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Cited by 536Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology Research

Autism spectrum disorder: neuropathology and animal models

Open access
Varghese, Merina, Keshav, Neha, Jacot-Descombes, Sarah, Warda, Tahia, Wicinski, Bridget, Dickstein, Dara L., Harony-Nicolas, Hala, De Rubeis, Silvia +3 more·2017·Acta Neuropathologica
DOI 10.1007/s00401-017-1736-4PMC PMC5693718
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Abstract

Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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Crossref · 10.1007/s00401-017-1736-4

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  • Premisecitation

    In young children with ASD, global brain developmental abnormalities occur in the archicortex, cerebellum, brainstem, and other subcortical structures, with severity varying by region.

    “Global brain developmental abnormalities manifest in the archicortex, cerebellum, brainstem, and other subcortical structures, with region-specific severity of neuropathology, in young children with ASD [376, 377].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [376] Wegiel J, Flory M, Kuchna I, Nowicki K, Ma SY, Imaki H, Cohen IL, London E, Brown WT, Wisniewski T (2014) Acta Neuropathol Commun 2:28. doi: 10.1186/2051-5960-2-28 source

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    • cites [377] Wegiel J, Flory M, Kuchna I, Nowicki K, Ma SY, Imaki H, Frackowiak J, Kolecka BM, Wierzba-Bobrowicz T, London E et al (2015) Acta Neuropathol Commun 3:2. doi: 10.1186/s40478-015-0183-5 source

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  • Premisecitation

    Vascular remodeling persists beyond childhood in the superior temporal cortex, fusiform cortex, midbrain, and cerebellum in ASD, indicated by nestin-immunoreactive pericytes and CD-34-immunoreactive endothelial cells.

    “The presence of nestin-immunoreactive pericytes and CD-34-immunoreactive endothelial cells indicates that vascular remodeling persists in the superior temporal cortex, fusiform cortex, midbrain and cerebellum in ASD beyond childhood when they usually decline in controls [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Azmitia EC, Saccomano ZT, Alzoobaee MF, Boldrini M, Whitaker-Azmitia PM (2016) J Autism Dev Disord 46:1307–1318. doi: 10.1007/s10803-015-2672-6 source

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  • Premisecitation

    Young children with ASD have significantly reduced neuronal and cytoplasmic volumes in most examined areas compared with age-matched controls.

    “Young children with ASD have significantly reduced neuronal and cytoplasmic volumes in the majority of examined areas compared to age-matched controls [376, 377].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [376] Wegiel J, Flory M, Kuchna I, Nowicki K, Ma SY, Imaki H, Cohen IL, London E, Brown WT, Wisniewski T (2014) Acta Neuropathol Commun 2:28. doi: 10.1186/2051-5960-2-28 source

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    • cites [377] Wegiel J, Flory M, Kuchna I, Nowicki K, Ma SY, Imaki H, Frackowiak J, Kolecka BM, Wierzba-Bobrowicz T, London E et al (2015) Acta Neuropathol Commun 3:2. doi: 10.1186/s40478-015-0183-5 source

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  • Interpretationreasoning

    The dysplasia and heterotopia observed in ASD reflect altered neuronal maturation and migration.

    “These defects reflect alterations in neuronal maturation and migration processes in subjects with ASD.”
    Quote in the paperSubstantial claim
  • Premisecitation

    A subset of individuals with ASD has increased brain size and head circumference relative to normal age-based values.

    “The brain size as well as the head circumference of a subset of subjects with ASD is increased compared to normal age-based values (see meta-analysis in [308]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [308] Sacco R, Gabriele S, Persico AM (2015) Psychiatry Res 234:239–251. doi: 10.1016/j.pscychresns.2015.08.016 source

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    Premisecitation

    Reelin expression is decreased in ASD brains, although the density of Reelin-expressing layer I neurons in the superior temporal cortex is comparable to controls.

    “Expression of Reelin, a protein necessary for neuronal migration during cortical lamination, is decreased in brains from subjects with ASD, although the density of layer I neurons expressing Reelin in the superior temporal cortex of subjects with ASD is comparable to that in controls [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Camacho J, Ejaz E, Ariza J, Noctor SC, Martínez-Cerdeño V (2014) Neurosci Lett 579:163–167. doi: 10.1016/j.neulet.2014.07.031 source

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    Premisecitation

    The number of parvalbumin-immunoreactive interneurons, but not calbindin- or calretinin-expressing ones, is decreased in the medial PFC in ASD, and this decrease is due to fewer chandelier interneurons.

    “The number of parvalbumin-immunoreactive interneurons, but not those expressing calbindin or calretinin, is decreased in the medial PFC [148], which was recently confirmed to be due to fewer chandelier interneurons [12].”
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    • cites [148] Hashemi E, Ariza J, Rogers H, Noctor SC, Martínez-Cerdeño V (2016) Cereb Cortex. doi: 10.1093/cercor/bhw021 source

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    • cites [12] Ariza J, Rogers H, Hashemi E, Noctor SC, Martínez-Cerdeño V (2016) Cereb Cortex. doi: 10.1093/cercor/bhw349 source

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    Premisecitation

    Cortical dysplasia and heterotopia of misplaced neurons can be detected in ASD individuals, and in some cases both occur in the same person.

