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Cited by 201Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersTryptophan and brain disorders

Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

Open access
Lombardo, M V, Moon, H M, Su, J, Palmer, T D, Courchesne, E, Pramparo, T·2018·Molecular Psychiatry
DOI 10.1038/mp.2017.15PMC PMC5608645

Published version of a preprint

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Abstract

Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

Maternal immune activation (MIA) in rodent models broadly dysregulates the fetal brain transcriptome, especially downregulating ASD-associated genes and upregulating translation/cell-cycle programs. These MIA effects overlap with ASD cortical transcriptome dysregulation, particularly via the Tsc1/2–mTOR–EIF4E translation-initiation axis.

Key findings

  • In the rat MIA dataset at 4 h post-LPS, 4,959 genes were downregulated and 4,033 upregulated at FDR q<0.01; at 24 h there was little DE signal (one downregulated gene, MAIN; two upregulated, LCP2 and RPL39, at q<0.05; none at q<0.01).
  • MIA-downregulated genes were enriched for ASD-associated classes: likely gene-disrupting variants 57% (20/35), OR=5.95, P=9.44e-6; SFARI High Confidence 75% (12/16), OR=13.38, P=1.18e-5; FMRP targets Darnell OR=7.81, P=2.56e-127 and Ascano OR=2.07, P=1.75e-30.
  • ASD cortical transcriptome overlap was significant: ASD-downregulated genes enriched in MIA-downregulated genes (Voineagu OR=1.26, P=0.024; Gupta OR=2.22, P=7.16e-21), and ASD-upregulated genes enriched in MIA-upregulated genes (Voineagu OR=1.57, P=9.56e-5; Gupta OR=1.69, P=3.84e-7). However, 94–97% of MIA-downregulated and 96–97% of MIA-upregulated genes were not commonly dysregulated in older child/adult ASD cortex.
  • The translation-initiation module M25 was replicably upregulated in ASD and preserved in MIA (Zsummary 8.5 and 8.8); EIF4E had the largest effect size among ASD-associated genes (Cohen’s d=8.27). Mouse MIA validation replicated downregulation of Tsc2 (t=−2.91, P=0.012), mTor (t=−2.83, P=0.012), Eif4ebp1 (t=−3.77, P=0.0024), Eif4ebp2 (t=−5.05, P=0.00078), and upregulation of Eif4e (t=2.13, P=0.029).

Methods

  • Reanalysis of a rat MIA microarray dataset (GEO GSE34058; LPS on gestational day 15; 4 h and 24 h post-injection) plus two post-mortem ASD cortical transcriptome datasets (Voineagu microarray, GSE28521; Gupta RNAseq).
  • Differential expression used sva/limma for rat MIA and linear mixed-effect models for ASD datasets with FDR correction; weighted gene co-expression network analysis (WGCNA) identified ASD consensus modules and tested preservation in MIA; MetaCore GeneGO was used for enrichment and network analyses.
  • Cross-species validation used an independent mouse MIA model (LPS at E12.5; seven LPS-treated offspring, six saline controls) with qRT-PCR for Tsc1/2, mTor, Eif4e, Eif4ebp1/2, and Rps6ka6.

Limitations

  • The paper states that future work is needed to compare different immunogens (LPS vs poly(I:C)) and that MIA is a temporally transient event, unlike persistent genetic mutations.
  • The paper notes that mature ASD cortex may provide limited insight into prenatal functional genomic pathology and could be prone to false negatives for early developmental processes.
  • Evident from the text: the main MIA transcriptome findings come from reanalysis of one rat LPS dataset, and the cross-species validation is limited to qRT-PCR of selected Tsc1/2–mTOR–EIF4E axis genes rather than genome-wide or behavioral/cellular validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/mp.2017.15

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 109 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e axis was validated across MIA rodent models.

    “This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models.”
    Quote in the paperSubstantial claim
  • Findingown data

    MIA downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life.

    “MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life”
    Quote in the paperSubstantial claim
  • Findingown data

    Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are heavily affected by MIA.

    “Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA.”
    Quote in the paperSubstantial claim
  • Findingown data

    MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions.

