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

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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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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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Figures

Fig. 1 Illustration of early brain overgrowth in ASD. Brain overgrowth in the first years of life occurs in many ASD toddlers and is due to prenatal cell cycle dysregulation that causes an overabundance of cortical neurons. This is theorized to lead to disrupted neural network development and function, and ASD symptoms [5–7, 24, 31–34]. Unbiased, blinded stereological analyses find that young ASD male children have an average 67% more prefrontal neurons than controls [24]. Since cortical neuron generation occurs only in prenatal life in humans, this is direct evidence that ASD begins in the womb. As discussed in this review and previously [56], abnormal early brain undergrowth in toddlers with ASD may also be due to cell cycle dysregulation. Adapted from Courchesne et al. [7]
Fig. 1 Illustration of early brain overgrowth in ASD. Brain overgrowth in the first years of life occurs in many ASD toddlers and is due to prenatal cell cycle dysregulation that causes an overabundance of cortical neurons. This is theorized to lead to disrupted neural network development and function, and ASD symptoms [5–7, 24, 31–34]. Unbiased, blinded stereological analyses find that young ASD male children have an average 67% more prefrontal neurons than controls [24]. Since cortical neuron generation occurs only in prenatal life in humans, this is direct evidence that ASD begins in the womb. As discussed in this review and previously [56], abnormal early brain undergrowth in toddlers with ASD may also be due to cell cycle dysregulation. Adapted from Courchesne et al. [7]CC BY · PubMed Central
Fig. 2 Developmental timeline relevant to ASD. Schematic of prominent processes occurring during different periods of human fetal and post-natal brain development. Adapted from Lombardo et al. [127]
Fig. 2 Developmental timeline relevant to ASD. Schematic of prominent processes occurring during different periods of human fetal and post-natal brain development. Adapted from Lombardo et al. [127]CC BY · PubMed Central
Fig. 3 Excess cell proliferation, abnormal synaptic development and reduced neural activity are associated with iPS cells of ASD toddlers with enlarged brains. a ASD iPS cells proliferate more rapidly than control. The iPS cells from ASD and control were differentiated to NPCs. From passages 2 to 6, cells were plated at the same density and population doubling time at each passage was calculated. Results of all lines (2 clones per line) are presented as mean ± s.e.m. (*repeated measurements P = 0.02, post hoc P < 0.04). b ASD cell cycle has abnormally short G1 phase. Adherent monolayer NPCs from control and ASD iPS cells were dissociated, counted for calculation of population doubling time and prepared for cell cycle analysis. Results are presented as the time spent in each cell cycle stage (n ⩾ 4, mean ± s.e.m., analysis of variance (ANOVA) P < 0.04, post hoc P < 0.04 for comparing the time spent in G1 phase in the ASD NPCs with those of the control NPCs, respectively). c Control and ASD NPCs were immunostained with 4′,6-diamidino-2- phenylindole (DAPI; blue), anti-pHH3 (green) and anti-ki67 (red) (scale bar: 200 μm). Representative images of the staining are shown. d Quantification of the percentage of Ki67+ − and Ki67+ pHH3+ −labeled cells are presented as mean ± s.e.m. (n ⩾ 5; *P < 0.03 for comparing the results of the ASD with those of the control NPCs). e Greater proliferation rates in ASD were correlated with greater early brain overgrowth. Pairwise correlation between individual brain size (volume) and respective NPC cell line proliferation rates (% of Ki67-positive cells). ASD displays reduced and deviant synaptic development as shown in panels f and g. f Representative images of synaptic processes from cells after neuronal differentiation (Map2, blue). The iPSC-derived neurons express markers for excitatory neurons, such as postsynaptic density protein 95 (PSD95, red) and vesicular glutamate transporter 1 (VGlut1, green) (scale bar: 5 μm). g Bar graphs show synaptic puncta size in ASD vs control neurons (P < 0.05 for comparing the results of the ASD with those of the control neurons), and GABA-positive neurons in all ASD-derived neurons compared with all controls (*P < 0.001). h ASD neural activity is sharply reduced. Representative image of number of spikes recorded over 10 min at 50 days of culture maturation (n = 3 wells per cell type). i ASD neural activity is sharply reduced. Top, total number of spikes from data obtained from controls (n = 6) and ASD (n = 10) clonal lines differentiating over 30 days and controls (n = 4) and ASD (n = 9) clonal lines at 50 days after differentiation over 10 min of recording. Results are presented as mean ± s.e.m. (*P = 0.0046 for comparing the results of the ASD with control networks). Bottom, number of network bursts from wells that were able to generate bursts (10 spikes over 100 ms). Results are presented as mean ± s.e.m. (*P < 0.0001 for comparing the results of the ASD with control networks). Images adapted from Marchetto et al. [54]
