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Cited by 334Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersChild Nutrition and Feeding Issues

The ASD Living Biology: from cell proliferation to clinical phenotype

Open access
Courchesne, Eric, Pramparo, Tiziano, Gazestani, Vahid H., Lombardo, Michael V., Pierce, Karen, Lewis, Nathan E.·2019·Molecular Psychiatry
DOI 10.1038/s41380-018-0056-yPMC PMC6309606
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Abstract

Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD ( hcASD ) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child’s development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD.

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Written from the paper’s full text.

TL;DR

This review argues that ASD is a multistage, progressive prenatal disorder beginning with disrupted cell proliferation/differentiation in the 1st and 2nd trimesters and continuing through migration, synaptogenesis, and neural network dysfunction, with 94% of high-confidence ASD genes expressed prenatally. It coins “ASD Living Biology” to call for within-child integration of in vitro prenatal iPSC measures with in vivo postnatal neural and clinical data.

Key findings

  • ASD begins in the womb: 94% of 69 reliably expressed high-confidence ASD (hcASD) genes are expressed prenatally, 68% peak prenatally then decline after birth, and 62% of 58 functionally annotated hcASD genes are pleiotropic across multiple developmental processes.
  • Postmortem evidence: young ASD male children have on average 67% more prefrontal neurons than controls (79% more in dorsolateral and 29% more in medial prefrontal cortex; range 12–106%), 36% more cortical neurons in another study, and ~53% more von Economo neurons in frontoinsular cortex; neuron size reduction varies from −4% in occipital to −18% in prefrontal cortex.
  • iPSC evidence: ASD neural progenitors doubled in number twice as fast as controls due to a shorter G1/S phase; ASD-derived neurons showed fewer excitatory synapses, and by 50 days synchronized neural bursts were 6 times lower than controls; one ASD child-based cellular model found a 10-fold decrease in spontaneous neural activity.
  • Maternal immune activation (MIA) models show upregulated cell cycle/proliferation, overproduction of neurons, a 24% increase in neuron numbers in cortical layers II/III, and when combined with Pten haploinsufficiency increased brain enlargement from 8% to 44%; non-genetic etiologies may account for 30–41% of ASD risk.

Methods

  • Narrative review integrating postmortem, genetic, genomic, transcriptomic, iPSC/cell model, animal model, and MIA evidence; no new primary human cohort is reported.
  • Reanalysis of 72 hcASD genes (38 recurrent/penetrant genes overlapping with 65 SFARI Level 1/2 genes), focusing on 69 with reliable BrainSpan RNA-Seq expression, plus manual literature search annotating 58 genes across proliferation/neurogenesis, cell fate/migration, neurite outgrowth, and spine/synaptogenesis/synapse function.
  • Reviews the first ASD Living Biology study (Marchetto et al.) linking iPSC-derived prenatal molecular/cellular measures to MRI-based early brain overgrowth in living ASD toddlers.

Limitations

  • Stated: current approaches cannot provide individualized fetal-stage information; postnatal phenotype data alone cannot reveal fetal-stage biology, and fetal-stage cellular models alone cannot explain postnatal development and clinical heterogeneity.
  • Stated: many proposed ASD gene associations may be “noise,” and the hcASD gene set is limited to 72 genes, with 3 not reliably detected and only 58 having functional annotation from the literature.
  • Evident: this is a narrative review rather than a systematic review or new primary study; causal and multistage claims rely on heterogeneous existing postmortem, animal, and cell-model evidence, with some key iPSC–MRI links being correlational.

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Registry

Crossref · 10.1038/s41380-018-0056-y

Cites

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Statistics

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Claims the paper makes

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  • Findingnone given

    Among the most commonly reported high-confidence ASD genes, 94% express during prenatal life and affect fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum.

    “Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Of the 72 hcASD genes, 3 are not detected in >10% of BrainSpan samples between prenatal and up to 8 years old post-natal.

    “Of the 72 genes, 3 are not detected (RPKM > 0.5) in >10% of BrainSpan samples between prenatal and up to 8 years old post-natal.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BrainSpan RNA-Seq expression patterns accurately represent developmental expression timing and roles of hcASD genes in living human brain development.
  • Findingown data

    47 hcASD genes (68%) have peak expression during much of prenatal development, and then are downregulated following birth.

    “Importantly, 47 genes (68%; green cluster in Fig. 4) have peak expression during much of prenatal development, and then are downregulated following birth.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BrainSpan RNA-Seq expression patterns accurately represent developmental expression timing and roles of hcASD genes in living human brain development.
  • Findingown data

    Of the 69 hcASD genes with reliable expression, 65 (94%) are expressed (RPKM > 1) in prenatal brain development.