    “MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions.”
    • Also stated in: § Results · plain
      “In contrast, MIA-upregulated genes displayed predominant enrichment in processes that can play key roles in neurogenesis and early brain development, such as translation, cell cycle, DNA damage and proteolysis processes (Figure 2a)”
    Quote in the paperSubstantial claim
  • Findingown data

    EIF4E is one of the most MIA-dysregulated of all ASD-associated genes.

    “The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes”
    Quote in the paperSubstantial claim
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations.

    “MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations.”
    • Also stated in: § Classes of ASD-associated genes are enriched with MIA-downregulated genes · plain
      “Remarkably, 57% (20/35) of LGD genes were present in the MIA-downregulated gene set, amounting to a substantial enrichment (OR=5.95, P=9.44e-6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life.

    “Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only 9 of the 84 genes were DE in ASD brains, resulting in a nonsignificant enrichment (OR=1.21, P=0.46).

    “Although only 9 of the 84 genes were DE in ASD brains resulting in a nonsignificant enrichment (OR=1.21, P=0.46)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The PI3K-TSC1/2-mTOR-EIF4E axis is significantly enriched in genes DE in MIA (OR=4.006, P=7.14e-5) and in M25 targets (OR=22.09, P=1.89e-36).

    “We found significant enrichments for genes DE in MIA (OR=4.006, P=7.14e-5) and for M25 targets (OR=22.09, P=1.89e-36) (Figure 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In human neural progenitor cells, both MIA-downregulated and MIA-upregulated genes are enriched in CHD8 targets.

    “In human neural progenitor cells both MIA-downregulated (OR=1.66, P=1.58e-7) and upregulated genes (OR=2.71, P=8.29e-87) were enriched in CHD8 targets75 (Figure 2b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P et al. CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc Natl Acad Sci USA 2014; 111: E4468–E4477. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Modules M3, M9 and M13 were replicably downregulated in Voineagu and Gupta ASD datasets and were enriched in a variety of synaptic functions.

    “Modules M3, M9 and M13 were replicably downregulated in Voineagu and Gupta ASD datasets, and were enriched in a variety of synaptic functions (Figure 3b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 2011; 474: 380–384. source

      Not checked in the free run.

    • cites [51] Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 2014; 5: 5748. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    94-97% of MIA-downregulated genes and 96-97% of MIA-upregulated genes were not commonly dysregulated in older child and adult ASD cortical tissue.

    “That is, 94–97% of MIA-downregulated genes and 96–97% of MIA-upregulated genes were not commonly dysregulated in older child and adult ASD cortical tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    M25 was replicably upregulated in post-mortem ASD cortical tissue and was heavily enriched in translation initiation and translation elongation-termination.

    “M25 was replicably upregulated in post-mortem ASD cortical tissue, and was heavily enriched in translation initiation and translation elongation-termination (Figure 3a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    M25 was the top hit in terms of preservation median rank and was the most preserved of any of the replicable DE modules with Zsummary preservation statistics of 8.5 and 8.8 across Voineagu and Gupta ASD datasets.

    “M25 was the top hit in terms of preservation median rank and was the most preserved of any of the replicable DE modules with Zsummary preservation statistics of 8.5 and 8.8 (indicating ‘moderate’ preservations), respectively, across Voineagu and Gupta ASD datasets (Figure 3c).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 2011; 474: 380–384. source

      Not checked in the free run.

    • cites [51] Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 2014; 5: 5748. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    At 4 h post-LPS, MIA causes massive transcriptome dysregulation: 6923 downregulated and 4981 upregulated genes at FDR q<0.05, and 4959 downregulated and 4033 upregulated genes at FDR q<0.01.

    “Generally consistent with analyses in Oskvig et al., here we found evidence for massive MIA transcriptome dysregulation at 4 h post-LPS injection. At an FDR q<0.05 there were 6923 downregulated genes (7561 probes) and 4981 upregulated genes (5513 probes).”
    • Also stated in: § Results · plain
      “we utilized an FDR threshold of q<0.01, which yielded 4959 downregulated genes (5398 probes) and 4033 upregulated genes (4462 probes)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four consensus modules in ASD, M25, M3, M9 and M13, show replicable on-average DE in both the Voineagu and Gupta datasets and moderate levels of preservation in the MIA dataset.

    “We identified four consensus modules in ASD, M25, M3, M9 and M13, that show replicable on-average DE in both the Voineagu and Gupta datasets, and also showed moderate levels of preservation in the MIA dataset.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 2011; 474: 380–384. source

      Not checked in the free run.