    “Disorganized cortical structure (dysplasia) and nodules of misplaced neurons (heterotopia) can be detected in individuals with ASD; in some cases dysplasia and heterotopia are observed concomitantly in the same individual [59, 339, 379].”
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    • cites [59] Casanova MF, El-Baz AS, Kamat SS, Dombroski BA, Khalifa F, Elnakib A, Soliman A, Allison-McNutt A, Switala AE (2013) Acta Neuropathol Commun 1:67. doi: 10.1186/2051-5960-1-67 source

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    • cites [339] Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E (2014) N Engl J Med 370:1209–1219. doi: 10.1056/NEJMoa1307491 source

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    • cites [379] Wegiel J, Kuchna I, Nowicki K, Imaki H, Marchi E, Ma SY, Chauhan A, Chauhan V, Bobrowicz TW, de Leon M et al (2010) Acta Neuropathol 119:755–770. doi: 10.1007/s00401-010-0655-4 source

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    Study design and conductreasoning

    Neuropathology studies of ASD are constrained by marked etiological and phenotypic heterogeneity and small samples, averaging 7.43 cases per study, so their reports should be treated as provisional until replicated.

    “However, with the extreme etiological and phenotypic heterogeneity of ASD and the small sample size (average number of cases/study = 7.43), all reports should be considered provisional and awaiting replication.”
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    Premisecitation

    ASD hippocampal neurons show reduced dendritic branching compared with controls, and the PFC shows fewer dendrites as detected by microtubule-associated protein 2 immunoreactivity.

    “Neurons show reduced dendritic branching in the hippocampus of ASD subjects compared to controls [296] and fewer dendrites as detected by microtubule-associated protein 2 immunoreactivity in the PFC [248].”
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    • cites [296] Raymond GV, Bauman ML, Kemper TL (1996) Acta Neuropathol 91:117–119 source

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    • cites [248] Mukaetova-Ladinska EB, Arnold H, Jaros E, Perry R, Perry E (2004) Neuropathol Appl Neurobiol 30:615–623. doi: 10.1111/j.1365-2990.2004.00574.x source

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    Premisecitation

    ASD brains show disorganized gray and white matter, including thickening in the subependymal layer.

    “Overall, there is a disorganization of gray and white matter in the form of thickening in the subependymal layer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [379] Wegiel J, Kuchna I, Nowicki K, Imaki H, Marchi E, Ma SY, Chauhan A, Chauhan V, Bobrowicz TW, de Leon M et al (2010) Acta Neuropathol 119:755–770. doi: 10.1007/s00401-010-0655-4 source

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    Interpretationreasoning

    The larger brain size seen in many ASD subjects may arise either from an increased number of neurons or from unchanged neuron numbers with increased neuropil.

    “The increase in brain size in many subjects with ASD may be due to various underlying reasons as discussed below, including an increase in the number of neurons or no change in neuron numbers but increased neuropil.”
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    Premisecitation

    ASD subjects have a significant increase in neuropil in the frontopolar region and anterior cingulate gyrus, but not in primary visual, motor, somatosensory, or dorsolateral prefrontal association cortices.

    “Subjects with ASD also have a significant increase in neuropil, comprising the dendrites, non-myelinated axons, synapses, vasculature and glial cell processes present in between cell bodies, in the frontopolar region and the anterior cingulate gyrus, but not in the primary visual, motor, and somatosensory and dorsolateral prefrontal association cortices [54].”
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    • cites [54] Casanova MF (2006) Neuroscientist 12:435–441. doi: 10.1177/1073858406290375 source

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    Interpretationcitation

    The convergence of neuronal size distributions between ASD and controls in adulthood likely reflects opposing developmental trajectories, with nuclear volume increasing with age in ASD in half of examined areas while control nuclear volumes decrease in most areas.

    “This is likely a result of opposing developmental trajectories, with nuclear volume increasing with age in ASD in half of the examined brain areas, whereas nuclear volumes are reduced in most brain areas of controls as they aged [377].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [377] Wegiel J, Flory M, Kuchna I, Nowicki K, Ma SY, Imaki H, Frackowiak J, Kolecka BM, Wierzba-Bobrowicz T, London E et al (2015) Acta Neuropathol Commun 3:2. doi: 10.1186/s40478-015-0183-5 source

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    Study design and conductreasoning

    Minicolumn findings in ASD come from one group using indirect two-dimensional quantification rather than three-dimensional stereology, so they require caution until independently replicated.

    “However, all these studies of minicolumn changes in ASD originated from one group that uses an indirect method of quantification from 2-dimensional images rather than 3-dimensional stereological techniques; hence, these findings need to be interpreted with caution until they are independently replicated.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Microglia density is significantly increased in both the frontoinsular cortex and visual cortex in ASD, suggesting the increase may be present throughout the brain.

    “One study quantified microglia density in the frontoinsular cortex and the visual cortex, and found significantly increased density in both, concluding that this increase in microglia is likely present throughout the brain [352].”
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    • cites [352] Tetreault NA, Hakeem AY, Jiang S, Williams BA, Allman E, Wold BJ, Allman JM (2012) J Autism Dev Disord 42:2569–2584. doi: 10.1007/s10803-012-1513-0 source

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    Premisecitation

    One study reported a 67% increase in neuron number in the entire PFC of boys with ASD, with a 79% increase in dorsolateral PFC and a 29% increase in medial PFC.

