Maternal Inflammation Contributes to Brain Overgrowth and Autism-Associated Behaviors through Altered Redox Signaling in Stem and Progenitor Cells
Open accessAbstract
A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX)-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species.
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Such augmented disruption occurs via activation of cellular redox signaling in response to infection.
“Such augmented disruption occurs via the activation of the cellular redox signaling in response to infection [130,133].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [130]
Brain enlargement due to Pten haploinsufficiency in mouse increased from 8 to 44% when combined with MIA, demonstrating interactive effects of MIA and ASD gene mutations in disruption of cortical development.
“Work by Le Belle et al. [130] identified that brain enlargement due to Pten haploinsufficiency in mouse increased from 8 to 44% when combined with MIA, thus demonstrating the interactive effects of MIA and ASD gene mutations in the disruption of cortical development.”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [130]
Similar to some ASD cases, MIA induces overproduction of neurons, and increases cortical thickness and brain size as seen in many toddlers with ASD.
“Similar to some ASD cases, MIA induces overproduction of neurons [129], and increases cortical thickness [129, 130] and brain size [130] as seen in many toddlers with ASD [5, 8, 10, 13, 14, 18].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [130]
Multiple perturbations may substantially amplify both the severity of disorder and outcome heterogeneity, such as a combination of PTEN mutation and MIA.
“Multiple perturbations may substantially amplify both the severity of disorder and outcome heterogeneity, such as, for example, a combination of PTEN mutation and MIA [130].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [130]
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 [39]
Increased proliferation of neural progenitor cells associated with brain overgrowth was observed after low-dose LPS treatment and was more pronounced in a Pten haploinsufficient background, demonstrating clear genetic-environmental effects on early brain growth.
“Increased proliferation of neural progenitor cells associated with brain overgrowth was observed after low-dose LPS treatment and was more pronounced in a Pten haploinsufficient background, demonstrating clear genetic–environmental effects on early brain growth.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 [39]
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 [94]
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Cites
Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism
Hallmayer, J. (2011) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.76 · Cited by 1,970 · see citing works
Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology
Voineagu, I., Wang, X., Johnston, P., Lowe, J. K., Tian, Y., Horvath, S., Mill, J., Cantor, R. M., Blencowe, B. J., & Geschwind, D. H. (2011) · Nature · doi:10.1038/nature10110 · Cited by 1,874 · cited 11× · see citing works
“Mutations in PTEN affect only 1 in 242,063 individuals in the general population, but are found in approximately 4%of ASD individuals (Hobert et al., 2013; Varga et al., 2009).”
BackgroundInfluentialEvidence of Brain Overgrowth in the First Year of Life in Autism
Courchesne, E. (2003) · JAMA · doi:10.1001/jama.290.3.337 · Cited by 1,120 · see citing works
Peñagarikano, O., Abrahams, B. S., Herman, E. I., Winden, K. D., Gdalyahu, A., Dong, H., Sonnenblick, L. I., Gruver, R., Almajano, J., Bragin, A., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.040 · Cited by 1,075 · see citing works
Microglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex
Cunningham, C. L., Martínez-Cerdeño, V., & Noctor, S. C. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3441-12.2013 · Cited by 976 · see citing works
Le Belle, J. E., Orozco, N. M., Paucar, A. A., Saxe, J. P., Mottahedeh, J., Pyle, A. D., Wu, H., & Kornblum, H. I. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2010.11.028 · Cited by 789 · see citing works
Self-citationNeuron Number and Size in Prefrontal Cortex of Children With Autism
Courchesne, E., Mouton, P. R., Calhoun, M. E., Semendeferi, K., Ahrens-Barbeau, C., Hallet, M. J., Barnes, C. C., & Pierce, K. (2011) · JAMA · doi:10.1001/jama.2011.1638 · Cited by 779 · see citing works
Patches of Disorganization in the Neocortex of Children with Autism
Stoner, R., Chow, M. L., Boyle, M. P., Sunkin, S. M., Mouton, P. R., Roy, S., Wynshaw-Boris, A., Colamarino, S. A., Lein, E. S., & Courchesne, E. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1307491 · Cited by 722 · see citing works
Schumann, C. M., Bloss, C. S., Barnes, C. C., Wideman, G. M., Carper, R. A., Akshoomoff, N., Pierce, K., Hagler, D., Schork, N., Lord, C., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5714-09.2010 · Cited by 554 · see citing works
Mouse Behavioral Assays Relevant to the Symptoms of Autism*
Crawley, J. N. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00096.x · Cited by 541 · cited 2× · see citing works
“Ultrasonic vocalization, three-chamber social interaction, and elevated plus maze tests were performed on adult mice according to the methods of Crawley (2007).”