    • cites [51] Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 2014; 5: 5748. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    MIA-downregulated genes are substantially enriched in SFARI ASD-associated gene categories, with the strongest enrichment in the High Confidence category, followed by Syndromic, Strong and Suggestive categories.

    “The strongest enrichments by enrichment odds ratio were within the SFARI High Confidence category (75%, 12/16, OR=13.38, P=1.18e-5), followed by Syndromic (54%, 25/46, OR=5.32, P=2.57e-6), Strong (41%, 10/24, OR=3.18, P=0.0277) and Suggestive gene categories (40%, 27/67, OR=3.01, P=7.91e-4) (Figure 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    57% (20/35) of likely gene-disrupting (LGD) ASD genes are present in the MIA-downregulated gene set, a substantial enrichment (OR=5.95, P=9.44e-6).

    “Remarkably, 57% (20/35) of LGD genes were present in the MIA-downregulated gene set, amounting to a substantial enrichment (OR=5.95, P=9.44e-6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 24 h post-LPS, there is little differential expression signal: only one downregulated gene and two upregulated genes at FDR q<0.05, and no DE genes at FDR q<0.01.

    “In contrast to the 4 h dataset, a dataset measured 24 h post-LPS injection (24 h) yielded little DE signal, with only one downregulated gene (MAIN) and two upregulated genes (LCP2, RPL39) at FDR q<0.05, and no DE genes at FDR q<0.01.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the MIA mouse model, there was significant MIA downregulation of Tsc2 (t=−2.91, P=0.012), mTor (t=−2.83, P=0.012), Eif4ebp1 (t=−3.77, P=0.0024) and Eif4ebp2 (t=−5.05, P=0.00078).

    “Consistent with the MIA rat gene expression findings, we replicated the effect of significant MIA downregulation of Tsc2 (t=−2.91, P=0.012), mTor (t=−2.83, P=0.012), Eif4ebp1 (t=−3.77, P=0.0024) and Eif4ebp2 (t=−5.05, P=0.00078).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MIA-downregulated, but not MIA-upregulated, genes are enriched in CHD8 targets identified in midgestation fetal brain tissue and human neural stem cells.

    “The MIA-downregulated (OR=2.10, P=3.52e-25), but not MIA-upregulated (OR=1.19, P=0.84) genes were enriched in CHD8 targets identified in midgestation fetal brain tissue and human neural stem cells.74”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W et al. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun 2015; 6: 6404. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Both TSC2 and PTEN are among the genes that are MIA-downregulated within the current dataset.

    “Intriguingly, both TSC2 and PTEN are among the genes that are MIA-downregulated within the current dataset”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MIA induces reproducible upregulation of EIF4E and downregulation of two binding proteins (EIF4EBP1/2).

    “Our evidence, showing reproducible MIA-induced upregulation of EIF4E and downregulation of two binding proteins (EIF4EBP1/2), suggest a possible imbalance in the regulation of neurogenic versus neural progenitor divisions during development.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Common variants may significantly contribute to a large proportion (up to 60%) of genetic liability for ASD.

    “common variants may also significantly contribute to a large proportion (up to 60%) of genetic liability for ASD,7, 8”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 2012; 3: 9. source

      Not checked in the free run.

    • cites [8] Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB et al. Most genetic risk for autism resides with common variation. Nat Genet 2014; 46: 881–885. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rare high-confidence mutations tend to be significantly enriched in genes involved in synaptic functions, transcriptional regulation, and chromatin remodeling functions, and/or are downstream targets of the fragile X syndrome protein (FMRP) complex.

    “such rare high-confidence mutations tend to be significantly enriched in genes involved in synaptic functions, transcriptional regulation, and chromatin remodeling functions, and/or are downstream targets of the fragile X syndrome protein (FMRP) complex.1, 3”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014; 515: 209–215. source

      Not checked in the free run.

    • cites [3] Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 2014; 515: 216–221. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Evidence from twin studies suggests that heritability is quite high and there is also a substantial environmental component for ASD susceptibility.

    “evidence from twin studies suggest that while heritability is quite high,9 there is also a substantial environmental component for ASD susceptibility.10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A . The familial risk of autism. JAMA 2014; 311: 1770–1777. source

      Not checked in the free run.

