Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism


The broad impairments in cognitive and neurologic functioning found in Autism Spectrum Disorder (ASD) patients are thought to originate during early prenatal developmental stages. Indeed, postmortem and imaging studies in ASD patients detected white-matter abnormalities, as well as prefrontal and temporal cortex deficits, evident from early childhood. Here, we used Maternal Immune Activation (MIA), a mouse model for ASD, in which the offsprings exhibit Autistic-like behaviors as well as cortical abnormalities. However, the dynamics that influence the number and the identity of newly born cortical neurons following maternal inflammation remains unknown. Our study shows early changes in the duration of the S-phase of PAX6+ progenitors, leading to an increased proportion of neurogenic divisions and a reciprocal decrease in the proliferative divisions. In two different time points of maternal inflammation, MIA resulted in an overproduction of CTIP2+ cortical neurons, which remained overrepresented at the end of gestation and in postnatal mice. Interestingly, MIA-resistant IL6-KO mice did not exhibit these changes. Lastly, we propose that elevated levels of the transcription factor PAX6 following MIA supports the overproduction of CTIP2+ neurons. Taken together, our data reveals a possible link between maternal immune activation and the excess of cortical neurons found in the cortex of ASD patients.

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  1. 1.

    Minshew NJ, Williams DL. The new neurobiology of autism. Arch Neurol. 2007;64:945.

  2. 2.

    Herbert MR, Kenet T. Brain abnormalities in language disorders and in autism. Pediatr Clin North Am. 2007;54:563–83. vii

  3. 3.

    McAlonan GM, Cheung C, Cheung V, Wong N, Suckling J, Chua SE. Differential effects on white-matter systems in high-functioning autism and Asperger’s syndrome. Psychol Med. 2009;39:1885.

  4. 4.

    Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, et al. Patches of disorganization in the neocortex of children with autism. N Engl J Med. 2014;370:1209–19.

  5. 5.

    Schumann CM, Bloss CS, Barnes CC, Wideman GM, Carper RA, Akshoomoff N, et al. Longitudinal magnetic resonance imaging study of cortical development through early childhood in autism. J Neurosci. 2010;30:4419–27.

  6. 6.

    Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, Croen LA. Maternal infection during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2015;45:4015–25.

  7. 7.

    Hornig M, Bresnahan MA, Che X, Schultz AF, Ukaigwe JE, Eddy ML et al. Prenatal fever and autism risk. Mol Psychiatry. 2017. https://doi.org/10.1038/mp.2017.119.

  8. 8.

    Zerbo O, Iosif A-M, Walker C, Ozonoff S, Hansen RL, Hertz-Picciotto I. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. J Autism Dev Disord. 2013;43:25–33.

  9. 9.

    Lee BK, Magnusson C, Gardner RM, Blomström Å, Newschaffer CJ, Burstyn I, et al. Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain Behav Immun. 2015;44:100–5.

  10. 10.

    Jiang H, Xu L, Shao L, Xia R, Yu Z, Ling Z, et al. Maternal infection during pregnancy and risk of autism spectrum disorders: a systematic review and meta-analysis. Brain Behav Immun. 2016;58:165–72.

  11. 11.

    Atladóttir HÓ, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2010;40:1423–30.

  12. 12.

    Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel H-M. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014;19:259–64.

  13. 13.

    Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27:10695–702.

  14. 14.

    Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012;26:607–16.

  15. 15.

    Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016;351:933–9.

  16. 16.

    Smith SEP, Elliott RM, Anderson MP. Maternal immune activation increases neonatal mouse cortex thickness and cell density. J Neuroimmune Pharmacol. 2012;7:529–32.

  17. 17.

    Shi L, Smith SEP, Malkova N, Tse D, Su Y, Patterson PH. Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav Immun. 2009;23:116–23.

  18. 18.

    Naviaux RK, Zolkipli Z, Wang L, Nakayama T, Naviaux JC, Le TP, et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS ONE. 2013;8:e57380.

  19. 19.

