Abstract

In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by six hours following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.

Data availability

Sequencing data (raw and gene-count data for RNA-seq) have been deposited in GEO under accession number GSE166376. Available at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166376Data analysis code is available at: https://github.com/NordNeurogenomicsLab/Publications/tree/master/Canales_eLife_2021Detailed DE analysis are included in the manuscript and supporting files (Supplementary files 1-15) and can be visualized using our interactive online browser at: https://nordlab.shinyapps.io/mia_browser/.

The following data sets were generated

Article and author information

Author details

  1. Cesar P Canales

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2505-8367
  2. Myka L Estes

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Karol Cichewicz

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kartik Angara

    Department of Pediatrics & Human Development, Michigan State University, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. John Paul Aboubechara

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Scott Cameron

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kathryn Prendergast

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Linda Su-Feher

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Iva Zdilar

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ellie J Kreun

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Emma C Connolly

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jin Myeong Seo

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Jack B Goon

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kathleen Farrelly

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Tyler W Stradleigh

    Center for Neuroscience, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Deborah van der List

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Lory Haapanen

    Div. of Rheumatology/Allergy and Clin. Immunol, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Judy Van de Water

    Div. of Rheumatology/Allergy and Clin. Immunol, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Daniel Vogt

    Department of Pediatrics & Human Development, Michigan State University, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Kim McAllister

    Center for Neuroscience, University of California, Davis, Davis, United States
    For correspondence
    kmcallister@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.
  21. Alex S Nord

    Psychiatry and Behavioral Sciences, University of California, Davis, Davis, United States
    For correspondence
    asnord@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4259-7514

Funding

National Institute of Mental Health (2T32MH073124-16)

  • Cesar P Canales

National Institute of Mental Health (5R21MH116681-02)

  • Kim McAllister
  • Alex S Nord

Brain Research Foundation

  • Alex S Nord

The UCD Clinical Translational Science Center

  • Kim McAllister
  • Alex S Nord

National Institute of General Medical Sciences (GM119831)

  • Alex S Nord

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was conducted in compliance with NIH guidelines and approved protocols from the University of California Davis Animal Care and Use Committee (IACUC) protocol #20229

Reviewing Editor

  1. Anita Bhattacharyya, University of Wisconsin, Madison, United States

Publication history

  1. Received: June 16, 2020
  2. Accepted: March 2, 2021
  3. Accepted Manuscript published: March 5, 2021 (version 1)
  4. Version of Record published: March 19, 2021 (version 2)

Copyright

© 2021, Canales et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Cesar P Canales
  2. Myka L Estes
  3. Karol Cichewicz
  4. Kartik Angara
  5. John Paul Aboubechara
  6. Scott Cameron
  7. Kathryn Prendergast
  8. Linda Su-Feher
  9. Iva Zdilar
  10. Ellie J Kreun
  11. Emma C Connolly
  12. Jin Myeong Seo
  13. Jack B Goon
  14. Kathleen Farrelly
  15. Tyler W Stradleigh
  16. Deborah van der List
  17. Lory Haapanen
  18. Judy Van de Water
  19. Daniel Vogt
  20. Kim McAllister
  21. Alex S Nord
(2021)
Sequential perturbations to mouse corticogenesis following in utero maternal immune activation
eLife 10:e60100.
https://doi.org/10.7554/eLife.60100