    • cites [10] Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 2011; 68: 1095–1102. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Key to this mechanism is the aberrant regulation of the PI3K-TSC1/2-mTOR signaling pathways, which in turn are responsible for the regulation of ribosomal protein S6 kinase (RPS6K) and EIF4E-binding partners (EIF4EBP1/2), acting to promote translation initiation.

    “Key to this mechanism is the aberrant regulation of the PI3K–TSC1/2–mTOR signaling pathways, which in turn are responsible for the regulation of ribosomal protein S6 kinase (RPS6K) and EIF4E-binding partners (EIF4EBP1/2), acting to promote translation initiation.80”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Chen J, Alberts I, Li X . Dysregulation of the IGF-I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders. Int J Dev Neurosci 2014; 35: 35–41. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Overall evidence supports that MIA does not directly affect FMR1 or CHD8 but potentially disrupts the same pathways by hitting their downstream targets.

    “Overall, this evidence supports our hypothesis that while MIA does not directly affect FMR1 or CHD8, two key genes with important transcriptional regulatory effects, it does potentially disrupt the same pathways by hitting their downstream targets.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The MIA-induced transcriptomic changes observed in rat fetal brain are informative about human fetal brain development and ASD pathophysiology.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The one-tailed predictions for qRT-PCR tests are justified by the directionality of differential expression observed in the rat microarray MIA dataset.

    “The one-tailed predictions are justified by the directionality of DE observed in the rat microarray MIA dataset.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control for multiple comparisons in qRT-PCR analyses was achieved by setting the FDR threshold to q<0.05.

    “Control for multiple comparisons was achieved by setting the FDR threshold to q<0.05.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mTOR has two main direct substrates, RPS6K and eukaryotic translation initiation factor 4E-binding proteins (EIF4EBP1/2), that are responsible for activating further downstream signaling pathways to regulate translational machinery.

    “mTOR has two main direct substrates, RPS6K and eukaryotic translation initiation factor 4E-binding proteins (EIF4EBP1/2), that are responsible for activating further downstream signaling pathways to regulate translational machinery.89”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Hay N, Sonenberg N . Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926–1945. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The ASD-upregulated translation initiation-enriched M25 module, which is preserved in MIA, may influence expression and activity of both PI3K-TSC1/2-mTOR signaling and EIF4E-dependent genes with predicted early neurodevelopmental effects on the timing of cell cycle phases during neural progenitor cell divisions.

    “These findings suggest that the ASD-upregulated translation initiation-enriched M25 module, which is preserved in MIA, may influence expression and activity of both PI3K–TSC1/2–mTOR signaling and EIF4E-dependent genes with predicted early neurodevelopmental effects on the timing of cell cycle phases during neural progenitor cell divisions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    mTOR kinase plays pivotal roles as a master regulator to integrate environmental cues and to modulate translation, cell growth, survival and proliferation.

    “Of note, mTOR kinase plays pivotal roles as a master regulator to integrate environmental cues and to modulate translation, cell growth, survival and proliferation.84”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Huber KM, Klann E, Costa-Mattioli M, Zukin RS . Dysregulation of mammalian target of rapamycin signaling in mouse models of autism. J Neurosci 2015; 35: 13836–13842. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These signaling pathways lead to the overexpression and activation of EIF4E-dependent mechanisms that have been directly linked to ASD, both in mouse models and humans.

    “Ultimately, these signaling pathways lead to the overexpression and activation of EIF4E-dependent mechanisms that have been directly linked to ASD, both in mouse models and humans.88”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Neves-Pereira M, Muller B, Massie D, Williams JH, O'Brien PC, Hughes A et al. Deregulation of EIF4E: a novel mechanism for autism. J Med Genet 2009; 46: 759–765. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exaggerated cap-dependent translation is a well-known molecular mechanism regulating neurogenesis and contributing to synaptic and behavioral phenotypes associated with ASD and related neurodevelopmental disorders.

    “Exaggerated cap-dependent translation is a well-known molecular mechanism regulating neurogenesis77 and contributing to synaptic and behavioral phenotypes associated with ASD and related neurodevelopmental disorders.78, 79”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [77] Yang G, Smibert CA, Kaplan DR, Miller FD . An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron 2014; 84: 723–739. source

      Not checked in the free run.