MethodMaternal infection and immune involvement in autism
Patterson, P. H. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.03.001 · Cited by 520 · see citing works
Neuron Number and Size in Prefrontal Cortex of Children With Autism
Stockman, J. A. (2012) · Yearbook of Pediatrics · doi:10.1016/j.yped.2011.12.022 · Cited by 491 · see citing works
Rose, S., Melnyk, S., Pavliv, O., Bai, S., Nick, T. G., Frye, R. E., & James, S. J. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.61 · Cited by 480 · see citing works
Groszer, M., Erickson, R., Scripture-Adams, D. D., Dougherty, J. D., Le Belle, J., Zack, J. A., Geschwind, D. H., Liu, X., Kornblum, H. I., & Wu, H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509939103 · Cited by 306 · see citing works
Self-citationVarga, E. A., Pastore, M., Prior, T. W., Herman, G. E., & McBride, K. L. (2009) · Genetics in Medicine · doi:10.1097/gim.0b013e31818fd762 · Cited by 293 · see citing works
Pten Deletion in Adult Neural Stem/Progenitor Cells Enhances Constitutive Neurogenesis
Gregorian, C., Nakashima, J. K., Belle, J. E. L., Ohab, J. J., Kim, R., Liu, A., Smith, K. B., Groszer, M., Garcia, A. D. R., Sofroniew, M. V., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3095-08.2009 · Cited by 265 · see citing works
Self-citationFatemi, S. H., Earle, J., Kanodia, R., Kist, D., Emamian, E. S., Patterson, P. H., Shi, L., & Sidwell, R. (2002) · Cellular and Molecular Neurobiology · doi:10.1023/a:1015337611258 · Cited by 261 · see citing works
Large Brains in Autism: The Challenge of Pervasive Abnormality
Herbert, M. R. (2005) · The Neuroscientist · doi:10.1177/0091270005278866 · Cited by 199 · see citing works
PTEN signaling in autism spectrum disorders
Zhou, J., & Parada, L. F. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.05.004 · Cited by 188 · see citing works
Bauman, M. D., Iosif, A.-M., Ashwood, P., Braunschweig, D., Lee, A., Schumann, C. M., Van de Water, J., & Amaral, D. G. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.47 · Cited by 174 · see citing works
Luo, R., Sanders, S. J., Tian, Y., Voineagu, I., Huang, N., Chu, S. H., Klei, L., Cai, C., Ou, J., Lowe, J. K., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.05.011 · Cited by 167 · see citing works
Genetic advances in autism: heterogeneity and convergence on shared pathways
Bill, B. R., & Geschwind, D. H. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.04.004 · Cited by 164 · see citing works
Macrocephaly in autism and other pervasive developmental disorders
Fidler, D. J., Bailey, J. N., & Smalley, S. L. (2000) · Developmental Medicine & Child Neurology · doi:10.1017/s0012162200001365 · Cited by 157 · see citing works
Endogenous microglia regulate development of embryonic cortical precursor cells
Antony, J. M., Paquin, A., Nutt, S. L., Kaplan, D. R., & Miller, F. D. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22533 · Cited by 157 · see citing works
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., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2010.115 · Cited by 120 · see citing works
Self-citationClinical, Morphological, and Biochemical Correlates of Head Circumference in Autism
Sacco, R., Militerni, R., Frolli, A., Bravaccio, C., Gritti, A., Elia, M., Curatolo, P., Manzi, B., Trillo, S., Lenti, C., et al. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.04.039 · Cited by 120 · see citing works
NADPH oxidase is involved in post-ischemic brain inflammation
Chen, H., Kim, G. S., Okami, N., Narasimhan, P., & Chan, P. H. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.01.027 · Cited by 116 · see citing works
Nordahl, C. W., Braunschweig, D., Iosif, A.-M., Lee, A., Rogers, S., Ashwood, P., Amaral, D. G., & Van de Water, J. (2013) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2013.01.084 · Cited by 95 · see citing works
Macrocephaly as a Clinical Indicator of Genetic Subtypes in Autism
Klein, S. D., Sharifi‐Hannauer, P., & Martínez-Agosto, J. A. (2013) · Autism Research · doi:10.1002/aur.1266 · Cited by 94 · see citing works
Hobert, J. A., Embacher, R. A., Mester, J. L., Frazier, T. W., & Eng, C. (2013) · European Journal of Human Genetics · doi:10.1038/ejhg.2013.114 · Cited by 84 · see citing works
