The DOI matches its Crossref record; 116 of the 117 references it cites were found in a registry or an index.
Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response
Open accessAbstract
Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Gene expression alterations also involve neuronal migration processes [128] that could underlie observed cortical layering defects, characterized by a 24% increase in neuron numbers in cortical layers II/III [131].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [128]
In the citing paper
“MIA strongly upregulates cell cycle gene expression and cell proliferation, and may cause brain overgrowth [127–129].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [128]
In the citing paper
“Both poly(I:C) and LPS affect maternal cytokine signaling (e.g., interleukin-6) that passes through the placenta to affect fetal brain development31”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [31]
In the citing paper
“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 [93]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Advances in autism genetics: on the threshold of a new neurobiology
Abrahams, B. S., & Geschwind, D. H. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2346 · Cited by 1,866 · cited 1×
“In addition, the placenta itself reacts strongly to MIA both morphologically and immunologically and likely contributes to fetal distress (Abrahams and Geschwind, 2008; Carpentier et al., 2011; Fatemi et al., 2011; Girard et al., 2010; Hauguel-de Mouzon and Guerre-Millo, 2006; Hsiao and Patterson,…”
Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Smith, S. E. P., Li, J., Garbett, K., Mirnics, K., & Patterson, P. H. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2178-07.2007 · Cited by 1,605 · cited 3×
“…perturb brain development remain unknown, but blocking the actions of the specific cytokines such as IL-6 or IL-1βprevents MIA-induced behavioral and physiological consequences in mouse offspring, offering further support for the cytokine hypothesis (Girard et al., 2010; Smith et al., 2007).”
Bellot, G., Garcia-Medina, R., Gounon, P., Chiche, J., Roux, D., Pouysségur, J., & Mazure, N. M. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00166-09 · Cited by 1,501 · cited 1×
“Bnip3 is a prominent and early responding hypoxia-induced cell death gene (Chinnadurai et al., 2008), and silencing of the gene using an siRNA suppresses hypoxia-induced autophagy (Bellot et al., 2009).”
Interneuron Migration from Basal Forebrain to Neocortex: Dependence on Dlx Genes
Anderson, S. A., Eisenstat, D. D., Shi, L., & Rubenstein, J. L. R. (1997) · Science · doi:10.1126/science.278.5337.474 · Cited by 1,462 · cited 2×
“Tangential migration from the ganglionic eminences to the cortex and hippocampus is virtually absent in double Dlx1/2 knock-out mice (Anderson et al., 1997; Cobos et al., 2005), whereas migration is fairly intact in single Dlx1 or Dlx2 knock-outs, but the mutants have fewer total numbers of…”
Autism spectrum disorders: developmental disconnection syndromes
Geschwind, D. H., & Levitt, P. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.01.009 · Cited by 1,411 · cited 1×
“Already evidence is surfacing to show that improper cortical interneuron development and function may play a role in maladaptive social behaviors associated with autism and schizophrenia (Belforte et al., 2009; Geschwind and Levitt, 2007; Levitt, 2005).”
Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4
Pålsson‐McDermott, E. M., & O'Neill, L. A. J. (2004) · Immunology · doi:10.1111/j.1365-2567.2004.01976.x · Cited by 1,254 · cited 1×
“The resulting activation of the transcription factor NF-κB induces pro-inflammatory cytokine expression (Palsson-McDermott and O'Neill, 2004).”
Welch, W. J. (1992) · Physiological Reviews · doi:10.1152/physrev.1992.72.4.1063 · Cited by 1,190 · cited 1×
“Members of the heat shock family of proteins, which respond to cellular stress signals including oxidative stress and hypoxia (Chi and Karliner, 2004; Tucker et al., 2011; Welch, 1992) were also significantly up-regulated in fetal brain further suggestive of intermittent fetal hypoxia.”
Serologic Evidence of Prenatal Influenza in the Etiology of Schizophrenia
Brown, A. S., Begg, M. D., Gravenstein, S., Schaefer, C. A., Wyatt, R. J., Bresnahan, M. A., Babulas, V. P., & Susser, E. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.8.774 · Cited by 1,048 · cited 2×
“, 2010; Ciaranello and Ciaranello, 1995) and schizophrenia (Brown et al., 2004).”
Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring
Shi, L., Fatemi, S. H., Sidwell, R. W., & Patterson, P. H. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-01-00297.2003 · Cited by 1,025 · cited 2×
“, 2007), influenza (Shi et al., 2003), or Borna disease virus (Pletnikov et al.”
Cytokines and the nervous system II: actions and mechanisms of action
Rothwell, N. J., & Hopkins, S. J. (1995) · Trends in Neurosciences · doi:10.1016/0166-2236(95)93890-a · Cited by 922 · cited 1×
“Cytokines are a class of secreted polypeptides that have diverse functions (Benveniste, 1998; Patterson and Nawa, 1993; Rothwell and Hopkins, 1995).”
Cited by
Sorted by citations
Maternal immune activation and abnormal brain development across CNS disorders
Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., Toovey, S., & Prinssen, E. P. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.187 · Cited by 880
The role of inflammation in perinatal brain injury
Hagberg, H., Mallard, C. E., Ferriero, D. M., Vannucci, S. J., Levison, S. W., Vexler, Z. S., & Gressèns, P. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.13 · Cited by 852
Fillman, S. G., Cloonan, N., Catts, V. S., Miller, L. C., Wong, J., McCrossin, T., Cairns, M., & Weickert, C. S. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.110 · Cited by 609
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
Hanamsagar, R., Alter, M. D., Block, C. S., Sullivan, H., Bolton, J. L., & Bilbo, S. D. (2017) · Glia · doi:10.1002/glia.23176 · Cited by 384
Metadata
- Authors
- Oskvig, D. B., Elkahloun, A. G., Johnson, K. R., Phillips, T. M., & Herkenham, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Herkenham, Miles
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 26
- Issue
- 4
- Pages
- 623-634
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC3285385
- OpenAlex
- W2052297858
- Cited by
- 248
- References
- 117
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 16 · 2023: 22 · 2022: 23 · 2021: 19 · 2020: 21 · 2019: 21 · 2018: 19 · 2017: 15 · 2016: 19 · 2015: 15 · 2014: 14 · 2013: 13 · 2012: 9
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH001090)
- National Human Genome Research Institute (ZICHG200365)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- maternal immune activation, lipopolysaccharide, oxidative stress, inflammatory cytokines, autism risk, schizophrenia risk, social behavior, brain development, prenatal infection, cortical development
- MeSH terms
- Amniotic Fluid, Animals, Autistic Disorder, Brain, Cell Movement, Exploratory Behavior, Female, Fetus, Interneurons, Lipopolysaccharides, Pregnancy, Pregnancy Complications, Infectious, Prenatal Exposure Delayed Effects, RNA, Messenger, Social Behavior, Transcription Factors, Down-Regulation, Cytokines, Rats, Sprague-Dawley, Oxidative Stress, Gene Expression Profiling, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