Fig. 3 Excess cell proliferation, abnormal synaptic development and reduced neural activity are associated with iPS cells of ASD toddlers with enlarged brains. a ASD iPS cells proliferate more rapidly than control. The iPS cells from ASD and control were differentiated to NPCs. From passages 2 to 6, cells were plated at the same density and population doubling time at each passage was calculated. Results of all lines (2 clones per line) are presented as mean ± s.e.m. (*repeated measurements P = 0.02, post hoc P < 0.04). b ASD cell cycle has abnormally short G1 phase. Adherent monolayer NPCs from control and ASD iPS cells were dissociated, counted for calculation of population doubling time and prepared for cell cycle analysis. Results are presented as the time spent in each cell cycle stage (n ⩾ 4, mean ± s.e.m., analysis of variance (ANOVA) P < 0.04, post hoc P < 0.04 for comparing the time spent in G1 phase in the ASD NPCs with those of the control NPCs, respectively). c Control and ASD NPCs were immunostained with 4′,6-diamidino-2- phenylindole (DAPI; blue), anti-pHH3 (green) and anti-ki67 (red) (scale bar: 200 μm). Representative images of the staining are shown. d Quantification of the percentage of Ki67+ − and Ki67+ pHH3+ −labeled cells are presented as mean ± s.e.m. (n ⩾ 5; *P < 0.03 for comparing the results of the ASD with those of the control NPCs). e Greater proliferation rates in ASD were correlated with greater early brain overgrowth. Pairwise correlation between individual brain size (volume) and respective NPC cell line proliferation rates (% of Ki67-positive cells). ASD displays reduced and deviant synaptic development as shown in panels f and g. f Representative images of synaptic processes from cells after neuronal differentiation (Map2, blue). The iPSC-derived neurons express markers for excitatory neurons, such as postsynaptic density protein 95 (PSD95, red) and vesicular glutamate transporter 1 (VGlut1, green) (scale bar: 5 μm). g Bar graphs show synaptic puncta size in ASD vs control neurons (P < 0.05 for comparing the results of the ASD with those of the control neurons), and GABA-positive neurons in all ASD-derived neurons compared with all controls (*P < 0.001). h ASD neural activity is sharply reduced. Representative image of number of spikes recorded over 10 min at 50 days of culture maturation (n = 3 wells per cell type). i ASD neural activity is sharply reduced. Top, total number of spikes from data obtained from controls (n = 6) and ASD (n = 10) clonal lines differentiating over 30 days and controls (n = 4) and ASD (n = 9) clonal lines at 50 days after differentiation over 10 min of recording. Results are presented as mean ± s.e.m. (*P = 0.0046 for comparing the results of the ASD with control networks). Bottom, number of network bursts from wells that were able to generate bursts (10 spikes over 100 ms). Results are presented as mean ± s.e.m. (*P < 0.0001 for comparing the results of the ASD with control networks). Images adapted from Marchetto et al. [54]CC BY · PubMed Central
Fig. 4 The majority of hcASD genes show peak expression during prenatal life in different brain regions. Heatmaps demonstrate the developmental expression patterns (x-axis) of 69 hcASD genes (y-axis) in different brain regions in prenatal and post-natal development. In the large neocortex heatmap, hierarchical clustering of neocortex developmental transcriptome reveals two main clusters of genes, one cluster displayed in green and the other in purple (see y-axis of heatmap). Proliferation and neurogenesis hcASD genes make the largest contribution to the green cluster, and synapse development and function hcASD genes make the largest contribution to the purple cluster; see the two pie charts on the far left. This clustering pattern is present across different neocortex regions and, to a lesser degree, in hippocampus and striatum (see green and purple hcASD gene cluster patterns on y-axis of the other six heatmaps). FC: frontal cortex, Hippo: Hippocampus, OC: occipital cortex, PC: parietal cortex, Str: striatum, TC: temporal cortex.
