Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism
Open accessAbstract
The core symptoms of autism are deficits in social interaction and language, and the presence of repetitive/stereotyped behaviors. We demonstrate that behaviors related to these symptoms are present in a mouse model of an environmental risk factor for autism, maternal infection. We stimulate the maternal immune system by injecting the viral mimic poly(I:C) during pregnancy, and analyze the social and communicative behaviors of the offspring. In one test, young pups respond to a brief separation from the mother with ultrasonic vocalizations (USVs). We find that, compared to pups born to saline-injected mothers, pups born to maternal immune activation (MIA) mothers produce a lower rate of USVs in the isolation test starting at day 8. The quality of the vocalizations is also different; analysis of sound spectrograms of 10 day-old pups shows that male pups from MIA mothers emit significantly fewer harmonic and more complex and short syllables. These communication differences are also apparent in adult offspring. Compared to controls, adult MIA males emit significantly fewer USVs in response to social encounters with females or males, and display reduced scent marking in response to female urine. Regarding a second autism symptom, MIA males display decreased sociability. In a third test of characteristic autism behaviors, MIA offspring exhibit increased repetitive/stereotyped behavior in both marble burying and self-grooming tests. In sum, these results indicate that MIA yields male offspring with deficient social and communicative behavior, as well as high levels of repetitive behaviors, all of which are hallmarks of autism.
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Maternal immune activation is associated with ASD risk.
“While mounting evidence points to the role of maternal immune activation in ASD risk,”
From The contribution of environmental exposure to the etiology of autism spectrum disorder (2019) · cites this paper as [103]
Animal models have yielded many insights into the effects and mechanisms of inflammation and immune activation, as well as the role of toxic agents, in inducing autism-like behaviors in rodent and other species.
“animal models have yielded many intriguing insights into the effects and mechanisms of inflammation and immune activation, as well as the role of toxic agents, in inducing autism-like behaviors in rodent and other species [103, 104, 112–115, 207].”
From The contribution of environmental exposure to the etiology of autism spectrum disorder (2019) · cites this paper as [103]
Poly(I:C) injection at mid-gestation in mice and non-human primates generates offspring that display all (in mice) or some (in non-human primates) of the three core behavioural symptoms of ASD.
“Poly(I:C) injection at mid-gestation in mice and non-human primates generates offspring that display all (in mice) or some (in non-human primates) of the three core behavioural symptoms of ASD95–97.”
From Immune mediators in the brain and peripheral tissues in autism spectrum disorder (2015) · cites this paper as [97]
In the MIA model, offspring of mice injected with polyinosinic-polycytidylic acid (poly(I:C)), a synthetic viral mimic that activates TLR3, demonstrate core symptoms of ASD, including repetitive behaviors, communication deficits, and decreased sociability.
“In the MIA model, offspring of mice injected with polyinosinic-polycytidylic acid (poly(I:C)), a synthetic viral mimic that activates TLR3, demonstrate core symptoms of ASD, including repetitive behaviors, communication deficits, and decreased sociability (Malkova et al., 2012).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Malkova et al., 2012
MIA models have ASD-like social, vocalization, ritualistic, exploration and other behavioral deficits.
“MIA models have ASD-like social, vocalization, ritualistic, exploration and other behavioral deficits [123–125].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [124]
Malkova et al. found that male MIA offspring had lower rates and total length of ultrasonic vocalizations, reduced sociability in the three-chamber test, and higher repetitive behaviors.
“The authors looked at ultrasonic vocalization (USV) responses among male offspring and found lower rates and total length of vocalizations.”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Malkova et al, 2012
The consequences of MIA include behavioral deficits of broad relevance to ASD.
“The consequences of MIA include behavioral deficits of broad relevance to ASD33, 34, 35”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [34]
Animal models of systemic prenatal infection induce deficits in social behavior in offspring.
“deficits in social behavior (Bitanihirwe et al., 2010; Machado et al., 2015; Malkova et al., 2012; Smith et al., 2007)”
From Neuroinflammation as a risk factor for attention deficit hyperactivity disorder (2019) · cites this paper as Malkova et al., 2012
Animal models of systemic prenatal infection induce increased repetitive behavior in offspring.
“increased repetitive behavior (Malkova et al., 2012; Smith et al., 2007)”
From Neuroinflammation as a risk factor for attention deficit hyperactivity disorder (2019) · cites this paper as Malkova et al., 2012
Maternal infection is a primary environmental risk factor for ASD.
“Maternal infection is a primary environmental risk factor for ASD based on numerous epidemiological, clinical and animal studies (93–98).”
From Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder (2017) · cites this paper as [96]
Maternal immune activation has been shown to cause increased gut permeability and gut dysbiosis.
“Interestingly, MIA has also been shown to cause increased gut permeability and gut dysbiosis 6869.”
From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [69]
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- Authors
- Malkova, N. V., Yu, C. Z., Hsiao, E. Y., Moore, M. J., & Patterson, P. H.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Malkova, Natalia V.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 26
- Issue
- 4
- Pages
- 607-616
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC3322300
- OpenAlex
- W2125531274
- Cited by
- 662
- References
- 66
- Citations by year
- 2026: 37 · 2025: 29 · 2024: 45 · 2023: 45 · 2022: 54 · 2021: 52 · 2020: 65 · 2019: 49 · 2018: 51 · 2017: 47 · 2016: 53 · 2015: 49 · 2014: 26 · 2013: 39 · 2012: 21
- FWCI
- 22.09
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Autism Speaks (AS7670)
- National Institute of Mental Health (F31MH090749, R01MH086781, R01MH067978)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- maternal immune activation, autism spectrum disorder, poly(I:C), maternal infection, ultrasonic vocalizations, social communication, sociability, repetitive behavior, scent marking, sex differences, mouse model
- MeSH terms
- Animals, Autistic Disorder, Disease Models, Animal, Female, Grooming, Male, Mice, Inbred C57BL, Pregnancy, Pregnancy Complications, Infectious, Prenatal Exposure Delayed Effects, Social Behavior, Stereotyped Behavior, Vocalization, Animal, Mice
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