    “Although one study reported a 67% increase in neuron number in the entire PFC of boys with ASD, with a striking 79% increase in the dorsolateral PFC and a 29% increase in the medial PFC, these results need to be interpreted with caution as the method used to estimate the volume of reference for the regions of interests in order to derive total cell counts is difficult to assess based on the report”
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    • cites [77] Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, Pierce K (2011) JAMA 306:2001–2010. doi: 10.1001/jama.2011.1638 source

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    Premisecitation

    ASD subjects have significantly lower neuron densities in fusiform gyrus layer III, lower total neuron numbers in layers III, V, and VI, and smaller mean perikaryal volumes in layers V and VI compared with controls.

    “Subjects with ASD have significantly lower neuron densities in layer III, significantly lower total neuron numbers in layers III, V, and VI, and significantly smaller mean perikaryal volumes in layers V and VI of the FG (Figure 2), compared to controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [362] van Kooten IA, Palmen SJ, von Cappeln P, Steinbusch HW, Korr H, Heinsen H, Hof PR, van Engeland H, Schmitz C (2008) Brain 131:987–999. doi: 10.1093/brain/awn033 source

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    Premisecitation

    ASD subjects have increased volume of white matter hypointensities around ventricles and in deep subcortical areas compared with controls, and these changes remain static with age, suggesting a developmental origin.

    “Subjects with ASD have increased volume of white matter hypointensities around ventricles and in deep subcortical areas as compared to controls, the changes remaining static with age suggesting a developmental origin [34].”
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    • cites [34] Blackmon K, Ben-Avi E, Wang X, Pardoe HR, Di Martino A, Halgren E, Devinsky O, Thesen T, Kuzniecky R (2016) Neuroimage Clin 10:36–45. doi: 10.1016/j.nicl.2015.10.017 source

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    Premisecitation

    ASD patients have smaller and more numerous minicolumns with more dispersed neurons in Brodmann areas 9, 21, and 22, while Asperger's syndrome patients have smaller, less compact minicolumns in the temporal neocortex.

    “Patients with ASD have smaller and more numerous minicolumns with more dispersed neurons in Brodmann’s areas 9, 21, and 22 [57, 58], and patients with Asperger’s syndrome have smaller, less compact minicolumns in the temporal neocortex [56].”
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    • cites [57] Casanova MF, Buxhoeveden DP, Switala AE, Roy E (2002) Neurology 58:428–432 source

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    • cites [58] Casanova MF, Buxhoeveden DP, Switala AE, Roy E (2002) J Child Neurol 17:515–521 source

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    • cites [56] Casanova MF, Buxhoeveden DP, Switala AE, Roy E (2002) J Child Neurol 17:142–145 source

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    Premisecitation

    Nlgn3R704C KI mice show decreased AMPA but not NMDA or GABA receptor-mediated hippocampal neurotransmission, possibly due to increased internalization of AMPA receptors.

    “Another mouse model mimicking an ASD-related mutation [393], the Nlgn3R704C KI shows decreased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), but not N-Methyl-D-aspartic acid (NMDA) or GABA, receptor-mediated hippocampal neurotransmission [100], possibly due to increased internalization of AMPA receptors [62].”
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    • cites [100] Etherton MR, Tabuchi K, Sharma M, Ko J, Südhof TC (2011) EMBO J 30:2908–2919. doi: 10.1038/emboj.2011.182 source

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    • cites [62] Chanda S, Aoto J, Lee SJ, Wernig M, Südhof TC (2016) Mol Psychiatry 21:169–177. doi: 10.1038/mp.2015.20 source

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    Premisecitation

    In young children with ASD, deep cerebellar nuclei and inferior olivary neurons appear enlarged, but with age these neurons become reduced in size.

    “In young children with ASD, deep cerebellar nuclei and inferior olivary neurons appear enlarged, but with age these neurons become reduced in size [191].”
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    • cites [191] Kemper TL, Bauman ML (1993) Neurol Clin 11:175–187 source

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    Interpretationreasoning

    Studies implicate the cerebellum in ASD pathology, although there is no clear mechanistic relationship between cerebellar neuropathologic alterations and symptomatic manifestations.

    “Although there is not a clear mechanistic relationship between the neuropathologic alterations observed in the cerebellum in ASD and the symptomatic manifestations of the disorder, the previously discussed studies implicate this region in ASD pathology.”
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    Interpretationreasoning

    Characterization of genetically modified animal models has led to identification of biochemical pathways likely relevant to a wider population and yielded promising results for novel ASD drugs.

    “The characterization of genetically modified animal models created based on these discoveries has led to the identification of biochemical pathways likely to be relevant to a wider population and has yielded promising results with regard to the development of novel ASD drugs.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Young children with ASD show anterior midcingulate cortex neuropathology, with a positive correlation between ASD severity and the number of pyramidal neurons and von Economo neurons, and they have significantly smaller pyramidal neurons than controls.