    “Of these 69 genes, 65 (94%) are expressed (RPKM > 1) in prenatal brain development.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BrainSpan RNA-Seq expression patterns accurately represent developmental expression timing and roles of hcASD genes in living human brain development.
  • Findingown data

    The remaining 22 (32%) of the hcASD genes start to increase in expression levels during the 3rd trimester and the first several years of post-natal life.

    “The remaining 22 (32%) of the hcASD genes start to increase in expression levels during the 3rd trimester and the first several years of post-natal life (Fig. 4; purple cluster).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BrainSpan RNA-Seq expression patterns accurately represent developmental expression timing and roles of hcASD genes in living human brain development.
  • May combine two claims. 54
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Findingreasoning

    A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development.

    “A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The hcASD genes with prenatal peak expression are largely associated with proliferation and differentiation, and many are also involved in neural migration, neurite outgrowth, and early synaptogenesis.

    “From the perspective of biological roles, these hcASD genes are largely associated with proliferation and differentiation. Many are also involved in neural migration, neurite outgrowth, and early synaptogenesis (Fig. 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BrainSpan RNA-Seq expression patterns accurately represent developmental expression timing and roles of hcASD genes in living human brain development.

  • May combine two claims.

    Findingown data

    Of these 58 hcASD genes, 33 (57%) are involved in cell proliferation and/or neurogenesis, while 34 (59%) are involved in spine development, synaptogenesis, and/or synapse function.

    “Of these 58 hcASD genes, 33 (57%) hcASD genes are involved in cell proliferation and/or neurogenesis, while 34 (59%) are involved in spine development, synaptogenesis, and/or synapse function (Fig. 5).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Functional annotation from animal/cell models and literature can be generalized to human hcASD gene roles in brain development.

  • May combine two claims.

    Findingcitation

    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].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [127] Lombardo MV, Moon HM, Su J, Palmer TD, Courchesne E, Pramparo T. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol Psychiatry. 2017;23:1001–13. source

      Not checked in the free run.

    • cites [156] 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.

    • cites [157] Huber KM, Klann E, Costa-Mattioli M, Zukin RS. Dysregulation of mammalian target of rapamycin signaling in mouse models of autism. J Neurosci. 2015;35:13836–42. source

      Not checked in the free run.

    • cites [158] 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;493:371–7. source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    Ninety-four percent of hcASD genes have peak expression prenatally, with the vast majority affecting proliferation/differentiation, cell fate, migration, neurite outgrowth and synaptogenesis.

    “Ninety-four percent of hcASD genes have peak expression prenatally, with the vast majority affecting proliferation/differentiation, cell fate, migration, neurite outgrowth and synaptogenesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    ASD continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning.

    “It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers.

    “Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ASD patient-derived neurons displayed fewer excitatory synapses, and downregulation of multiple neurotransmitter and synapse markers including GABA receptor markers.

    “ASD patient-derived neurons additionally displayed fewer excitatory synapses, and downregulation of multiple neurotransmitter and synapse markers including GABA receptor markers (Fig. 3f, g).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] 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;22:820–35. source

      Not checked in the free run.

    • Rests on an assumption: iPSC-derived neural progenitor cells and neurons from ASD toddlers recapitulate the prenatal brain developmental processes relevant to ASD in vivo.

  • May combine two claims.

    Premisecitation

    In analyses of gene expression and MRI measures of brain size at young ages, ASD toddlers with the most abnormal expression of cell cycle hub genes had the most brain overgrowth, while those with milder cell cycle disruption had smaller than normal brain size.

    “In analyses of gene expression and MRI measures of brain size at young ages, ASD toddlers with the most abnormal expression of cell cycle hub genes had the most brain overgrowth, while those with milder cell cycle disruption had smaller than normal brain size [56].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Pramparo T, Lombardo MV, Campbell K, Barnes CC, Marinero S, Solso S, et al. Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers. Mol Syst Biol. 2015;11:841. source

      Not checked in the free run.

    • Rests on an assumption: Leukocyte transcriptomics in ASD toddlers reflects molecular processes in the developing brain.

  • May combine two claims.

    Premisecitation

    ASD neural progenitor cells display excess proliferation compared to normal controls, and that excess proliferation was correlated with the degree of each child's MRI-based brain overgrowth.

    “ASD neural progenitor cells display excess proliferation compared to normal controls (Fig. 3a–d), and that excess proliferation was correlated with the degree of each child’s MRI-based brain overgrowth (Fig. 3e).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] 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;22:820–35. source

      Not checked in the free run.

    • Rests on an assumption: iPSC-derived neural progenitor cells and neurons from ASD toddlers recapitulate the prenatal brain developmental processes relevant to ASD in vivo.

