Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice
Open accessAbstract
Approximately 40-50% of individuals affected by tuberous sclerosis (TSC) develop autism spectrum disorders (ASDs). One possible explanation for this partial penetrance is an interaction between TSC gene mutations and other risk factors such as gestational immune activation. In this study, we report the interactive effects of these two ASD risk factors in a mouse model of TSC. Combined, but not single, exposure had adverse effects on intrauterine survival. Additionally, provisional results suggest that these factors synergize to disrupt social approach behavior in adult mice. Moreover, studies in human populations are consistent with an interaction between high seasonal flu activity in late gestation and TSC mutations in ASD. Taken together, our studies raise the possibility of a gene × environment interaction between heterozygous TSC gene mutations and gestational immune activation in the pathogenesis of TSC-related ASD.
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Prior work provides some evidence in support of MIA-gene interactions, such as co-occurrence of MIA with TSC2 haploinsuffiency, rare de novo CNVs and PTEN mutations.
“Prior work provides some evidence in support of such MIA-gene interactions, such as co-occurrence of MIA with TSC2 haploinsuffiency,92 rare de novo CNVs93 and PTEN mutations.39”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [92]
Mice haploinsufficient for the TSC2 gene demonstrated a lack of normal social approach behavior only when exposed to maternal immune activation.
“mice haploinsufficient for the TSC2 gene demonstrated a lack of normal social approach behavior only when exposed to maternal immune activation.”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [106]
In a cohort of individuals with tuberous sclerosis, late gestation with peak seasonal flu activity was associated with ASD.
“the authors found an association of late gestation with peak seasonal flu activity specifically in individuals affected by ASD.”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [106]
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- Authors
- Ehninger, D., Sano, Y., de Vries, P. J., Dies, K., Franz, D., Geschwind, D. H., Kaur, M., Lee, Y.-S., Li, W., Lowe, J. K., Nakagawa, J. A., Sahin, M., Smith, K., Whittemore, V, & Silva, A. J.
- Affiliations
- University of California, Los Angeles (US)
- Boston Children's Hospital (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Ehninger, D
- Silva, A J
- Venue
- Molecular Psychiatry
- Published
- 2010-11-16
- Volume
- 17
- Issue
- 1
- Pages
- 62-70
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3118259
- OpenAlex
- W1981079086
- Cited by
- 120
- References
- 55
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 11 · 2022: 5 · 2021: 5 · 2020: 11 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 7 · 2015: 13 · 2014: 11 · 2013: 8 · 2012: 18
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-03-26)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- National Institutes of Health
- National Institute on Aging (R37AG013622)
- National Institute of Mental Health (R01MH084315)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- tuberous sclerosis complex, autism spectrum disorder, social behavior, gene-environment interaction, mouse model, ASD risk factors
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Age Factors, Animals, Animals, Newborn, Behavior, Animal, Child Development Disorders, Pervasive, Disease Models, Animal, Embryo, Mammalian, Exploratory Behavior, Female, Humans, Immunity, Active, Infant, Newborn, Male, Mice, Inbred C57BL, Mice, Transgenic, Poly I-C, Pregnancy, Pregnancy Complications, Social Behavior, Tumor Suppressor Proteins, Mice, Haploinsufficiency
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