    “Young children with ASD do present with neuropathology in the aMCC, showing a positive correlation between ASD severity and number of pyramidal neurons and VENs [360]. Additionally, young children with ASD have significantly smaller pyramidal neurons than controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [360] Uppal N, Wicinski B, Buxbaum JD, Heinsen H, Schmitz C, Hof PR (2014) J Neuropathol Exp Neurol 73:891–902. doi: 10.1097/NEN.0000000000000108 source

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    Premisecitation

    Nlgn3 KI mice show greater postnatal turnover of excitatory spines in layer II and III pyramidal neurons in the anterior frontal cortex and increased vesicular GABA transporter expression without changes in inhibitory synapse number or ultrastructure in the somatosensory cortex.

    “Synaptic changes in the Nlgn3 KI mice include greater postnatal turnover of excitatory spines in layer II and III pyramidal neurons in the anterior frontal cortex [172], and increased vesicular GABA transporter expression without changes in inhibitory synapse number or ultrastructure in neurons in the somatosensory cortex [345].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] Isshiki M, Tanaka S, Kuriu T, Tabuchi K, Takumi T, Okabe S (2014) Nat Commun 5:4742. doi: 10.1038/ncomms5742 source

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    • cites [345] Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC (2007) Science 318:71–76. doi: 10.1126/science.1146221 source

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    Premisecitation

    ASD is one of the most heritable psychiatric disorders, with heritability estimated at about 50% and monozygotic twin concordance rates between 70 and 90%.

    “Twin, family and population-based studies have shown ASD to be one of the most heritable of all psychiatric disorders, with heritability estimated at ~50% (see reviews in [119, 310]) and monozygotic twin concordance rates between 70 to 90% [1, 113, 139, 304, 344].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [119] Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J et al (2014) Nat Genet 46:881–885. doi: 10.1038/ng.3039 source

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    • cites [310] Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A (2014) JAMA 311:1770–1777. doi: 10.1001/jama.2014.4144 source

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    • cites [1] Abrahams BS, Geschwind DH (2008) Nat Rev Genet 9:341–355. doi: 10.1038/nrg2346 source

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    • cites [139] Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K et al (2011) Arch Gen Psychiatry 68:1095–1102. doi: 10.1001/archgenpsychiatry.2011.76 source

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    Premisecitation

    Early assessments of the amygdala in ASD report decreased size and increased neuron density in the medial, central, and cortical nuclei.

    “Early assessments of the amygdala in ASD report decreased size and increased neuron density in the medial, central, and cortical nuclei [23, 191]”
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    • cites [23] Bauman M, Kemper TL (1985) Neurology 35:866–874 source

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    • cites [191] Kemper TL, Bauman ML (1993) Neurol Clin 11:175–187 source

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    Interpretationcitation

    Data support the notion that neuroligins regulate the balance between inhibitory and excitatory transmission and that enhanced inhibitory transmission in Nlgn3 KIs is due to increased strength of inhibitory synapses rather than a change in synapse number.

    “Taken together, these data support the notion that neuroligins play a pivotal role in regulating the balance between inhibitory and excitatory transmission and that the enhanced inhibitory transmission in Nlgn3 KIs is due to increased strength of inhibitory synapses rather than a change in the number of synapses [345].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [345] Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC (2007) Science 318:71–76. doi: 10.1126/science.1146221 source

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    Premisecitation

    A subset of subjects with ASD have olivary dysplasia and abnormally placed neurons relative to the olivary complex.

    “Similarly, a subset of subjects with ASD have olivary dysplasia and abnormally placed neurons, relative to the olivary complex [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, Rutter M, Lantos P (1998) Brain 121(Pt 5):889–905 source

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    Interpretationreasoning

    The stark differences between amygdala study results may be accounted for by epileptic comorbidity in early cases and differences in quantification methodologies.

    “The stark differences between the results of these studies may be accounted for by the presence of epileptic comorbidity in many of the cases in early studies, as well as by the differences in quantification methodologies.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The primary visual area and whole cortical gray matter show no differences between ASD subjects and controls, confirming that the fusiform gyrus changes are region-specific.

    “The primary visual area and the whole cortical gray matter show no differences between subjects with ASD and controls, confirming that the observed changes are FG-specific.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [362] van Kooten IA, Palmen SJ, von Cappeln P, Steinbusch HW, Korr H, Heinsen H, Hof PR, van Engeland H, Schmitz C (2008) Brain 131:987–999. doi: 10.1093/brain/awn033 source

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    Premisecitation

    Von Economo neurons are consistently affected in ASD and are present almost exclusively in the frontoinsular and anterior cingulate cortices.

    “a particular population of distinct neurons, the von Economo neurons (VENs), present almost exclusively in the frontoinsular (FI) and anterior cingulate cortices (ACC) have been found to be consistently affected in ASD [4, 104, 256, 258].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Allman J, Hakeem A, Watson K (2002) Neuroscientist 8:335–346 source

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    • cites [104] Fajardo C, Escobar MI, Buritica E, Arteaga G, Umbarila J, Casanova MF, Pimienta H (2008) Neurosci Lett 435:215–218. doi: 10.1016/j.neulet.2008.02.048 source

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    • cites [256] Nimchinsky EA, Gilissen E, Allman JM, Perl DP, Erwin JM, Hof PR (1999) Proc Natl Acad Sci USA 96:5268–5273 source

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    • cites [258] Nimchinsky EA, Vogt BA, Morrison JH, Hof PR (1995) J Comp Neurol 355:27–37 source

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    Premisecitation

    In the anterior cingulate cortex of ASD subjects, neuronal densities are higher in layers I-III of area 24a in the left hemisphere, neuronal size is reduced in all layers of area 24b, and packing density is reduced in layers V-VI of area 24c.