    Meyer U. Prenatal poly(I:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry. 2014;75:307–15.

  20. 20.

    Garbett KA, Hsiao EY, Kálmán S, Patterson PH, Mirnics K. Effects of maternal immune activation on gene expression patterns in the fetal brain. Transl Psychiatry. 2012;2:e98.

  21. 21.

    Gallagher D, Norman AA, Woodard CL, Yang G, Gauthier-Fisher A, Fujitani M, et al. Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway. Cell Stem Cell. 2013;13:564–76.

  22. 22.

    Götz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol. 2005;6:777–88.

  23. 23.

    Osumi N, Shinohara H, Numayama-Tsuruta K, Maekawa M. Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator. Stem Cells. 2008;26:1663–72.

  24. 24.

    Sun J, Rockowitz S, Xie Q, Ashery-Padan R, Zheng D, Cvekl A. Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development. Nucleic Acids Res. 2015;43:6827–46.

  25. 25.

    Mi D, Carr CB, Georgala PA, Huang Y-T, Manuel MN, Jeanes E, et al. Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb. Neuron. 2013;78:269–84.

  26. 26.

    Molyneaux BJ, Arlotta P, Menezes JRL, Macklis JD. Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci. 2007;8:427–37.

  27. 27.

    Englund C, Fink A, Lau C, Pham D, Daza RAM, Bulfone A, et al. Pax6, Tbr2, and Tbr1 Are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci. 2005;25:247–51.

  28. 28.

    Götz M, Stoykova A, Gruss P. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron. 1998;21:1031–44.

  29. 29.

    Sansom SN, Griffiths DS, Faedo A, Kleinjan D-J, Ruan Y, Smith J, et al. The Level of the Transcription Factor Pax6 Is Essential for Controlling the Balance between Neural Stem Cell Self-Renewal and Neurogenesis. PLoS Genet. 2009;5:e1000511.

  30. 30.

    Manuel MN, Mi D, Mason JO, Price DJ. Regulation of cerebral cortical neurogenesis by the Pax6 transcription factor. Front Cell Neurosci. 2015;9:70.

  31. 31.

    Wong FK, Fei J-F, Mora-Bermúdez F, Taverna E, Haffner C, Fu J, et al. Sustained Pax6 expression generates primate-like basal radial glia in developing mouse neocortex. PLOS Biol. 2015;13:e1002217.

  32. 32.

    Stoykova A, Gruss P. Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J Neurosci. 1994;14:1395–412.

  33. 33.

    Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, et al. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci. 2002;5:308–15.

  34. 34.

    Arai Y, Pulvers JN, Haffner C, Schilling B, Nüsslein I, Calegari F, et al. Neural stem and progenitor cells shorten S-phase on commitment to neuron production. Nat Commun. 2011;2:154.

  35. 35.

    Supekar K, Uddin LQ, Khouzam A, Phillips J, Gaillard WD, Kenworthy LE, et al. Brain hyperconnectivity in children with autism and its links to social deficits. Cell Rep. 2013;5:738–47.

  36. 36.

    Sauer ME, Walker BE. Radioautographic study of interkinetic nuclear migration in the neural tube. Proc Soc Exp Biol Med. 1959;101:557–60.

  37. 37.

    Reiner O, Sapir T, Gerlitz G. Interkinetic nuclear movement in the ventricular zone of the cortex. J Mol Neurosci. 2012;46:516–26.

  38. 38.

    Takahashi T, Nowakowski RS, Caviness VS. The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J Neurosci. 1995;15:6046–57.

  39. 39.

    Nowakowski RS, Lewin SB, Miller MW. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J Neurocytol. 1989;18:311–8.

  40. 40.

    Shen Q, Zhong W, Jan YN, Temple S. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development. 2002;129:4843–53.

  41. 41.

    Bultje RS, Castaneda-Castellanos DR, Jan LY, Jan Y-N, Kriegstein AR, Shi S-H. Mammalian Par3 regulates progenitor cell asymmetric division via notch signaling in the developing neocortex. Neuron. 2009;63:189–202.