    • cites [78] Kelleher RJ 3rd, Bear MF . The autistic neuron: troubled translation? Cell 2008; 135: 401–406. source

      Not checked in the free run.

    • cites [79] Santini E, Klann E . Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci Signal 2014; 7: re10. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Loss-of-function of the TSC1/2 complex has been implicated in ASD etiology and is an important upstream effector of mTOR-dependent signaling cascades.

    “Loss-of-function of the TSC1/2 complex has been implicated in ASD etiology81, 82 and is an important upstream effector of mTOR-dependent signaling cascades.83”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [81] Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002; 4: 699–704. source

      Not checked in the free run.

    • cites [82] Smalley SL . Autism and tuberous sclerosis. J Autism Dev Disord 1998; 28: 407–414. source

      Not checked in the free run.

    • cites [83] Inoki K, Li Y, Xu T, Guan KL . Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17: 1829–1834. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    MIA dysregulates systems-level structure of transcriptome in a manner similar to the dysregulation present in the ASD cortical transcriptome, with emphasis on upregulation of translation initiation processes as the strongest preserved signal across MIA and ASD.

    “These results further strengthen the evidence that MIA dysregulates systems-level structure of transcriptome in a manner similar to the dysregulation present in the ASD cortical transcriptome, with emphasis on upregulation of translation initiation processes as the strongest preserved signal across MIA and ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The rat gestational day 15 LPS manipulation corresponds roughly to post-conception day 68 of human prenatal cortical development, analogous to the end of the first trimester of pregnancy.

    “This manipulation in rat corresponds roughly to post-conception day 68 of human prenatal cortical development, which is analogous to the end of the first trimester of pregnancy66”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Clancy B, Darlington RB, Finlay BL . Translating developmental time across mammalian species. Neuroscience 2001; 105: 7–17. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In prior work, upregulation of translation initiation was demonstrated in postnatal blood leukocyte expression in ASD toddlers.

    “In prior work, we demonstrated upregulation of translation initiation in postnatal blood leukocyte expression in ASD toddlers.98”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Pramparo T, Pierce K, Lombardo MV, Carter Barnes C, Marinero S, Ahrens-Barbeau C et al. Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. JAMA Psychiatry 2015; 72: 386–394. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MIA alters proliferation of cortical neural progenitor cells, laminar allocation of neurons, increased cortical thickness, increased cell density and patches of cortical dysplasia.

    “MIA alters proliferation of cortical neural progenitor cells, laminar allocation of neurons, increased cortical thickness, increased cell density and patches of cortical dysplasia.32, 38, 42”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science (New York, NY) 2016; 351: 933–939. source

      Not checked in the free run.

    • cites [38] Smith SE, Elliott RM, Anderson MP . Maternal immune activation increases neonatal mouse cortex thickness and cell density. J Neuroimmune Pharmacol 2012; 7: 529–532. source

      Not checked in the free run.

    • cites [42] Soumiya H, Fukumitsu H, Furukawa S . Prenatal immune challenge compromises the normal course of neurogenesis during development of the mouse cerebral cortex. J Neurosci Res 2011; 89: 1575–1585. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    MIA upregulation of cell cycle processes and increased neurogenesis, and/or changes in timing of cell differentiation in early fetal development, is likely a shared ASD-relevant aspect of pathophysiology.

    “We argue that MIA upregulation of cell cycle processes and increased neurogenesis, and/or changes in timing of cell differentiation in early fetal development, is likely a shared ASD-relevant aspect of pathophysiology.36, 37”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Packer A . Neocortical neurogenesis and the etiology of autism spectrum disorder. Neurosci Biobehav Rev 2016; 64: 185–195. source

      Not checked in the free run.

    • cites [37] Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria KC et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 2016; doi: 10.1038/mp.2016.95. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Le Belle JE, Sperry J, Ngo A, Ghochani Y, Laks DR, Lopez-Aranda M et al. Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells. Stem Cell Rep 2014; 3: 725–734. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During the acute stage of inflammation/injury, expression of cell cycle and translation processes have been shown to be upregulated, while many of the MIA-downregulated synaptic and neuronal processes implicated here are also known to be downregulated in acute stages of inflammation/injury.