Seaberg, R. M., Smukler, S. R., & van der Kooy, D. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.10.017 · Cited by 62 · see citing works
Beloosesky, R., Weiner, Z., Ginsberg, Y., & Ross, M. G. (2012) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.3109/14767058.2011.632793 · Cited by 31 · see citing works
Clement, H., Vazquez-Costa, J. F., Sommer, O., Heiser, P., Morawietz, H., Hopt, U. T., Schulz, E., & von Dobschütz, E. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0327-5 · Cited by 29 · see citing works
Rebello, C. M., & Ramos, J. L. A. (2006) · Clinics · doi:10.1590/s1807-59322006000200007 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Chronic inflammation in the etiology of disease across the life span
Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., Ferrucci, L., Gilroy, D. W., Fasano, A., Miller, G. W., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0675-0 · Cited by 4,915 · see citing works
Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder
Vuong, H. E., & Hsiao, E. Y. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.08.024 · Cited by 595 · see citing works
The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders
Réus, G. Z., Fries, G. R., Stertz, L., Badawy, M., Passos, I. C., Barichello, T., Kapczinski, F., & Quevedo, J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.05.018 · Cited by 594 · see citing works
Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects
Kim, H.-J., Cho, M.-H., Shim, W. H., Kim, J. K., Jeon, E.-Y., Kim, D.-H., & Yoon, S.-Y. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.103 · Cited by 475 · see citing works
The ASD Living Biology: from cell proliferation to clinical phenotype
Courchesne, E., Pramparo, T., Gazestani, V. H., Lombardo, M. V., Pierce, K., & Lewis, N. E. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0056-y · Cited by 333 · see citing works
Lombardo, M. V., Moon, H. M., Su, J., Palmer, T. D., Courchesne, E., & Pramparo, T. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.15 · Cited by 201 · see citing works
Mor, M., Nardone, S., Sams, D. S., & Elliott, E. (2015) · Molecular Autism · doi:10.1186/s13229-015-0040-1 · Cited by 118 · see citing works
Pierce, K., Courchesne, E., & Bacon, E. (2016) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2016.06.004 · Cited by 91 · see citing works
Klocke, C., Allen, J. L., Sobolewski, M., Mayer-Pröschel, M., Blum, J. L., Lauterstein, D., Zelikoff, J. T., & Cory-Slechta, D. A. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx010 · Cited by 87 · see citing works
Hierarchical cortical transcriptome disorganization in autism
Lombardo, M. V., Courchesne, E., Lewis, N. E., & Pramparo, T. (2016) · doi:10.1101/042937 · Cited by 7 · see citing works
- Authors
- Le Belle, J. E., Sperry, J., Ngo, A., Ghochani, Y., Laks, D. R., López-Aranda, M., Silva, A. J., & Kornblum, H. I.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Kornblum, Harley I.
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 3
- Issue
- 5
- Pages
- 725-734
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC4235743
- OpenAlex
- W2110691073
- Cited by
- 105
- References
- 34
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 3 · 2023: 8 · 2022: 14 · 2021: 12 · 2020: 8 · 2019: 11 · 2018: 10 · 2017: 7 · 2016: 12 · 2015: 8 · 2014: 1
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of Mental Health (R01MH065756, R01MH084315, MH65756)
- National Cancer Institute (CA-16 042, P30CA016042)
- National Institute of Allergy and Infectious Diseases (AI-28 697, P30AI028697)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD055784)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- maternal inflammation, brain overgrowth, autism spectrum disorder, neural stem cells, progenitor cells, redox signaling, reactive oxygen species, lipopolysaccharide, NADPH oxidase, PI3K signaling, microglia, neural stem cell proliferation
- MeSH terms
- Animals, Animals, Newborn, Autistic Disorder, Brain, Cells, Cultured, Female, Grooming, Inflammation, Lipopolysaccharides, Male, Oxidation-Reduction, Pregnancy, Prenatal Exposure Delayed Effects, Stem Cells, Blotting, Western, Signal Transduction, Reactive Oxygen Species, Microglia, Maze Learning, NADPH Oxidases, Phosphatidylinositol 3-Kinases, Cell Proliferation, Mice
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