  • May combine two claims.

    Interpretationcitation

    ASD patient-derived iPSC studies find evidence of multiple fetal stage defects with commonality in excess proliferation and cell cycle acceleration defects, but heterogeneity in synaptogenesis effects; this points to fetal stage subtypes in ASD.

    “Thus, ASD patient-derived iPSC studies find evidence of multiple fetal stage defects with commonality in excess proliferation and cell cycle acceleration defects, but heterogeneity in synaptogenesis effects. This points to fetal stage subtypes in ASD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] 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;22:820–35. source

      Not checked in the free run.

    • cites [55] Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, et al. FOXG1-dependent dysregulation of GABA/Glutamate neuron differentiation in autism spectrum disorders. Cell. 2015;162:375–90. source

      Not checked in the free run.

    • Rests on an assumption: iPSC-derived neural progenitor cells and neurons from ASD toddlers recapitulate the prenatal brain developmental processes relevant to ASD in vivo.

  • May combine two claims.

    Interpretationcitation

    Because proliferation of cortical neurons is exponential between 10 and 20 weeks of gestation and does not occur postnatally, pathological neuron excess cannot be caused by post-natal events and instead indicates neural disorder in ASD has a prenatal origin, likely by the first and/or second trimester.

    “Because proliferation of cortical neurons is exponential between 10 and 20 weeks of gestation [43, 44] and does not occur postnatally, pathological neuron excess cannot be caused by post-natal events and instead indicates neural disorder in ASD has a prenatal origin, likely by the first and/or second trimester.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Rabinowicz T, de Courten-Myers GM, Petetot JM, Xi G, de los Reyes E. Human cortex development: estimates of neuronal numbers indicate major loss late during gestation. J Neuropathol Exp Neurol. 1996;55:320–8. source

      Not checked in the free run.

    • cites [44] Gohlke JM, Griffith WC, Faustman EM. Computational models of neocortical neuronogenesis and programmed cell death in the developing mouse, monkey, and human. Cereb Cortex. 2007;17:2433–42. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuropathology examination of 4-year-old to 60-year-old ASD brains shows evidence of multiregional dysregulation of neurogenesis and neuronal migration in several cases, including subcortical, periventricular, hippocampal and cerebellar heterotopias reflecting abnormal neuronal migration and multifocal cerebral dysplasias.

    “Neuropathology examination of 4-year-old to 60-year-old ASD brains shows evidence of multiregional dysregulation of neurogenesis and neuronal migration in several cases, including subcortical, periventricular, hippocampal and cerebellar heterotopias reflecting abnormal neuronal migration and multifocal cerebral dysplasias [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Wegiel J, Kuchna I, Nowicki K, Imaki H, Marchi E, Ma SY, et al. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 2010;119:755–70. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Neural developmental disorder in ASD spans prenatal and early post-natal life, beginning with dysregulation of cell cycle G1/S and excess cell proliferation and ending with disrupted synaptogenesis and dysfunctional nascent neural circuit activity.

    “These ASD Living Biology experiments suggest that neural developmental disorder in ASD spans prenatal and early post-natal life, beginning with dysregulation of cell cycle G1/S and excess cell proliferation and ending with disrupted synaptogenesis and dysfunctional nascent neural circuit activity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: iPSC-derived neural progenitor cells and neurons from ASD toddlers recapitulate the prenatal brain developmental processes relevant to ASD in vivo.

  • May combine two claims.

    Premisecitation

    Neuron excess in ASD prefrontal cortex is not uniform: 79% in dorsolateral and 29% in medial prefrontal cortex.

    “Neuron overabundance is not uniform in prefrontal cortex: Neuron excess was 79% in dorsolateral and 29% in medial prefrontal cortex [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306:2001–10. source

      Not checked in the free run.

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    Premisecitation

    Reduced growth of neuronal cell size and dendritic arbors in ASD postmortem cases have long been reported and are now recognized as an important neuropathological attribute of ASD cortex; neuron size reduction varies from −4% in occipital to −18% in prefrontal cortex.

    “Reduced growth of neuronal cell size and dendritic arbors in ASD postmortem cases have long been reported [25, 52] and are now recognized as an important neuropathological attribute of ASD cortex [46]; neuron size reduction varies from −4% in occipital to −18% in prefrontal cortex [24, 40, 53].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [25] Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23:183–7. source

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    • cites [52] Raymond GV, Bauman ML, Kemper TL. Hippocampus in autism: a Golgi analysis. Acta Neuropathol. 1996;91:117–9. source

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    • cites [46] Varghese M, Keshav N, Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL, et al. Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol. 2017;134:537–66. source

      Not checked in the free run.

    • cites [24] Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306:2001–10. source

      Not checked in the free run.

    • cites [40] van Kooten IA, Palmen SJ, von Cappeln P, Steinbusch HW, Korr H, Heinsen H, et al. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain. 2008;131(Pt 4):987–99. source

      Not checked in the free run.

    • cites [53] Jacot-Descombes S, Uppal N, Wicinski B, Santos M, Schmeidler J, Giannakopoulos P, et al. Decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism. Acta Neuropathol. 2012;124:67–79. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cell cycle, differentiation, and DNA damage response genes and pathways are dysregulated in prefrontal cortex at young ages in ASD, and immune gene expression is upregulated.

    “Cell cycle, differentiation, and DNA damage response genes and pathways are dysregulated in prefrontal cortex at young ages in ASD, and immune gene expression is upregulated [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L, et al. Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genet. 2012;8:e1002592. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysregulation of proliferating precursor cells will perturb the number of generated neurons as well as the balance between neurogenesis and gliogenesis in the developing brain.

    “Therefore, dysregulation of proliferating precursor cells will perturb the number of generated neurons as well as the balance between neurogenesis and gliogenesis in the developing brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A newly generated cell can differentiate into a neuron or become an IPC.

    “The newly generated cell can differentiate into a neuron, or become an IPC [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci. 2004;7:136–44. source

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    Premisecitation

    In precursor and radial glial cells (RGCs), upregulation of PI3K/AKT, WNT and β-catenin or downregulation of RAS/ERK leads to elevated proliferation.

    “In precursor and radial glial cells (RGCs), upregulation of PI3K/AKT, WNT and β-catenin or downregulation of RAS/ERK leads to elevated proliferation [86, 88, 89].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [86] Rhim JH, Luo X, Gao D, Xu X, Zhou T, Li F, et al. Cell type-dependent Erk-Akt pathway crosstalk regulates the proliferation of fetal neural progenitor cells. Sci Rep. 2016;6:26547. source

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  • May combine two claims.

    Interpretationreasoning

    In neural development, these pathways are crucial in different fetal and early post-natal stages, suggesting that the pleiotropic concept can be extended from genes to molecular pathways.

    “In neural development, these pathways are crucial in different fetal and early post-natal stages (Fig. 6; Table 1), suggesting that the pleiotropic concept can be extended from genes to molecular pathways.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fig. 6

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    • cites Table 1

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    Premisecitation

    Activity of β-catenin enhances premature differentiation of neurons, while activity of RAS/ERK reduces neurogenesis of IPCs and increases astrogenesis.

    “Activity of β-catenin (downstream of PI3K/AKT and WNT, Fig. 6) enhances premature differentiation of neurons [88], while activity of RAS/ERK reduces neurogenesis of IPCs and increases astrogenesis [90].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [88] Munji RN, Choe Y, Li G, Siegenthaler JA, Pleasure SJ. Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors. J Neurosci. 2011;31:1676–87. source

      Not checked in the free run.

    • cites [90] Wang Y, Kim E, Wang X, Novitch BG, Yoshikawa K, Chang LS, et al. ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell. 2012;150:816–30. source

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    Premisecitation

    Activity of receptor tyrosine kinases, metabotropic glutamic receptors and NMDA receptors leads to activation of PI3K/AKT and RAS/ERK signaling pathways, and thereby influences synaptic plasticity by mediating expression and trafficking of AMPA receptors in excitatory synapses and controlling LTD and LTP responses.

    “Activity of receptor tyrosine kinases, metabotropic glutamic receptors and NMDA receptors lead to the activation of PI3K/AKT and RAS/ERK signaling pathways [185, 189], and thereby influence synaptic plasticity by mediating expression and trafficking of AMPA receptors in excitatory synapses and controlling long-term depression (LTD) and long-term potentiation (LTP) responses [188–190].”
    Quote in the paperSubstantial claim0 of 4 sources checked
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    • cites [188] Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci. 2004;5:173–83. source

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    • cites [190] Derkach VA, Oh MC, Guire ES, Soderling TR. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci. 2007;8:101–13. source

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    Premisecitation

    During brain development, RGCs can divide symmetrically or asymmetrically; symmetric divisions result in two daughter RGCs, while asymmetric divisions produce a RGC and one other cell.

    “During brain development, RGCs can divide symmetrically or asymmetrically. While symmetric divisions result in two daughter RGCs, asymmetric divisions produce a RGC and one another cell [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Chenn A, McConnell SK. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell. 1995;82:631–41. source

      Not checked in the free run.

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    Premisecitation

    Gsk3 knockout resulted in expanded RGC pools, fewer IPCs, reduced cortical thickness and increased ventricular apical surface length.

    “This resulted in expanded RGC pools, fewer IPCs, reduced cortical thickness and increased ventricular apical surface length [102].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR, et al. GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci. 2009;12:1390–7. source

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    Premisecitation

    Loss of Erk2 can induce strong G1/S dysregulation causing mouse cells to miss the neurogenesis time window E14.5-E16.5, resulting in fewer neurons, precocious astrogenesis, and potentially microcephaly.

    “loss of Erk2 can induce such strong G1/S dysregulation that mice cells miss the time window of neurogenesis (E14.5–E16.5), resulting in fewer neurons, precocious astrogenesis, and potentially microcephaly [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Samuels IS, Karlo JC, Faruzzi AN, Pickering K, Herrup K, Sweatt JD, et al. Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function. J Neurosci. 2008;28:6983–95. source

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    Premisecitation

    As a result of Gsk3 knockout, RGCs were locked in a proliferative state with attenuated neurogenesis.

    “As a result, RGCs were locked in proliferative state with attenuated neurogenesis [102].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR, et al. GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci. 2009;12:1390–7. source

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    Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [127] Lombardo MV, Moon HM, Su J, Palmer TD, Courchesne E, Pramparo T. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol Psychiatry. 2017;23:1001–13. source

      Not checked in the free run.

    • cites [128] Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M. 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. Brain Behav Immun. 2012;26:623–34. source

      Not checked in the free run.

    • cites [129] Smith SE, Elliott RM, Anderson MP. Maternal immune activation increases neonatal mouse cortex thickness and cell density. J Neuroimmune Pharmacol. 2012;7:529–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Non-genetic etiologies may account for 30-41% of the risk for ASD, and such factors may act independently or in combination with genetic factors.

    “Non-genetic etiologies may account for 30–41% of the risk for ASD [113], and such factors may act independently or in combination with genetic factors [113].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] 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;46:881–5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in Mecp2 and Shank3 suppress the PI3K/AKT pathway, leading to delayed and sparse spine development and reduced synaptic amplitude.

    “mutations in Mecp2 and Shank3 are reported to suppress the pathway, leading to delayed and sparse spine development and reduced synaptic amplitude [110, 111].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [110] Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA. 2009;106:2029–34. source

      Not checked in the free run.

    • cites [111] Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, et al. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism. 2010;1:15. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    RAS/ERK, PI3K/AKT, WNT and β-catenin are highly integrated and pleiotropic, exhibiting different and successive roles throughout prenatal and early post-natal life.

    “Thus, RAS/ERK, PI3K/AKT, WNT and β-catenin are highly integrated and pleiotropic, exhibiting different and successive roles throughout prenatal and early post-natal life (Fig. 6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 6

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reactive oxygen species can increase stem cell self-renewal and neurogenesis through reversible inactivation of PTEN and hyper-activation of the NADPH oxidase (NOX)-PI3K pathway, which ultimately during early post-natal development will result in enlarged brains and autistic behaviors.

    “Reactive oxygen species (ROS) can increase stem cell self-renewal and neurogenesis through the reversible inactivation of PTEN and hyper-activation of the NADPH oxidase (NOX)-PI3K pathway [134], which ultimately, during early post-natal development, will result in enlarged brains and autistic behaviors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, et al. Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell. 2011;8:59–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gene expression alterations in MIA also involve neuronal migration processes that could underlie observed cortical layering defects, characterized by a 24% increase in neuron numbers in cortical layers II/III.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [128] Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M. 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. Brain Behav Immun. 2012;26:623–34. source

      Not checked in the free run.

    • cites [131] 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;89:1575–85. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [129] Smith SE, Elliott RM, Anderson MP. Maternal immune activation increases neonatal mouse cortex thickness and cell density. J Neuroimmune Pharmacol. 2012;7:529–32. source

      Not checked in the free run.

    • cites [130] 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;3:725–34. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in Fmr1 and Pten lead to over-activity of the PI3K/AKT pathway with increased synaptogenesis and hyperconnectivity of neurons.

    “while mutations in Fmr1 and Pten lead to the over-activity of PI3K/AKT pathway with increased synaptogenesis and hyperconnectivity of the neurons [107–109]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [107] Huang WC, Chen Y, Page DT. Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome. Nat Commun. 2016;7:13421. source

      Not checked in the free run.

    • cites [108] Gross C, Chang CW, Kelly SM, Bhattacharya A, McBride SM, Danielson SW, et al. Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep. 2015;11:727–36. source

      Not checked in the free run.

    • cites [109] Gross C, Raj N, Molinaro G, Allen AG, Whyte AJ, Gibson JR et al. Selective role of the catalytic PI3K subunit p110beta in impaired higher order cognition in fragile X syndrome. Cell Rep 2015;11:681–88. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytoarchitecture heterogeneity is seen in MIA models and is characteristic of ASD cases.

    “Also, cytoarchitecture heterogeneity is seen that is characteristic of ASD cases [34, 132].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, et al. Patches of disorganization in the neocortex of children with autism. N Engl J Med. 2014;370:1209–19. source

      Not checked in the free run.

    • cites [132] 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. 2016;351:933–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When focal cortical dysplasia is present, ASD-like behaviors occur; but when its development is prevented, ASD-like behaviors do not occur.

    “When focal cortical dysplasia is present, ASD-like behaviors occur; but when its development is prevented, ASD-like behaviors do not occur [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Yim YS, Park A, Berrios J, Lafourcade M, Pascual LM, Soares N, et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature. 2017;549:482–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] 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;3:725–34. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Across ASD individuals, variation in how and when these pleiotropic pathways are dysregulated will cause early heterogeneity of pathophysiology and potentially later neural and clinical heterogeneous outcomes.

    “Across ASD individuals, variation in how and when these pleiotropic pathways are dysregulated will cause early heterogeneity of pathophysiology and potentially later neural and clinical heterogeneous outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Prenatal injection of a small molecule that stabilizes axin prolongs cell cycle proliferation and causes an excess of layer 2 and 3 neurons and early brain overgrowth, abnormal synaptogenesis and increased excitatory neural activity.

    “by prenatal injection of a small molecule that stabilizes axin, a component of the WNT and β-catenin signaling pathway, cell cycle proliferation is prolonged and causes an excess of layer 2 and 3 neurons and early brain overgrowth, abnormal synaptogenesis and increased excitatory neural activity [112].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Fang WQ, Chen WW, Jiang L, Liu K, Yung WH, Fu AK, et al. Overproduction of upper-layer neurons in the neocortex leads to autism-like features in mice. Cell Rep. 2014;9:1635–43. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This evidence suggests shared disrupted pathways between genetic and non-genetic etiologies and the possibility for a much more relevant interplay between a genetic background at-risk for ASD and environmental triggers.

    “This evidence suggests shared disrupted pathways between genetic and non-genetic etiologies and the possibility for a much more relevant interplay between a genetic background at-risk for ASD and environmental triggers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These results strengthen the causal link between cell cycle disruption and ASD and suggest that non-genetic etiologies may underlie deviant neurodevelopmental trajectories.

    “These results strengthen the causal link between cell cycle disruption and ASD and also suggest that non-genetic etiologies may underlie deviant neurodevelopmental trajectories.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Many known and proposed ASD etiologies such as MECP2, PTEN, MIA and XAV939 may perturb the pleiotropic RAS/ERK-PI3K/AKT pathway, which in turn modulates each of the ASD-critical fetal and early post-natal stages discussed.

    “Moreover, many known and proposed ASD etiologies (e.g., MECP2, PTEN, MIA, XAV939) may perturb the pleiotropic RAS/ERK-PI3K/AKT pathway (Fig. 6), which in turn modulates each of the ASD-critical fetal and early post-natal stages discussed here.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 6

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammatory mediators such as cytokines induce alterations during neurodevelopment by histone modifications, methylation changes at the promoter of ASD-critical genes such as MECP2 or genes involved in synaptic functions, and global methylation changes.

    “Inflammatory mediators (e.g., cytokines) induce such alterations during neurodevelopment [138] by histone modifications [139], methylation changes at the promoter of ASD-critical genes (e.g., MECP2) [140] or genes involved in synaptic functions [141] and global methylation changes [136].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [138] Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64:61–78. source

      Not checked in the free run.

    • cites [139] Tang B, Jia H, Kast RJ, Thomas EA. Epigenetic changes at gene promoters in response to immune activation in utero. Brain Behav Immun. 2013;30:168–75. source

      Not checked in the free run.

    • cites [140] Basil P, Li Q, Dempster EL, Mill J, Sham PC, Wong CC, et al. Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain. Transl Psychiatry. 2014;4:e434. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of pathogenic processes.

    “Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of pathogenic processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The Wdfy3 mutation mouse model of ASD displays heterogeneity of migration and focal patch defects across individual animals, as well as disrupted proliferation/differentiation and cortical overgrowth.

    “The Wdfy3 mutation mouse model of ASD likewise displays heterogeneity of migration and focal patch defects across individual animals, as well as disrupted proliferation/differentiation and cortical overgrowth [177].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Orosco LA, Ross AP, Cates SL, Scott SE, Wu D, Sohn J, et al. Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology. Nat Commun. 2014;5:4692. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Excess or reduction of synapse formation may occur in different ASD cases; excess brain growth occurs in most while reduced size occurs in a small subset.

    “Thus, an excess or reduction of synapse formation may occur in different ASD cases; excess brain growth occurs in most while reduced size occurs in a small subset.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Impairment in regulation of microglia functions is consistently seen in ASD studies and is likely involved in abnormal regulation of neuron numbers both at pre- and post-natal stages.

    “Impairment in the regulation of microglia functions is consistently seen in ASD studies [42, 159, 160] and is likely involved in abnormal regulation of neuron numbers both at pre- and post-natal stages.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L, et al. Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genet. 2012;8:e1002592. source

      Not checked in the free run.

    • cites [159] Morgan JT, Chana G, Abramson I, Semendeferi K, Courchesne E, Everall IP. Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res. 2012;1456:72–81. source

      Not checked in the free run.

    • cites [160] 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;474:380–4. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Courchesne et al., two ASD individuals had >100% the normal mean prefrontal neuron number, but one had small neurons and a modestly enlarged brain weight while the other had typical neuron size and one of the largest brain weights ever recorded for ASD.

    “In Courchesne et al. [24], two ASD individuals had >100% the normal mean prefrontal neuron number, but one had small neurons and a modestly enlarged brain weight while the other had typical neuron size and one of the largest brain weights ever recorded for ASD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306:2001–10. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ASD is a multi-etiology, multi-stage, progressive disorder that spans most of fetal life.

    “ASD is a multi-etiology, multi-stage, progressive disorder that spans most of fetal life.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the Marchetto et al. study, even though neural progenitors from every ASD toddler doubled cell numbers faster than every control, proliferation rates among ASD toddlers varied and that variation correlated with variation in MRI volume.

    “In the Marchetto et al. [54] study, even though neural progenitors from every ASD toddler doubled cell numbers faster than every control, the proliferation rates among ASD toddlers varied and that variation correlated with variation in MRI volume.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] 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;22:820–35. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    ASD begins during prenatal life, which is the least studied and understood of all developmental periods of ASD.

    “Evidence shows that ASD begins during prenatal life, which is the least studied and understood of all developmental periods of ASD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    At the molecular level, IL-6 increases the activity of DNMT1 with activating effects on JAK/STAT3, NF-κB and PI3K/AKT/mTOR signaling pathways, affecting regulation of autophagy-related functions required to maintain cellular homeostasis under stress such as a prenatal insult.

    “At the molecular level, IL-6 increases the activity of DNA methyltransferases 1 (DNMT1) with activating effects on the JAK/STAT3, NF-κB and PI3K/AKT/mTOR signaling pathways [144–148] affecting the regulation of autophagy-related functions, that are required to maintain cellular homeostasis under stress [149], such as a prenatal insult.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [144] Liu CC, Lin JH, Hsu TW, Su K, Li AF, Hsu HS, et al. IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation. Int J Cancer. 2015;136:547–59. source

      Not checked in the free run.

    • cites [145] Huang L, Hu B, Ni J, Wu J, Jiang W, Chen C, et al. Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis. J Exp Clin Cancer Res. 2016;35:27. source

      Not checked in the free run.

    • cites [146] Gerard C, Gonze D, Lemaigre F, Novak B. A model for the epigenetic switch linking inflammation to cell transformation: deterministic and stochastic approaches. PLoS Comput Biol. 2014;10:e1003455. source

      Not checked in the free run.

    • cites [147] Hodge DR, Cho E, Copeland TD, Guszczynski T, Yang E, Seth AK, et al. IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the AKT kinase. Cancer Genom Proteom. 2007;4:387–98.

      Not checked in the free run.

    • cites [148] Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. 2016;82:943–56. source

      Not checked in the free run.

    • cites [149] You L, Wang Z, Li H, Shou J, Jing Z, Xie J, et al. The role of STAT3 in autophagy. Autophagy. 2015;11:729–39. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Early interventions and services may improve an ASD child's developmental outcome and help parents at a crucial time in human brain development.

    “Early interventions and services may improve an ASD child’s developmental outcome and help parents at a crucial time in human brain development.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Neural circuits are sculpted by experience.
54 of 54

  • The paper relies on this without support.

    iPSC-derived neural progenitor cells and neurons from ASD toddlers recapitulate the prenatal brain developmental processes relevant to ASD in vivo.

    “To test whether disruptions in proliferation and prenatal neural developmental stages are related to early brain overgrowth in vitro in ASD, Marchetto et al [54] derived iPS cells from fibroblasts from living ASD toddlers with early brain overgrowth and from control toddlers.”
    “These ASD Living Biology experiments suggest that neural developmental disorder in ASD spans prenatal and early post-natal life, beginning with dysregulation of cell cycle G1/S and excess cell proliferation and ending with disrupted synaptogenesis and dysfunctional nascent neural circuit activity.”

  • The paper relies on this without support.

    Leukocyte transcriptomics in ASD toddlers reflects molecular processes in the developing brain.

    “Transcriptomics of leukocytes from ASD toddlers reveal further insights into ASD Living Biology.”

  • The paper relies on this without support.

    BrainSpan RNA-Seq expression patterns accurately represent developmental expression timing and roles of hcASD genes in living human brain development.

    “First, we addressed the “when and where” roles of these hcASD genes by leveraging the most recent BrainSpan RNA-Seq dataset (http://www.brainspan.org/).”

  • The paper relies on this without support.

    Functional annotation from animal/cell models and literature can be generalized to human hcASD gene roles in brain development.

    “Functional annotation could be found for 58 hcASD genes based on a manual literature search.”

  • The paper relies on this without support.

    Maternal immune activation in the 1st trimester can disrupt proliferation and subsequent fetal stages in ASD.

    “Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester.”

  • The paper relies on this without support.

    The balance between cell cycle re-entry (proliferative divisions) and exit (neurogenesis) controls neuron numbers.

    “The other key factor that controls neuron numbers is the balance between cell cycle re-entry (proliferative divisions) and exit (neurogenesis).”

  • The paper relies on this without support.

    Somatic mutations can lead to dysregulation of these signaling pathways during brain development.

    “Somatic mutations can also lead to dysregulation of these signaling pathways during brain development.”

  • The paper relies on this without support.

    Nearly all current approaches—postmortem, molecular, genomic, genetic, computational and animal models—cannot get answers to foundational questions about fetal and early post-natal ASD processes.

    “nearly all current approaches—postmortem, molecular, genomic, genetic, computational and animal models—cannot get answers to foundational questions”

  • The paper relies on this without support.

    Post-natal phenotype data alone cannot reveal fetal-stage biology, and fetal-stage cellular models alone cannot explain post-natal development and clinical heterogeneity.

    “Post-natal phenotype data alone cannot reveal fetal-stage biology, and fetal-stage cellular models alone cannot explain post-natal development and clinical heterogeneity.”

  • The paper relies on this without support.

    Neural circuits are sculpted by experience.

    “Because neural circuits are sculpted by experience”
10 of 10

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?

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Prenatal peak expression is reported as both 94% and 68%

    Major

    The conclusions say 94% of hcASD genes have peak expression prenatally, but the results identify 47 of 69 genes (68%) as having prenatal peak expression. The 94% figure elsewhere refers to genes expressed prenatally, not genes whose expression peaks then.

  • Cited study is described as finding both more and fewer neurons

    Minor

    The text attributes a finding of 36% more neurons to reference [40], whose title says neurons in the fusiform gyrus are fewer in autism.

2 of 2

Cites

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Related

Authors
Courchesne, E., Pramparo, T., Gazestani, V. H., Lombardo, M. V., Pierce, K., & Lewis, N. E.
Affiliations
  • University of California San Diego (US)
  • University of Cambridge (GB)
Corresponding author
Courchesne, Eric
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-06-22
Volume
24
Issue
1
Pages
88-107
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-018-0056-y
PMC
PMC6309606
OpenAlex
W2809176836
Semantic Scholar
7a329c7a1b967c4dec4df0d83af4d604a469e01c
Cited by
333
References
200
Citations by year
2026: 33 · 2025: 29 · 2024: 41 · 2023: 42 · 2022: 44 · 2021: 44 · 2020: 74 · 2019: 17 · 2018: 8 · 2017: 1
FWCI
4.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Alliance for Research on Schizophrenia and Depression
  • Novo Nordisk Fonden (NNF10CC1016517)
  • National Institutes of Health (5r01mh110558-05)
  • National Institute of Mental Health (MH036840, R01MH104446, R01-MH110558, R01MH036840, U01MH108898, R01MH080134)
  • National Institute on Deafness and Other Communication Disorders (R01DC016385)
  • National Institute of General Medical Sciences (GM119850, R35GM119850)
  • National Institute of Neurological Disorders and Stroke (P30NS047101)
  • Congressionally Directed Medical Research Programs (AR130409)
  • H2020 European Research Council (755816)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
Keywords
autism spectrum disorder, fetal brain development, cell proliferation, neuronal differentiation, neuronal migration, synaptogenesis, neuronal maturation, neurite outgrowth, maternal immune activation, PI3K/Akt signaling, Ras/ERK pathway, pleiotropic genes, clinical heterogeneity, precision medicine, prenatal biomarkers, cell culture model
MeSH terms
Autism Spectrum Disorder, Amygdala, Animals, Brain, Cell Differentiation, Female, Humans, Male, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Cell Proliferation

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.

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