    “In particular, during the acute stage of inflammation/injury, expression of cell cycle and translation processes have been shown to be upregulated, while many of the MIA-downregulated synaptic and neuronal processes implicated here are also known to be downregulated in acute stages of inflammation/injury.106, 107, 108”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [106] Lu XC, Williams AJ, Yao C, Berti R, Hartings JA, Whipple R et al. Microarray analysis of acute and delayed gene expression profile in rats after focal ischemic brain injury and reperfusion. J Neurosci Res 2004; 77: 843–857. source

      Not checked in the free run.

    • cites [107] Matzilevich DA, Rall JM, Moore AN, Grill RJ, Dash PK . High-density microarray analysis of hippocampal gene expression following experimental brain injury. J Neurosci Res 2002; 67: 646–663. source

      Not checked in the free run.

    • cites [108] Schreiber G, Howlett G, Nagashima M, Millership A, Martin H, Urban J et al. The acute phase response of plasma protein synthesis during experimental inflammation. J Biol Chem 1982; 257: 10271–10277. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Kelleher and Bear suggested a 'troubled translation' hypothesis of ASD by linking mutations associated with syndromic forms of ASD to altered translation and disturbance of synaptic processes.

    “Kelleher and Bear78 suggested a ‘troubled translation’ hypothesis of ASD by linking mutations associated with syndromic forms of ASD to altered translation and disturbance of synaptic processes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Kelleher RJ 3rd, Bear MF . The autistic neuron: troubled translation? Cell 2008; 135: 401–406. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    MIA-induced effects may converge to many of the same or overlapping pathways hit by some highly penetrant ASD mutations, and this can occur without actual dysregulation of the target genes themselves.

    “This evidence provides additional proof-of-concept that MIA-induced effects may converge to many of the same or overlapping pathways hit by some highly penetrant ASD mutations, and this can occur without actual dysregulation of the target genes themselves.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    This finding is consistent with other evidence from genetic and environmental models of ASD as well as evidence showing that mTOR protein levels in post-mortem cortical tissue of ASD patients can be increased or decreased.

    “Although this finding is in the opposite direction of known hyperactivation of mTOR by some highly ASD-penetrant mutations, it is consistent with other evidence from genetic103 and environmental models104 of ASD as well as evidence showing that mTOR protein levels in post-mortem cortical tissue of ASD patients can be increased105 or decreased.104”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Kim S, Lehtinen MK, Sessa A, Zappaterra MW, Cho SH, Gonzalez D et al. The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron 2010; 66: 69–84. source

      Not checked in the free run.

    • cites [104] Nicolini C, Ahn Y, Michalski B, Rho JM, Fahnestock M . Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid. Acta Neuropathol Commun 2015; 3: 3. source

      Not checked in the free run.

    • cites [105] Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 2014; 83: 1131–1143. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Naviaux et al. refer to MIA eliciting a 'cell danger response'.

    “A related concept here could also be to link such phenomena with what Naviaux et al.55, 94, 95 refer to as MIA eliciting a ‘cell danger response’.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [55] Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB et al. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Transl Psychiatry 2014; 4: e400. source

      Not checked in the free run.

    • cites [94] Naviaux JC, Wang L, Li K, Bright AT, Alaynick WA, Williams KR et al. Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model. Mol Autism 2015; 6: 1. source

      Not checked in the free run.

    • cites [95] Naviaux RK, Zolkipli Z, Wang L, Nakayama T, Naviaux JC, Le TP et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS ONE 2013; 8: e57380. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    MIA as an environmental risk factor for ASD enhances known biological processes that may mimic effects seen during acute stages of inflammation/injury, and MIA's shared pathways with ASD may also overlap with general processes known to occur under these circumstances.

    “This similarity is important to underscore since it may point towards the idea that MIA as an environmental risk factor for ASD enhances known biological processes that may mimic effects seen during acute stages of inflammation/injury, and that MIA’s shared pathways with ASD may also overlap with general processes known to occur under these circumstances.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Gene expression data from the mature ASD brain could be prone to false negatives and should be interpreted with caution.

    “As such, gene expression data from the mature ASD brain could be prone to false negatives and, as such, should be interpreted with caution.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    There are potential downstream effects involving genes that regulate cell proliferation, specifically controlling G1-S and G2-M cell cycle phase transition, with regard to MIA dysregulation of the TSC1/2-mTOR-EIF4E axis.