  42. 42.

    Sanada K, Tsai L-H. G protein βγ subunits and AGS3 control spindle orientation and asymmetric cell fate of cerebral cortical progenitors. Cell. 2005;122:119–31.

  43. 43.

    Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis JD. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron. 2005;45:207–21.

  44. 44.

    Nieto M, Monuki ES, Tang H, Imitola J, Haubst N, Khoury SJ, et al. Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II–IV of the cerebral cortex. J Comp Neurol. 2004;479:168–80.

  45. 45.

    Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27:10695–702.

  46. 46.

    Stoykova A, Treichel D, Hallonet M, Gruss P. Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J Neurosci. 2000;20:8042–50.

  47. 47.

    Britanova O, de Juan Romero C, Cheung A, Kwan KY, Schwark M, Gyorgy A, et al. Satb2 Is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron. 2008;57:378–92.

  48. 48.

    Alcamo EA, Chirivella L, Dautzenberg M, Dobreva G, Fariñas I, Grosschedl R, et al. Satb2 regulates callosal projection neuron identity in the developing cerebral cortex. Neuron. 2008;57:364–77.

  49. 49.

    Chen B, Schaevitz LR, McConnell SK. Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc Natl Acad Sci USA. 2005;102:17184–9.

  50. 50.

    Chen B, Wang SS, Hattox AM, Rayburn H, Nelson SB, McConnell SK. The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex. Proc Natl Acad Sci USA. 2008;105:11382–7.

  51. 51.

    Chen J-G, Rasin M-R, Kwan KY, Sestan N. Zfp312 is required for subcortical axonal projections and dendritic morphology of deep-layer pyramidal neurons of the cerebral cortex. Proc Natl Acad Sci USA. 2005;102:17792–7.

  52. 52.

    Leone DP, Srinivasan K, Chen B, Alcamo E, McConnell SK. The determination of projection neuron identity in the developing cerebral cortex. Curr Opin Neurobiol. 2008;18:28–35.

  53. 53.

    Clancy B, Darlington R, Finlay B. Translating developmental time across mammalian species. Neuroscience. 2001;105:7–17.

  54. 54.

    Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria KC, et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry. 2017;22:820–35.

  55. 55.

    Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306:2001.

  56. 56.

    Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003;23:297–302.

  57. 57.

    Liboska R, Ligasová A, Strunin D, Rosenberg I, Koberna K. Most Anti-BrdU antibodies react with 2′-deoxy-5-ethynyluridine—the method for the effective suppression of this cross-reactivity. PLoS ONE. 2012;7:e51679.

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We are grateful for the help of Ofira Higfa, Yehuda Melamed, Osnat Amram, Oz Yirmiyahu, Michael Tsoory, and Tamar Sapir from the Weizmann Institute of Science. OR is the incumbent of the Bernstein-Mason Chair of Neurochemistry and the Head of M. Judith Ruth Institute for Preclinical Brain Research. The research has been supported by the Israel Science Foundation (Grant No. 347/15), the Legacy Heritage Biomedical Program of the Israel Science Foundation (Grant No. 2041/16), Israel Science Foundation (ISF)—National Natural Science Foundation of China (NSFC) (grant No. 2449/16), grant No. 2397/18 from the Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation, by the European Cooperation on Science and Technology (COST Action CA16118), Weizmann-FAPESP supported by a research grant from Sergio and Sonia Lozinsky, Nella and Leon Benoziyo Center for Neurological Diseases, Jeanne and Joseph Nissim Foundation for Life Sciences Research, Wohl Biology Endowment Fund, Lulu P. and David J. Levidow, Fund for Alzheimers Diseases and Neuroscience Research, the Helen and Martin Kimmel Stem Cell Research Institute, the Kekst Family Institute for Medical Genetics, the David and Fela Shapell Family Center for Genetic Disorders Research.

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Ben-Reuven, L., Reiner, O. Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0594-y

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