    “Neuronal densities are higher in layers I-III of area 24a in the left hemisphere, neuronal size is reduced in all layers of area 24b, and neuronal packing density is reduced in layers V-VI in area 24c, consistent with previously reported reductions in neuronal density in the FG and amygdala [318, 362].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [327] Simms ML, Kemper TL, Timbie CM, Bauman ML, Blatt GJ (2009) Acta Neuropathol 118:673–684. doi: 10.1007/s00401-009-0568-2 source

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    • cites [318] Schumann CM, Amaral DG (2006) J Neurosci 26:7674–7679. doi: 10.1523/JNEUROSCI.1285-06.2006 source

      Not checked in the free run.

    • cites [362] van Kooten IA, Palmen SJ, von Cappeln P, Steinbusch HW, Korr H, Heinsen H, Hof PR, van Engeland H, Schmitz C (2008) Brain 131:987–999. doi: 10.1093/brain/awn033 source

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    Premisecitation

    There is no significant difference between ASD subjects and controls in packing density of basket and stellate interneurons or in their ratio to Purkinje neurons.

    “No significant difference was found between ASD subjects and controls in packing density of either type of interneuron or in their ratio to Purkinje neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [386] Whitney ER, Kemper TL, Rosene DL, Bauman ML, Blatt GJ (2009) J Neurosci Res 87:2245–2254. doi: 10.1002/jnr.22056 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nlgn4 KO mice have decreased volume of the whole brain, cerebellum, and brainstem.

    “Nlgn4 KO mice have decreased volume of the whole brain, as well as the cerebellum and brainstem, as detected by MRI [175].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J, Ronnenberg A, Winter D et al (2008) Proc Natl Acad Sci USA 105:1710–1715. doi: 10.1073/pnas.0711555105 source

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  • May combine two claims.

    Interpretationcitation

    These changes are apparently due to a delay in development and synapse formation in neurons resulting from Mecp2 haploinsufficiency, abnormalities that do not recover with age.

    “These changes are apparently due to a delay in development and synapse formation in neurons resulting from Mecp2 haploinsufficiency [115, 330], which are abnormalities in development that do not recover with age.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Fukuda T, Itoh M, Ichikawa T, Washiyama K, Goto Y (2005) J Neuropathol Exp Neurol 64:537–544 source

      Not checked in the free run.

    • cites [330] Smrt RD, Eaves-Egenes J, Barkho BZ, Santistevan NJ, Zhao C, Aimone JB, Gage FH, Zhao X (2007) Neurobiol Dis 27:77–89. doi: 10.1016/j.nbd.2007.04.005 source

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  • May combine two claims.

    Premisecitation

    Expansion of the CGG repeat over 200 copies leads to transcriptional silencing of the gene and loss of FMRP.

    “The expansion of the CGG repeat over 200 copies leads to the transcriptional silencing of the gene and loss of the fragile X mental retardation protein (FMRP).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Bagni C, Tassone F, Neri G, Hagerman R (2012) J Clin Invest 122:4314–4322. doi: 10.1172/JCI63141 source

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  • May combine two claims.

    Premisecitation

    Cntnap2−/− mice show abnormal migration of neurons in the corpus callosum and somatosensory cortex, have fewer parvalbumin-immunoreactive interneurons in the hippocampus and striatum, fewer GABAergic interneurons in the somatosensory cortex, and fewer oxytocin-expressing neurons in the hypothalamic paraventricular nucleus.

    “When compared to WT controls, Cntnap2−/− mice show abnormal migration of neurons in the corpus callosum and somatosensory cortex, have fewer parvalbumin-immunoreactive interneurons in the hippocampus and striatum, fewer GABAergic interneurons in the somatosensory cortex [278] and fewer oxytocin-expressing neurons in the hypothalamic paraventricular nucleus [279].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [278] Peñagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, Sonnenblick LI, Gruver R, Almajano J, Bragin A et al (2011) Cell 147:235–246. doi: 10.1016/j.cell.2011.08.040 source

      Not checked in the free run.

    • cites [279] Peñagarikano O, Lazaro MT, Lu XH, Gordon A, Dong H, Lam HA, Peles E, Maidment NT, Murphy NP, Yang XW et al (2015) Sci Transl Med 7(271r):a278. doi: 10.1126/scitranslmed.3010257 source

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    Premisecitation

    Shank3B−/− mice show increased dendritic length and complexity but reduced spine density, PSD length, and thickness in striatal medium spiny neurons.

    “Deletion of the two longer Shank3 isoforms (Shank3α and β) in the Shank3B−/− mice is associated with increased dendritic length and complexity but reduced spine density, PSD length and thickness in striatal medium spiny neurons [277].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [277] Peça J, Feliciano C, Ting JT, Wang WT, Wells MF, Venkatraman TN, Lascola CD, Fu ZY, Feng GP (2011) Nature 472:437–442. doi: 10.1038/nature09965 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fragile X syndrome is caused by expansion of a CGG trinucleotide in the promoter of the FMR1 gene or, more rarely, by point mutations.