    “With regard to MIA dysregulation of the TSC1/2–mTOR–EIF4E axis, we predicted that there are potential downstream effects involving genes that regulate cell proliferation, specifically controlling G1–S and G2–M cell cycle phase transition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The current data support the ideas that translation processes are integral to ASD, and that MIA induces substantial early dysregulation of such processes.

    “The current data support these ideas that translation processes are integral to ASD, and that MIA induces substantial early dysregulation of such processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    MIA-induced disruption may work in a manner similar in directionality to rare highly penetrant ASD mutations, and may act as 'priming' or fetal programming mechanisms that enhance risk of later developing ASD.

    “MIA-induced disruption may work in a manner similar in directionality to rare highly penetrant ASD mutations, and may act as ‘priming’27, 28, 29, 30 or fetal programming21, 22 mechanisms that enhance risk of later developing ASD.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [27] Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol 2014; 10: 643–660. source

      Not checked in the free run.

    • cites [28] Patterson PH . Maternal infection and immune involvement in autism. Trends Mol Med 2011; 17: 389–394. source

      Not checked in the free run.

    • cites [29] Estes ML, McAllister AK . Maternal immune activation: implications for neuropsychiatric disorders. Science (New York, NY) 2016; 353: 772–777. source

      Not checked in the free run.

    • cites [30] Meyer U . Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry 2014; 75: 307–315. source

      Not checked in the free run.

    • cites [21] Barker DJ . In utero programming of chronic disease. Clin Sci (Lond) 1998; 95: 115–128. source

      Not checked in the free run.

    • cites [22] Gluckman PD, Hanson MA, Cooper C, Thornburg KL . Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 2008; 359: 61–73. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    When such environmental and gene mutation effects co-occur, pathology could be amplified and/or lead to more complex heterogeneous phenotypes.

    “These results would further predict that when such environmental and gene mutation effects co-occur, pathology could be amplified and/or lead to more complex heterogeneous phenotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This hypothesis has been further elaborated by Santini and Klann and others, with new evidence supporting the crucial role of cap-dependent translation protein EIF4E in ASD pathophysiology.

    “This hypothesis has been further elaborated by Santini and Klann and others, with new evidence supporting the crucial role of cap-dependent translation protein EIF4E79, 88, 100, 101 in ASD pathophysiology.77”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [79] Santini E, Klann E . Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci Signal 2014; 7: re10. source

      Not checked in the free run.

    • cites [88] Neves-Pereira M, Muller B, Massie D, Williams JH, O'Brien PC, Hughes A et al. Deregulation of EIF4E: a novel mechanism for autism. J Med Genet 2009; 46: 759–765. source

      Not checked in the free run.

    • cites [100] Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 2013; 493: 371–377. source

      Not checked in the free run.

    • cites [101] Santini E, Huynh TN, MacAskill AF, Carter AG, Pierre P, Ruggero D et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 2013; 493: 411–415. source

      Not checked in the free run.

    • cites [77] Yang G, Smibert CA, Kaplan DR, Miller FD . An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron 2014; 84: 723–739. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    MIA represents a potential etiology that could be more amenable to novel treatments.

    “In addition, MIA represents a potential etiology that could be more amenable to novel treatments.54, 55”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013; 155: 1451–1463. source

      Not checked in the free run.

    • cites [55] Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB et al. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Transl Psychiatry 2014; 4: e400. source

      Not checked in the free run.

50 of 50

  • The paper relies on this without support.

    The MIA-induced transcriptomic changes observed in rat fetal brain are informative about human fetal brain development and ASD pathophysiology.

    “Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology.”

  • The paper relies on this without support.

    MIA in the animal models used corresponds to late first trimester of gestation in humans.

    “In this study we examined animal models of MIA corresponding to late first trimester of gestation in humans”

  • The paper relies on this without support.

    MIA is an environmental risk factor that increases risk for ASD.

    “in order to better understand how MIA may lead to increased risk for ASD”

  • The paper relies on this without support.

    In the child and adult ASD brain, the developmental time period corresponds to a period where neurogenesis and cell differentiation processes are much less prominent and synaptic plasticity, circuit-dependent activity regulation play more important roles.

    “However, this developmental time period corresponds to a period where neurogenesis and cell differentiation processes are much less prominent and synaptic plasticity, circuit-dependent activity regulation play more important roles.”

  • The paper relies on this without support.

