Article | Published:

Reversing behavioural abnormalities in mice exposed to maternal inflammation

Nature volume 549, pages 482487 (28 September 2017) | Download Citation

Abstract

Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA-affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the behavioural abnormalities in MIA-affected offspring. Sociability and repetitive behavioural phenotypes could be selectively modulated according to the efferent targets of S1DZ. Our work identifies a cortical region primarily, if not exclusively, centred on the S1DZ as the major node of a neural network that mediates behavioural abnormalities observed in offspring exposed to maternal inflammation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 40, 1423–1430 (2010)

  2. 2.

    Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav. Brain Res. 204, 313–321 (2009)

  3. 3.

    et al. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol. Psychiatry 19, 259–264 (2014)

  4. 4.

    et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124, 687–694 (2009)

  5. 5.

    , & The immune response in autism: a new frontier for autism research. J. Leukoc. Biol. 80, 1–15 (2006)

  6. 6.

    et al. Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain Behav. Immun. 44, 100–105 (2015)

  7. 7.

    , , , & Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 27, 10695–10702 (2007)

  8. 8.

    & Neural basis of psychosis-related behaviour in the infection model of schizophrenia. Behav. Brain Res. 204, 322–334 (2009)

  9. 9.

    , , & Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23, 297–302 (2003)

  10. 10.

    , , , & Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26, 607–616 (2012)

  11. 11.

    et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016)

  12. 12.

    . & The Mouse Brain in Stereotaxic Coordinates 2nd edn (Elsevier Academic Press, 2004)

  13. 13.

    & Descending projections from the dysgranular zone of rat primary somatosensory cortex processing deep somatic input. J. Comp. Neurol. 520, 1021–1046 (2012)

  14. 14.

    , & Patterns of afferent projections to transitional zones in the somatic sensorimotor cerebral cortex of albino rats. Brain Res. 292, 261–267 (1984)

  15. 15.

    & Mapping the body representation in the SI cortex of anesthetized and awake rats. J. Comp. Neurol. 229, 199–213 (1984)

  16. 16.

    et al. Common circuit defect of excitatory–inhibitory balance in mouse models of autism. J. Neurodev. Disord. 1, 172–181 (2009)

  17. 17.

    et al. Peripheral mechanosensory neuron dysfunction underlies tactile and behavioral deficits in mouse models of ASDs. Cell 166, 299–313 (2016)

  18. 18.

    , & Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci. Lett. 412, 227–232 (2007)

  19. 19.

    & Interneuron cell types are fit to function. Nature 505, 318–326 (2014)

  20. 20.

    , & NeuN, a neuronal specific nuclear protein in vertebrates. Development 116, 201–211 (1992)

  21. 21.

    et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature (2017)

  22. 22.

    et al. Molecular dissection of Pax6 function: the specific roles of the paired domain and homeodomain in brain development. Development 131, 6131–6140 (2004)

  23. 23.

    et al. Ank3-dependent SVZ niche assembly is required for the continued production of new neurons. Neuron 71, 61–75 (2011)

  24. 24.

    et al. Behavioral phenotyping of Nestin-Cre mice: implications for genetic mouse models of psychiatric disorders. J. Psychiatr. Res. 55, 87–95 (2014)

  25. 25.

    & Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003)

  26. 26.

    et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010)

  27. 27.

    , , , & Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81, 1282–1289 (2014)

  28. 28.

    et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011)

  29. 29.

    & Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87, 684–698 (2015)

  30. 30.

    et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Transl. Psychiatry 5, e525 (2015)

  31. 31.

    et al. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol. Psychiatry 21, 956–968 (2016)

  32. 32.

    et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J. Neurosci. 30, 2115–2129 (2010)

  33. 33.

    et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007)

  34. 34.

    , , & Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009)

  35. 35.

    , , & Channelrhodopsin-2 and optical control of excitable cells. Nat. Methods 3, 785–792 (2006)

  36. 36.

    et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007)

  37. 37.

    et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011)

  38. 38.

    et al. A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol. 3, e159 (2005)

  39. 39.