    “Fragile X syndrome is caused by expansion of a cytosine-guanine-guanine (CGG) trinucleotide in the promoter of the fragile X mental retardation (FMR1) gene or, more rarely, due to point mutations [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Bagni C, Tassone F, Neri G, Hagerman R (2012) J Clin Invest 122:4314–4322. doi: 10.1172/JCI63141 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knock-down of the CHD8 ortholog results in macrocephaly in zebrafish and increased brain weight and volume in mice, phenotypes that reflect clinical observations in subjects with loss-of-function mutations in the gene.

    “Knock-down of the CHD8 ortholog results in macrocephaly in zebrafish [32, 343] and increased brain weight and volume [187, 287] in mice, phenotypes that reflect clinical observations in subjects with loss-of-function mutations in the gene [32].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [32] Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT et al (2014) Cell 158:263–276. doi: 10.1016/j.cell.2014.06.017 source

      Not checked in the free run.

    • cites [343] Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J et al (2014) Proc Natl Acad Sci USA 111:E4468–E4477. doi: 10.1073/pnas.1405266111 source

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    • cites [187] Katayama Y, Nishiyama M, Shoji H, Ohkawa Y, Kawamura A, Sato T, Suyama M, Takumi T, Miyakawa T, Nakayama KI (2016) Nature 537:675–679. doi: 10.1038/nature19357 source

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    • cites [287] Platt RJ, Zhou Y, Slaymaker IM, Shetty AS, Weisbach NR, Kim JA, Sharma J, Desai M, Sood S, Kempton HR et al (2017) Cell Rep 19:335–350. doi: 10.1016/j.celrep.2017.03.052 source

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  • May combine two claims.

    Premisecitation

    Triple and double Nrxn KO mice show fewer inhibitory synapses in the brainstem and neocortex, respectively, compared to wild-type controls.

    “Triple and double KO mice show fewer inhibitory synapses in the brainstem and neocortex, respectively, compared to the wild-type (WT) controls [242].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Missler M, Zhang W, Rohlmann A, Kattenstroth G, Hammer RE, Gottmann K, Südhof TC (2003) Nature 423:939–948. doi: 10.1038/nature01755 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMRP is an RNA-binding protein that interacts with specific mRNAs in the brain and regulates synaptic plasticity-dependent local protein synthesis.

    “FMRP is an RNA-binding protein known to interact with specific mRNAs in the brain and regulate synaptic plasticity-dependent local protein synthesis [18, 80, 275].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Bagni C, Tassone F, Neri G, Hagerman R (2012) J Clin Invest 122:4314–4322. doi: 10.1172/JCI63141 source

      Not checked in the free run.

    • cites [80] Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW et al (2011) Cell 146:247–261. doi: 10.1016/j.cell.2011.06.013 source

      Not checked in the free run.

    • cites [275] Pasciuto E, Bagni C (2014) Cell 158(1446–1446):e1441. doi: 10.1016/j.cell.2014.08.035 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Human fragile X neuropathology shows long spines, reduced PSD length, almost no stubby spines, and increased spine density and length with more immature and fewer mature spines in temporal and visual cortices.

    “The first neuropathologic studies in the neocortex of subjects with fragile X syndrome noted the presence of long spines and reduced PSD length, almost no stubby spines and the absence of differences in synaptic vesicle density [305, 389].”
    • Also stated in: § Animal models based on single ASD genes · boosted
      “Subsequently, increased spine density and spine length, with more immature spines and fewer mature spines was quantitatively confirmed in the temporal and visual cortices of subjects with fragile X syndrome compared to controls [169].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [305] Rudelli RD, Brown WT, Wisniewski K, Jenkins EC, Laure-Kamionowska M, Connell F, Wisniewski HM (1985) Acta Neuropathol 67:289–295 source

      Not checked in the free run.

    • cites [389] Wisniewski KE, Segan SM, Miezejeski CM, Sersen EA, Rudelli RD (1991) Am J Med Genet 38:476–480 source

      Not checked in the free run.

    • cites [169] Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP, Kooy F, Willems PJ, Cras P, Kozlowski PB et al (2001) Am J Med Genet 98:161–167. doi: 10.1002/1096-8628(20010115)98:2<161:AID-AJMG1025>3.0.CO;2-B source

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  • May combine two claims.

    Premisecitation

    Increased spine length and density observed in human fragile X postmortem studies were replicated in Fmr1 KO mice, although differences were noted dependent on age and brain area.

    “The increased spine length and density observed in human postmortem studies were replicated in Fmr1 KO mice [74, 167–169], although differences were noted dependent on age and brain area.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [74] Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ, Greenough WT (1997) Proc Natl Acad Sci USA 94:5401–5404 source

      Not checked in the free run.

    • cites [167] Irwin SA, Galvez R, Greenough WT (2000) Cereb Cortex 10:1038–1044 source

      Not checked in the free run.

    • cites [168] Irwin SA, Idupulapati M, Gilbert ME, Harris JB, Chakravarti AB, Rogers EJ, Crisostomo RA, Larsen BP, Mehta A, Alcantara CJ et al (2002) Am J Med Genet 111:140–146. doi: 10.1002/ajmg.10500 source

      Not checked in the free run.

    • cites [169] Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP, Kooy F, Willems PJ, Cras P, Kozlowski PB et al (2001) Am J Med Genet 98:161–167. doi: 10.1002/1096-8628(20010115)98:2<161:AID-AJMG1025>3.0.CO;2-B source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The above findings confirm a role for Shank3 in orchestrating the assembly of multiple glutamate receptors at the PSD and coupling synaptic signaling to spine dynamics.

    “The above findings all confirm a role for Shank3 in orchestrating the assembly of multiple glutamate receptors at the PSD and coupling synaptic signaling to spine dynamics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Loss of MeCp2 results in reduced brain weight and thinning of the neocortex in some mouse models.

    “Loss of MeCp2 results in reduced brain weight [67, 126], with thinning of the neocortex described in some mouse models [115, 200, 302].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [67] Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Nat Genet 27:327–331. doi: 10.1038/85906 source

      Not checked in the free run.

    • cites [126] Goffin D, Allen M, Zhang L, Amorim M, Wang IT, Reyes AR, Mercado-Berton A, Ong C, Cohen S, Hu L et al (2012) Nat Neurosci 15:274–283. doi: 10.1038/nn.2997 source

      Not checked in the free run.

    • cites [115] Fukuda T, Itoh M, Ichikawa T, Washiyama K, Goto Y (2005) J Neuropathol Exp Neurol 64:537–544 source

      Not checked in the free run.

    • cites [200] Kishi N, Macklis JD (2004) Mol Cell Neurosci 27:306–321. doi: 10.1016/j.mcn.2004.07.006 source

      Not checked in the free run.

    • cites [302] Robinson L, Guy J, McKay L, Brockett E, Spike RC, Selfridge J, De Sousa D, Merusi C, Riedel G, Bird A et al (2012) Brain 135:2699–2710. doi: 10.1093/brain/aws096 source

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  • May combine two claims.

    Interpretationreasoning

    Overall, findings indicate a role for FMR1 in the maturation of synapses, with age- and brain-area specific effects.

    “Overall, these findings indicate a role for FMR1 in the maturation of synapses, with age- and brain-area specific effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Overall, studies in Mecp2 animal models indicate that neuronal and dendritic morphology changes may appear transiently during development or be variously affected, depending on developmental stage and MeCp2 gain- or loss-of-function.

    “Overall, studies in the Mecp2 animal models indicate that neuronal and dendritic morphology changes may appear transiently during development or be variously affected, depending on developmental stage and MeCp2 gain- or loss-of-function [64, 180].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Chapleau CA, Boggio EM, Calfa G, Percy AK, Giustetto M, Pozzo-Miller L (2012) Neural Plast 2012:976164. doi: 10.1155/2012/976164 source

      Not checked in the free run.

    • cites [180] Jiang M, Ash RT, Baker SA, Suter B, Ferguson A, Park J, Rudy J, Torsky SP, Chao HT, Zoghbi HY et al (2013) J Neurosci 33:19518–19533. doi: 10.1523/JNEUROSCI.1745-13.2013 source

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  • May combine two claims.

    Premisecitation

    Human TSC neuropathology shows abnormal migration and differentiation of neurons within and proximal to tubers in the cerebral cortex and abnormally large cells with features of neurons or astrocytes or both, indicating a defect in differentiation.

    “Neuropathologic observations in human subjects with TSC indicate abnormal migration and differentiation of neurons within and proximal to the tubers in the cerebral cortex [163] and the presence of abnormally large cells, which show features of either neurons or astrocytes or both, indicating a defect in differentiation [243].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Huttenlocher PR, Wollmann RL (1991) Ann N Y Acad Sci 615:140–148 source

      Not checked in the free run.

    • cites [243] Mizuguchi M, Takashima S (2001) Brain Dev 23:508–515 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MeCp2 deficiency results in reduction of glutamatergic synapses and increased basal levels of AMPA, indicating a failure in activity-dependent synaptic trafficking of the receptor.

    “MeCp2 deficiency results in reduction of glutamatergic synapses [63] and increased basal levels of AMPA, indicating a failure in activity-dependent synaptic trafficking of the receptor [217].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] Chao HT, Zoghbi HY, Rosenmund C (2007) Neuron 56:58–65. doi: 10.1016/j.neuron.2007.08.018 source

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    • cites [217] Li W, Xu X, Pozzo-Miller L (2016) Proc Natl Acad Sci USA. doi: 10.1073/pnas.1517244113 source

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  • May combine two claims.

    Premisecitation

    Nlgn4 KO mice have decreased excitatory PSD-95-immunolabeled puncta in the stratum lucidum and lower density of GABAA receptor and gephyrin-immunoreactive synapses in the stratum pyramidale of the CA3 field.

    “These mice have decreased excitatory PSD-95-immunolabeled puncta in the stratum lucidum as well as lower density of GABAA receptor and gephyrin-immunoreactive synapses in the stratum pyramidale of the CA3 field [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Hammer M, Krueger-Burg D, Tuffy LP, Cooper BH, Taschenberger H, Goswami SP, Ehrenreich H, Jonas P, Varoqueaux F, Rhee JS et al (2015) Cell Rep 13:516–523. doi: 10.1016/j.celrep.2015.09.011 source

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  • May combine two claims.

    Premisecitation

    Tsc2+/− mice show increased spine density and decreased pruning with age but comparable cell size and dendritic branching to wild-type.