    Transcriptome dysregulation in fetal brain development is relevant to the pathophysiology of ASD.

    “in order to better understand how MIA may lead to increased risk for ASD via impairments of early fetal brain development that are relevant to the pathophysiology behind ASD.”

  • The paper relies on this without support.

    The MIA mouse model validation experiment is a valid cross-species model for human MIA effects on the TSC1/2–mTOR–EIF4E axis.

    “To directly test this hypothesis and validate inferences across model species, we performed a MIA mouse model validation experiment.”

  • The paper relies on this without support.

    MIA is a prominent risk factor for ASD.

    “Finally, this work explains why MIA is a prominent risk factor for ASD”

  • The paper relies on this without support.

    The LPS-injected rat model of MIA is relevant to human maternal infection and fetal brain development.

    “This idea has further impact when hypothesizing about the effects of temporal duration of infections in humans.”
8 of 8

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?

  • MIA causes long-lasting deleterious effects on the post-natal brain similar to those expected from germline mutations in patients with neurodevelopmental disorders.

    “MIA also causes long-lasting deleterious effects on the post-natal brain similar to those expected from germline mutations in patients with neurodevelopmental disorders [127].”

    From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [127]

  • MIA strongly upregulates cell cycle gene expression and cell proliferation, and may cause brain overgrowth.

    “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 [127]

  • MIA disrupts fetal development by involving transcriptional programs that are abnormal in adult ASD brain tissue and genes with high-confidence ASD mutations or their downstream targets.

    “MIA disrupts fetal development by involving transcriptional programs that are abnormal in adult ASD brain tissue and genes with high-confidence ASD mutations or their downstream targets [127].”

    From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [127]

  • MIA alters key components of the TSC/mTOR signaling pathway with ultimate activation of the translation initiation factor EIF4E, which is predicted to alter regulation of neural progenitor cell divisions during midgestation.

    “Consistently, we found that MIA alters key components of the TSC/mTOR signaling pathway with ultimate activation of the translation initiation factor EIF4E which is predicted to alter the regulation of neural progenitor cell divisions during midgestation [127, 156–158].”

    From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [127]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Strong-category percentage is rounded incorrectly

    Info

    Ten of 24 genes is 41.67%, which rounds to 42% at the reported precision, not 41%.

    Reported 41 · recomputed 41.666667

1 of 1

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Related

Authors
Lombardo, M. V., Moon, H. M., Su, J., Palmer, T. D., Courchesne, E., & Pramparo, T.
Affiliations
  • University of Cambridge (GB)
  • Institute for Stem Cell Biology and Regenerative Medicine (US)
  • University of California San Diego (US)
Corresponding author
  • Lombardo, M V
  • Pramparo, T
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2017-03-21
Volume
23
Issue
4
Pages
1001-1013
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2017.15
PMC
PMC5608645
OpenAlex
W2952743173
Semantic Scholar
d7dbdf93a29739c4b97e359a1a0c8625dfd95b9b
Cited by
201
References
111
Citations by year
2026: 14 · 2025: 13 · 2024: 22 · 2023: 28 · 2022: 31 · 2021: 21 · 2020: 21 · 2019: 19 · 2018: 27 · 2017: 3 · 2016: 2
FWCI
11.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Simons Foundation
  • Simons Foundation Autism Research Initiative (323220)
  • National Institutes of Health (KL2TR000099, 5r01mh110558-05, KL2TR001444, UL1TR001442)
  • School of Medicine, Stanford University
  • University of California, San Diego (1KL2TR001444)
  • National Institute of Mental Health (R01MH108659, R01-MH110558, R01MH096815)
  • National Center for Advancing Translational Sciences
  • School of Medicine, University of California, San Diego
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
maternal immune activation, autism spectrum disorder, prenatal infection, FMR1 gene, CHD8, eIF4E, mTOR signaling, TSC2, translation initiation, cell cycle, synaptic development, ASD risk, rat model
MeSH terms
Autism Spectrum Disorder, Animals, Brain, Disease Models, Animal, Female, Humans, Maternal-Fetal Exchange, Nuclear Proteins, Pregnancy, Prenatal Exposure Delayed Effects, Risk Factors, Eukaryotic Initiation Factor-4E, Proteomics, Rats, Fragile X Messenger Ribonucleoprotein 1, Gene Regulatory Networks, Transcriptome

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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