    , , & Retrograde neuronal tracing with a deletion-mutant rabies virus. Nat. Methods 4, 47–49 (2007)

  40. 40.

    et al. Independent optical excitation of distinct neural populations. Nat. Methods 11, 338–346 (2014)

  41. 41.

    et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 463, 98–102 (2010)

  42. 42.

    et al. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370, 1209–1219 (2014)

  43. 43.

    et al. An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J. Invest. Dermatol. 133, 441–451 (2013)

  44. 44.

    , , & Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism. PLoS One 3, e3067 (2008)

Download references

Acknowledgements

We thank J. T. Kwon, M. D. Reed, D. Cho, and S. Bigler for assistance with experiments and B. Noro and C. Jennings for critical reading of the manuscript. This work was supported by the Simons Foundation Autism Research Initiative (J.R.H. and D.R.L.), Simons Foundation to the Simons Center for the Social Brain at MIT (Y.S.Y., J.R.H. and G.B.C.), Robert Buxton (G.B.C.), Hock E. Tan and K. Lisa Yang Center for Autism Research (G.B.C.), the DFG grants CRC/TRR 128 project A07 and WA1600/8-1 (A.W.), the Howard Hughes Medical Institute (D.R.L.), the National Research Foundation of Korea grants MEST-35B-2011-E00012 (S.K.) and NRF-2014R1A1A1006089 (H.K.), the Searle Scholars Program (J.R.H.), the Pew Scholar for Biomedical Sciences (J.R.H.), the Kenneth Rainin Foundation (J.R.H.) and the National Institutes of Health grants R01DK106351 and R01DK110559 (J.R.H.).

Author information

Author notes

    • Jun R. Huh

    Present address: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA and Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Affiliations

  1. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Yeong Shin Yim
    • , Ashley Park
    • , Janet Berrios
    • , Mathieu Lafourcade
    • , Leila M. Pascual
    • , Natalie Soares
    • , Joo Yeon Kim
    • , Ian R. Wickersham
    • , Mark T. Harnett
    •  & Gloria B. Choi
  2. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Yeong Shin Yim
    • , Ashley Park
    • , Janet Berrios
    • , Mathieu Lafourcade
    • , Leila M. Pascual
    • , Natalie Soares
    • , Joo Yeon Kim
    • , Mark T. Harnett
    •  & Gloria B. Choi
  3. Division of Infectious Diseases and Immunology and Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Sangdoo Kim
    • , Hyunju Kim
    •  & Jun R. Huh
  4. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    • Ari Waisman
  5. Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA

    • Dan R. Littman
  6. Howard Hughes Medical Institute, New York, New York 10016, USA

    • Dan R. Littman

Authors

  1. Search for Yeong Shin Yim in:

  2. Search for Ashley Park in:

  3. Search for Janet Berrios in:

  4. Search for Mathieu Lafourcade in:

  5. Search for Leila M. Pascual in:

  6. Search for Natalie Soares in:

  7. Search for Joo Yeon Kim in:

  8. Search for Sangdoo Kim in:

  9. Search for Hyunju Kim in:

  10. Search for Ari Waisman in:

  11. Search for Dan R. Littman in:

  12. Search for Ian R. Wickersham in:

  13. Search for Mark T. Harnett in:

  14. Search for Jun R. Huh in:

  15. Search for Gloria B. Choi in:

Contributions

Y.S.Y., I.R.W., M.T.H., D.R.L., A.W., J.R.H., and G.B.C. designed the experiments and/or provided advice and technical expertise. Y.S.Y., A.P., J.B., M.L., L.M.P., N.S., J.Y.K., S.K., and H.K. performed the experiments. Y.S.Y., J.R.H., and G.B.C. wrote the manuscript with inputs from the co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jun R. Huh or Gloria B. Choi.

Reviewer Information Nature thanks C. Powell, W. Wetsel and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains supplementary details regarding the figure legends and supplementary statistic results.

  2. 2.

    Reporting Summary

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature23909

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing