possible implications for schizophrenia and other disorders. Neurosci Biobehav Rev 27:91-101.

10. Broadbelt K, Byne W, Jones LB (2002) Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex. Schizophr Res 58:75-81.

11. Brown AS, Schaefer CA, Wyatt RJ, Goetz R, Begg MD, Gorman JM, Susser ES (2000) Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study. Schizophr Bull 26:287-295.

12. Brown AS, Susser ES (2002) In utero infection and adult schizophrenia. Ment Retard Dev Disabil Res Rev 8:51-57.

13. Cai ZW, Pan ZL, Pang Y, Evans OB, Rhodes PG (2000) Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatric Research 47:64-72.

14. Cannon M, Clarke MC (2005) Risk for schizophrenia--broadening the concepts, pushing back the boundaries. Schizophr Res 79:5-13.

15. Carvey PM, Chang Q, Lipton JW, Ling Z (2003) Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson's disease. Front Biosci 8:s826-s837.

16. Casanova MF, Rothberg B (2002b) Shape distortion of the hippocampus: a possible explanation of the pyramidal cell disarray reported in schizophrenia. Schizophr Res 55:19-24.

17. Casanova MF, Rothberg B (2002a) Shape distortion of the hippocampus: a possible explanation of the pyramidal cell disarray reported in schizophrenia. Schizophr Res 55:19-24.

18. Chattopadhyaya B, Di CG, Higashiyama H, Knott GW, Kuhlman SJ, Welker E, Huang ZJ (2004) Experience and activity-dependent maturation of perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period. J Neurosci 24:9598-9611.

19. Clarke MC, Harley M, Cannon M (2006) The role of obstetric events in schizophrenia. Schizophr Bull 32:3-8.

20. Coe CL, Kramer M, Czeh B, Gould E, Reeves AJ, Kirschbaum C, Fuchs E (2003) Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol Psychiatry 54:1025-1034.

21. Colom LV, Castaneda MT, Reyna T, Hernandez S, Garrido-Sanabria E (2005) Characterization of medial septal glutamatergic neurons and their projection to the hippocampus. Synapse 58:151-164.

22. Dean K, Murray RM (2005) Environmental risk factors for psychosis. Dialogues Clin Neurosci 7:69-80.

23. Deumens R, Koopmans GC, Jaken RJ, Morren K, Comhair T, Kosar S, Steinbusch HW, Den Bakker CG, Joosten EA (2006) Stimulation of neurite outgrowth on neonatal cerebral astrocytes is enhanced in the presence of BDNF. Neurosci Lett 407:268-273.

24. Di CG (2007) Development of cortical GABAergic circuits and its implications for neurodevelopmental disorders. Clin Genet 72:1-8.

25. Ding DC, Gabbott PL, Totterdell S (2001) Differences in the laminar origin of projections from the medial prefrontal cortex to the nucleus accumbens shell and core regions in the rat. Brain Res 917:81-89.

26. Elovitz MA, Mrinalini C, Sammel MD (2006) Elucidating the early signal transduction pathways leading to fetal brain injury in preterm birth. Pediatr Res 59:50-55.

27. Fan J, Wojnar MM, Theodorakis M, Lang CH (1996) Regulation of insulin-like growth factor (IGF)-I mRNA and peptide and IGF-binding proteins by interleukin-1. Am J Physiol 270:R621-R629.

28. Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R (2002a) 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.

29. Fatemi SH, Earle JA, McMenomy T (2000) Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry 5:654-63, 571.

30. Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, Shier A, Sheikh S, Bailey K (1999) Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry 4:145-154.

31. Fatemi SH, Emamian ES, Sidwell RW, Kist DA, Stary JM, Earle JA, Thuras P (2002b) Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice. Mol Psychiatry 7:633-640.

32. Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, Smee DF, Pearce DA, Winter C, Sohr R, Juckel G (2008) Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders. Schizophr Res 99:56-70.

33. Fiala JC, Feinberg M, Popov V, Harris KM (1998) Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci 18:8900-8911.

34. Flores C, Wen X, Labelle-Dumais C, Kolb B (2007) Chronic phencyclidine treatment increases dendritic spine density in prefrontal cortex and nucleus accumbens neurons. Synapse 61:978-984.

35. Flores G, Alquicer G, Silva-Gomez AB, Zaldivar G, Stewart J, Quirion R, Srivastava LK (2005) Alterations in dendritic morphology of prefrontal cortical and nucleus accumbens neurons in post-pubertal rats after neonatal excitotoxic lesions of the ventral hippocampus. Neuroscience 133:463-470.

36. Fortier ME, Joober R, Luheshi GN, Boksa P (2004) Maternal exposure to bacterial endotoxin during pregnancy enhances amphetamine-induced locomotion and startle responses in adult rat offspring. J Psychiatr Res 38:335-345.

37. Fortier ME, Luheshi GN, Boksa P (2007) Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy. Behav Brain Res 181:270-277.

38. Fujioka A, Fujioka T, Ishida Y, Maekawa T, Nakamura S (2006) Differential effects of prenatal stress on the morphological maturation of hippocampal neurons. Neuroscience 141:907-915.

39. Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM, Barnes TR, Hirsch SR (1998) Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 65:446-453.

40. Gayle DA, Beloosesky R, Desai M, Amidi F, Nunez SE, Ross MG (2004) Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain. American Journal of Physiology-Regulatory Integrative and Comparative Physiology 286:R1024-R1029.

41. Gibb R, Kolb B (1998) A method for vibratome sectioning of Golgi-Cox stained whole rat brain. J Neurosci Methods 79:1-4.

42. Gilmore J.H., Jarskog L.F., Swarooparani V, Lauder J.M. (2004) Prenatal Infection and Risk for Schizophrenia: IL-1?, IL-6, and TNF? Inhibit Cortical Neuron Dendrite Development. Neuropsychopharmacology 29:1221-1229.

43. Gilmore JH, Jarskog LF, Vadlamudi S (2003) Maternal infection regulates BDNF and NGF expression in fetal and neonatal brain and maternal-fetal unit of the rat. J Neuroimmunol 138:49-55.

44. Gilmore JH, Jarskog LF, Vadlamudi S (2005) Maternal poly I : C exposure during pregnancy regulates TNF alpha BDNF, and NGF expression in neonatal brain and the maternal-fetal unit of the rat. Journal of Neuroimmunology 159:106-112.

45. Glantz LA, Lewis DA (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57:65-73.

46. Guan Z, Fang J (2006) Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav Immun 20:64-71.

47. Hajszan T, Leranth C, Roth RH (2006) Subchronic phencyclidine treatment decreases the number of dendritic spine synapses in the rat prefrontal cortex. Biol Psychiatry 60:639-644.

48. Harris KM (1999) Structure, development, and plasticity of dendritic spines. Curr Opin Neurobiol 9:343-348.

49. Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40-68.

50. Heinz A, Romero B, Gallinat J, Juckel G, Weinberger DR (2003) Molecular brain imaging and the neurobiology and genetics of schizophrenia. Pharmacopsychiatry 36 Suppl 3:S152-S157.

51. Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andrade M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A 104:14501-14506.

52. Jan YN, Jan LY (2003) The control of dendrite development. Neuron 40:229-242.

53. Jeohn GH, Kong LY, Wilson B, Hudson P, Hong JS (1998) Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures. J Neuroimmunol 85:1-10.

54. Juarez I, Gratton A, Flores G (2008) Ontogeny of altered dendritic morphology in the rat prefrontal cortex, hippocampus, and nucleus accumbens following Cesarean delivery and birth anoxia. J Comp Neurol 507:1734-1747.

55. Kajiwara R, Wouterlood FG, Sah A, Boekel AJ, Baks-te Bulte LT, Witter MP (2008) Convergence of entorhinal and CA3 inputs onto pyramidal neurons and interneurons in hippocampal area CA1--an anatomical study in the rat. Hippocampus 18:266-280.

56. Kalus P, Muller TJ, Zuschratter W, Senitz D (2000) The dendritic architecture of prefrontal pyramidal neurons in schizophrenic patients. Neuroreport 11:3621-3625.

57. Kawamura T, Chen J, Takahashi T, Ichitani Y, Nakahara D (2006) Prenatal stress suppresses cell proliferation in the early developing brain. Neuroreport 17:1515-1518.

58. Kessler JA, Mehler MF, Michaelson MD (1998) Effects of cytokines on neuronal development. Journal of Neurochemistry 70:S60.

59. Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN, Kenny LC, Mortensen PB (2008) Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry 65:146-152.

60. Kim IJ, Beck HN, Lein PJ, Higgins D (2002) Interferon gamma induces retrograde dendritic retraction and inhibits synapse formation. J Neurosci 22:4530-4539.

61. Kolluri N, Sun Z, Sampson AR, Lewis DA (2005) Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am J Psychiatry 162:1200-1202.

62. Kremlev SG, Palmer C (2005) Interleukin-10 inhibits endotoxin-induced pro-inflammatory cytokines in microglial cell cultures. J Neuroimmunol 162:71-80.

63. Kuroda M, Yokofujita J, Murakami K (1998) An ultrastructural study of the neural circuit between the prefrontal cortex and the mediodorsal nucleus of the thalamus. Prog Neurobiol 54:417-458.

64. Labelle C, Leclerc N (2000) Exogenous BDNF, NT-3 and NT-4 differentially regulate neurite outgrowth in cultured hippocampal neurons. Brain Res Dev Brain Res 123:1-11.

65. Lante F, Meunier J, Guiramand J, Maurice T, Cavalier M, de Jesus Ferreira MC, Aimar R, Cohen-Solal C, Vignes M, Barbanel G (2007) Neurodevelopmental damage after prenatal infection: role of oxidative stress in the fetal brain. Free Radic Biol Med 42:1231-1245.

66. Lemaire V, Koehl M, Le MM, Abrous DN (2000) Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci U S A 97:11032-11037.

67. Ling Z, Gayle DA, Ma SY, Lipton JW, Tong CW, Hong JS, Carvey PM (2002) In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain. Mov Disord 17:116-124.

68. Lynch AM, Walsh C, Delaney A, Nolan Y, Campbell VA, Lynch MA (2004) Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10--a role for IL-1 beta? J Neurochem 88:635-646.

69. MacLaurin SA, Krucker T, Fish KN (2007) Hippocampal dendritic arbor growth in vitro: regulation by Reelin-Disabled-1 signaling. Brain Res 1172:1-9.

70. MalekAhmadi P (1996) Neuropsychiatric aspects of cytokines research: An overview. Neuroscience and Biobehavioral Reviews 20:359-365.

71. Mandyam CD, Crawford EF, Eisch AJ, Rivier CL, Richardson HN (2008) Stress experienced in utero reduces sexual dichotomies in neurogenesis, microenvironment, and cell death in the adult rat hippocampus. Dev Neurobiol 68:575-589.

72. Marenco S, Weinberger DR (2000) The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave. Dev Psychopathol 12:501-527.

73. Marx CE, Jarskog LF, Lauder JM, Lieberman JA, Gilmore JH (2001) Cytokine effects on cortical neuron MAP-2 immunoreactivity: Implications for schizophrenia. Biological Psychiatry 50:743-749.

74. McClellan JM, Susser E, King MC (2006) Maternal famine, de novo mutations, and schizophrenia. JAMA 296:582-584.

75. McDonald C, Murray RM (2000) Early and late environmental risk factors for schizophrenia. Brain Res Brain Res Rev 31:130-137.

76. Merrill JE (1992) Tumor-Necrosis-Factor-Alpha, Interleukin-1 and Related Cytokines in Brain-Development - Normal and Pathological. Developmental Neuroscience 14:1-10.

77. Meyer U, Feldon J, Schedlowski M, Yee BK (2006a) Immunological stress at the maternal-foetal interface: A link between neurodevelopment and adult psychopathology. Brain Behavior and Immunity 20:378-388.

78. Meyer U, Feldon J, Schedlowski M, Yee BK (2006b) Immunological stress at the maternal-foetal interface: a link between neurodevelopment and adult psychopathology. Brain Behav Immun 20:378-388.

79. Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J (2006c) The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci 26:4752-4762.

80. Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J (2007a) Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge. Neuropsychopharmacology.

81. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J (2007b) Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun.

82. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J (2007c) Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun.

83. Michelsen KA, Van den Hove DL, Schmi
All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page

Downloads per month over past year

Research related to the current document (at the CORE website)
- Research related to the current document (at the CORE website)
Back to top Back to top