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Cited by 277Tryptophan and brain disordersAutism Spectrum Disorder ResearchNeuroinflammation and Neurodegeneration Mechanisms

Activation of the maternal immune system alters cerebellar development in the offspring

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Shi, Limin, Smith, Stephen E.P., Malkova, Natalia, Tse, Doris, Su, Yixuan, Patterson, Paul H.·2009·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2008.07.012PMC PMC2614890
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Abstract

A common pathological finding in autism is a localized deficit in Purkinje cells (PCs). Cerebellar abnormalities have also been reported in schizophrenia. Using a mouse model that exploits a known risk factor for these disorders, maternal infection, we asked if the offspring of pregnant mice given a mid-gestation respiratory infection have cerebellar pathology resembling that seen in these disorders. We also tested the effects of maternal immune activation in the absence of virus by injection of the synthetic dsRNA, poly(I:C). We infected pregnant mice with influenza on embryonic day 9.5 (E9.5), or injected poly(I:C) i.p. on E12.5, and assessed the linear density of PCs in the cerebellum of adult or postnatal day 11 (P11) offspring. To study granule cell migration, we also injected BrdU on P11. Adult offspring of influenza- or poly(I:C)-exposed mice display a localized deficit in PCs in lobule VII of the cerebellum, as do P11 offspring. Coincident with this are heterotopic PCs, as well as delayed migration of granule cells in lobules VI and VII. The cerebellar pathology observed in the offspring of influenza- or poly(I:C)-exposed mice is strikingly similar to that observed in autism. The poly(I:C) findings indicate that deficits are likely caused by the activation of the maternal immune system. Finally, our data suggest that cerebellar abnormalities occur during embryonic development, and may be an early deficit in autism and schizophrenia.

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Crossref · 10.1016/j.bbi.2008.07.012

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  • Mouse MIA offspring show localized aberrations in Purkinje cells, similar to the localized deficits in cerebellar Purkinje cells that have been reported in many postmortem ASD cases.

    “mouse MIA offspring show localized aberrations in Purkinje cells98, similar to the localized deficits in cerebellar Purkinje cells that have been reported in many postmortem ASD cases99.”

    From Immune mediators in the brain and peripheral tissues in autism spectrum disorder (2015) · cites this paper as [99]

  • In follow-up work, pregnant mice challenged with influenza at E9.5 or poly(I:C) at E12.5 both had offspring with altered cerebellar development similar to autism.

    “both groups had offspring with altered cerebellar development, akin to that seen in autism”

    From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Shi et al, 2009

  • MIA mice have delayed cell development in the neocortex and reduced cell density and abnormal developmental migration in the cerebellum.

    “MIA mice have delayed cell development in the neocortex [333] and reduced cell density and abnormal developmental migration in the cerebellum [325].”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [325]

  • Mice and/or non-human primates exposed to maternal immune activation through maternal infection with poly(I:C) or maternal influenza infection have offspring that develop abnormal social behaviors, deficits in immune profiles and anxiety-like phenotypes.

    “Similarly, mice and/or non-human primates that are exposed to maternal immune activation (MIA) through maternal infection with the viral mimetic, polyinosinic: polycitidylic acid (poly (I:C)), or maternal influenza infection, have offspring that develop abnormal social behaviors 646566, deficits in their immune profiles and anxiety-like phenotypes 67.”

    From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [64]

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Research works printed but not linked: 2

  1. Hyman S Arndt TL Rodier PM 2006 Environmental agents and autism: Once and future associations International Review of Research in Mental Retardation 30 171 194
  2. Schmahmann JD 2001 The cerebrocerebellar system: Anatomic substrates of the cerebellar contribution to cognition and emotion International Review of Psychiatry 13 247 260

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Authors
Shi, L., Smith, S. E. P., Malkova, N., Tse, D., Su, Y., & Patterson, P. H.
Affiliations
California Institute of Technology (US)
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2009-01
Volume
23
Issue
1
Pages
116-123
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2008.07.012
PMC
PMC2614890
OpenAlex
W2157489226
Cited by
277
References
58
Citations by year
2026: 3 · 2025: 8 · 2024: 7 · 2023: 9 · 2022: 16 · 2021: 10 · 2020: 17 · 2019: 12 · 2018: 19 · 2017: 21 · 2016: 16 · 2015: 15 · 2014: 18 · 2013: 29 · 2012: 19
FWCI
5.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
  • Autism Speaks (AS1606)
  • National Institute of Mental Health (R01MH067978)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
maternal immune activation, cerebellar development, Purkinje cells, autism spectrum disorder, schizophrenia, influenza, poly(I:C), granule cell migration, prenatal infection, mouse model
MeSH terms
Age Factors, Animals, Animals, Newborn, Bromodeoxyuridine, Cell Movement, Cerebellum, Female, Humans, Immunohistochemistry, Influenza, Human, Interferon Inducers, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Microscopy, Fluorescence, Influenza A virus, Poly I-C, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Purkinje Cells, Respiratory Tract Infections, Mice

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