Fig. 4 The majority of hcASD genes show peak expression during prenatal life in different brain regions. Heatmaps demonstrate the developmental expression patterns (x-axis) of 69 hcASD genes (y-axis) in different brain regions in prenatal and post-natal development. In the large neocortex heatmap, hierarchical clustering of neocortex developmental transcriptome reveals two main clusters of genes, one cluster displayed in green and the other in purple (see y-axis of heatmap). Proliferation and neurogenesis hcASD genes make the largest contribution to the green cluster, and synapse development and function hcASD genes make the largest contribution to the purple cluster; see the two pie charts on the far left. This clustering pattern is present across different neocortex regions and, to a lesser degree, in hippocampus and striatum (see green and purple hcASD gene cluster patterns on y-axis of the other six heatmaps). FC: frontal cortex, Hippo: Hippocampus, OC: occipital cortex, PC: parietal cortex, Str: striatum, TC: temporal cortex.CC BY · PubMed Central
Fig. 5 Distribution of 58 hcASD genes in four main categories of neural development. Functional annotation could be found for 58 hcASD genes based on a manual literature search. Most highly penetrant ASD genes are pleiotropic, being involved in multiple stages of brain development. The small pie-charts in each region indicate the percentage of genes in green and purple clusters from Fig. 4. The gray color in pie-charts represents percentage of genes with no strong expression level in fetal and early post-natal periods. A gene is marked by an asterisk (*) if its function was inferred from evidence in adult neural stem cells, embryonic or hematopoietic stem cells, central nervous system other than brain, or, for one gene, cancer (see Table S2 for details and references).
Fig. 5 Distribution of 58 hcASD genes in four main categories of neural development. Functional annotation could be found for 58 hcASD genes based on a manual literature search. Most highly penetrant ASD genes are pleiotropic, being involved in multiple stages of brain development. The small pie-charts in each region indicate the percentage of genes in green and purple clusters from Fig. 4. The gray color in pie-charts represents percentage of genes with no strong expression level in fetal and early post-natal periods. A gene is marked by an asterisk (*) if its function was inferred from evidence in adult neural stem cells, embryonic or hematopoietic stem cells, central nervous system other than brain, or, for one gene, cancer (see Table S2 for details and references).CC BY · PubMed Central
Fig. 6 The RAS/ERK, PI3K/AKT, WNT and β-catenin signaling pathways are involved in different stages of brain development and are commonly disrupted in ASD. The schematic on the left indicates that these signaling pathways are highly interconnected and modulate different aspects of brain development. For this illustration, the pathways are simplified and some intermediate genes are not shown. In the table on the right, a plus sign (+) for each pathway indicates that its dysregulation has been reported in the corresponding fetal developmental stages based on studies on either hcASD genes, ASD-derived neurons, or both (double plus signs).
Fig. 6 The RAS/ERK, PI3K/AKT, WNT and β-catenin signaling pathways are involved in different stages of brain development and are commonly disrupted in ASD. The schematic on the left indicates that these signaling pathways are highly interconnected and modulate different aspects of brain development. For this illustration, the pathways are simplified and some intermediate genes are not shown. In the table on the right, a plus sign (+) for each pathway indicates that its dysregulation has been reported in the corresponding fetal developmental stages based on studies on either hcASD genes, ASD-derived neurons, or both (double plus signs).CC BY · PubMed Central
Fig. 7 In a single litter, a single prenatal poly(I:C) injection may cause different cortical layering defects across pups that resemble some types of focal cortical dysplasias seen in different individuals with ASD. a Expression of multiple layer-specific markers (II–IV and V, VI) in mouse cortex from Choi and colleagues [81, 132]. Typical mouse cortex layer development is shown in upper left corner (PBS), while heterogeneous types of focal cortical dysplasia are caused by prenatal maternal immune activation (MIA) by synthetic dsRNA, poly(I:C) as shown in the other three panels. b In a single litter, a single prenatal poly(I:C) injection may cause different layering defects across pups including protrusions, intrusions and laminar disorganization and other types of focal cortical dysplasia as well as pups with typical cortex. The cortical and ASD-like behavioral MIA-caused phenotypes are dependent on maternal IL-17a. c A 9 year old ASD postmortem case with ADNP gene mutation has focal macroscopic frontal cortical surface malformation (white arrow) and interruption of underlying cortical layering as visualized by expression of multiple layer-specific and cell type specific markers (see region marked by the two light blue arrows; see Fig. 1 in Stoner et al [34]). Different marker genes represented by different colors. This focal region also has clusters of mis-migrated cells (not shown in this section). Inset shows the same cortex location visualized by nissl staining to further reveal surface undulation and protrusion (see black arrow). A 2 year old ASD postmortem case shown in d with surface intrusions visualized by nissl staining and in e with surface intrusion visualized by multiple layer-specific and cell type specific markers [34]. Adapted from Choi et al. [132] and Stoner et al. [34]
Fig. 7 In a single litter, a single prenatal poly(I:C) injection may cause different cortical layering defects across pups that resemble some types of focal cortical dysplasias seen in different individuals with ASD. a Expression of multiple layer-specific markers (II–IV and V, VI) in mouse cortex from Choi and colleagues [81, 132]. Typical mouse cortex layer development is shown in upper left corner (PBS), while heterogeneous types of focal cortical dysplasia are caused by prenatal maternal immune activation (MIA) by synthetic dsRNA, poly(I:C) as shown in the other three panels. b In a single litter, a single prenatal poly(I:C) injection may cause different layering defects across pups including protrusions, intrusions and laminar disorganization and other types of focal cortical dysplasia as well as pups with typical cortex. The cortical and ASD-like behavioral MIA-caused phenotypes are dependent on maternal IL-17a. c A 9 year old ASD postmortem case with ADNP gene mutation has focal macroscopic frontal cortical surface malformation (white arrow) and interruption of underlying cortical layering as visualized by expression of multiple layer-specific and cell type specific markers (see region marked by the two light blue arrows; see Fig. 1 in Stoner et al [34]). Different marker genes represented by different colors. This focal region also has clusters of mis-migrated cells (not shown in this section). Inset shows the same cortex location visualized by nissl staining to further reveal surface undulation and protrusion (see black arrow). A 2 year old ASD postmortem case shown in d with surface intrusions visualized by nissl staining and in e with surface intrusion visualized by multiple layer-specific and cell type specific markers [34]. Adapted from Choi et al. [132] and Stoner et al. [34]CC BY · PubMed Central
Fig. 8 ASD is a multistage, progressive disorder of prenatal brain development. ASD children show a continuum of disorder severity because a wide range of heterogeneous insults can affect brain development in a not fully deterministic way. We propose the general theory that ASD arises from disruption of gene regulatory circuits with multiscale, hierarchical consequences on brain development starting from very early fetal stages. One possible prenatal trajectory of ASD is illustrated here. As compared with four fetal stages illustrated in typical development (lower panel; increasing fetal age from left to right), this ASD trajectory begins in the 1st and 2nd trimesters with abnormally high rates of proliferation; this results in excess neural precursor cells (ASD first panel). Disorder continues with disruption of migration, laminar disorganization, reduced cell growth, and reduced neurite outgrowth, resulting in neurons with a 10-fold decrease in spontaneous neural activity (ASD second panel). At still later stages, ASD neurons show defects in synaptogenesis, receptor and neurotransmitter development (ASD third panel). This deviant development of neurons leads to abnormal neural circuitry with a 6-fold decrease in synchronized bursts of neural network activity (ASD fourth panel). This also illustrates that ASD pathogenesis is not set at one point in time and does not reside in one process, but rather is a cascade of pathogenic processes. Different causes and prenatal times of insult combined with individual-dependent background genetics may alter details of developmental trajectories, resulting in differences in number, size and type of neurons in different cortical layers as well as number and functionality of synapses. This fetal heterogeneity leads to post-natal heterogeneity in neural circuits, behavior and clinical outcomes. Discovery of prenatal causes, processes and trajectories as they occur in children with ASD requires a paradigm shift: the ASD Living Biology approach. Courtesy of Eric Courchesne and Vahid H. Gazestani
Fig. 8 ASD is a multistage, progressive disorder of prenatal brain development. ASD children show a continuum of disorder severity because a wide range of heterogeneous insults can affect brain development in a not fully deterministic way. We propose the general theory that ASD arises from disruption of gene regulatory circuits with multiscale, hierarchical consequences on brain development starting from very early fetal stages. One possible prenatal trajectory of ASD is illustrated here. As compared with four fetal stages illustrated in typical development (lower panel; increasing fetal age from left to right), this ASD trajectory begins in the 1st and 2nd trimesters with abnormally high rates of proliferation; this results in excess neural precursor cells (ASD first panel). Disorder continues with disruption of migration, laminar disorganization, reduced cell growth, and reduced neurite outgrowth, resulting in neurons with a 10-fold decrease in spontaneous neural activity (ASD second panel). At still later stages, ASD neurons show defects in synaptogenesis, receptor and neurotransmitter development (ASD third panel). This deviant development of neurons leads to abnormal neural circuitry with a 6-fold decrease in synchronized bursts of neural network activity (ASD fourth panel). This also illustrates that ASD pathogenesis is not set at one point in time and does not reside in one process, but rather is a cascade of pathogenic processes. Different causes and prenatal times of insult combined with individual-dependent background genetics may alter details of developmental trajectories, resulting in differences in number, size and type of neurons in different cortical layers as well as number and functionality of synapses. This fetal heterogeneity leads to post-natal heterogeneity in neural circuits, behavior and clinical outcomes. Discovery of prenatal causes, processes and trajectories as they occur in children with ASD requires a paradigm shift: the ASD Living Biology approach. Courtesy of Eric Courchesne and Vahid H. GazestaniCC BY · PubMed Central

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89 Not checked yet · 26 Own interpretation · 8 Own result · 6 Partly supported · 6 No basis given · 3 Supported · accuracy not yet measured

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  • It may state two separate claims as one. 54
  • Probably not a substantial claim. 1
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  • 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”
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Metadata

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
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

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