    “Layer V neurons in the temporal cortex of Tsc2+/− mice show increased spine density and decreased pruning with age but comparable cell size and dendritic branching to the WT [349].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [349] Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A et al (2014) Neuron 83:1131–1143. doi: 10.1016/j.neuron.2014.07.040 source

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  • May combine two claims.

    Premisecitation

    Nrxn1α/2α double KO mice show no gross anatomical changes but increased cell density and decreased dendritic length in the visual cortex, with no changes in synaptic ultrastructure, compared to Nrxn2α KO.

    “The Nrxn1α/2α double KO mice show no gross anatomical changes but increased cell density and decreased dendritic length in the visual cortex, with no changes in synaptic ultrastructure, compared to Nrxn2α KO [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Dudanova I, Tabuchi K, Rohlmann A, Südhof TC, Missler M (2007) J Comp Neurol 502:261–274. doi: 10.1002/cne.21305 source

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  • May combine two claims.

    Premisecitation

    In utero knockdown of Grin2b delays cortical neuron migration and increases dendritic length and branching.

    “In utero knockdown of Grin2b results in delayed migration of cortical neurons, together with increased dendritic length and branching [179].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Jiang H, Jiang W, Zou J, Wang B, Yu M, Pan Y, Lin Y, Mao Y, Wang Y (2015) Brain Res 1610:20–32. doi: 10.1016/j.brainres.2015.03.031 source

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  • May combine two claims.

    Premisecitation

    Another study reported absence of cerebellar changes and smaller frontal and temporal lobes in Angelman syndrome.

    “Another study reported the absence of cerebellar changes and smaller frontal and temporal lobes [209].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Kyriakides T, Hallam LA, Hockey A, Silberstein P, Kakulas BA (1992) Acta Neuropathol 83:675–678 source

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  • May combine two claims.

    Premisecitation

    A neuropathological study of an Angelman syndrome subject found a smaller brain with no gross morphological changes except cerebellar atrophy due to loss of Purkinje and granule cells.

    “A neuropathological study of a subject with Angelman’s syndrome revealed a smaller brain, with no gross morphological changes, except for cerebellar atrophy, due to loss of Purkinje and granule cells [176].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Jay V, Becker LE, Chan FW, Perry TL Sr (1991) Neurology 41:416–422 source

      Not checked in the free run.

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

    Premisecitation

    UBE3A is an E3 ubiquitin ligase that flags proteins, including itself, for degradation, and the UBE3A gene is located in the 15q11-q13 chromosomal region.

    “UBE3A is an E3 ubiquitin ligase that flags proteins, including itself, for degradation [260] and the UBE3A gene is located in the 15q11–q13 chromosomal region.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [260] Nuber U, Schwarz SE, Scheffner M (1998) Eur J Biochem 254:643–649 source

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    Premisecitation

    Interactions of several genes with Tbr1 determine corticothalamic projection of layer VI neurons, callosal projection of superficial cortical layer neurons, and subcortical projection of layer V neurons.

    “Complex interactions of several genes with Tbr1 determine the corticothalamic projection of layer VI neurons, callosal projection of neurons in the cortical superficial layers [335] and subcortical projection of layer V neurons [50, 142, 232].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [335] Srinivasan K, Leone DP, Bateson RK, Dobreva G, Kohwi Y, Kohwi-Shigematsu T, Grosschedl R, McConnell SK (2012) Proc Natl Acad Sci USA 109:19071–19078. doi: 10.1073/pnas.1216793109 source

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    • cites [50] Canovas J, Berndt FA, Sepulveda H, Aguilar R, Veloso FA, Montecino M, Oliva C, Maass JC, Sierralta J, Kukuljan M (2015) J Neurosci 35:7552–7564. doi: 10.1523/JNEUROSCI.0169-15.2015 source

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    • cites [142] Han W, Kwan KY, Shim S, Lam MM, Shin Y, Xu X, Zhu Y, Li M, Sestan N (2011) Proc Natl Acad Sci USA 108:3041–3046. doi: 10.1073/pnas.1016723108 source

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    • cites [232] McKenna WL, Betancourt J, Larkin KA, Abrams B, Guo C, Rubenstein JL, Chen B (2011) J Neurosci 31:549–564. doi: 10.1523/JNEUROSCI.4131-10.2011 source

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  • May combine two claims.

    Premisecitation

    In adult mouse hippocampal CA1, mushroom spine density is increased in Syngap1+/− mice compared with wild-type, while thin and stubby spine densities are not increased.

    “In the hippocampal CA1 of adult mice, the density of mushroom spines, but not those of thin or stubby spines, is increased in Syngap1+/− mice compared to WT mice [51]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Carlisle HJ, Manzerra P, Marcora E, Kennedy MB (2008) J Neurosci 28:13673–13683. doi: 10.1523/JNEUROSCI.4695-08.2008 source

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  • May combine two claims.

    Premisecitation

    Tbr1 regulates expression of rostrocaudal and layer-specific markers in the cerebral cortex, with the rostrocaudal effect partly through activation of AUTS2.

    “Tbr1 in turn regulates the expression of rostrocaudal and layer-specific markers in the cerebral cortex, the former being partly through activation of the autism gene AUTS2 [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Bedogni F, Hodge RD, Elsen GE, Nelson BR, Daza RA, Beyer RP, Bammler TK, Rubenstein JL, Hevner RF (2010) Proc Natl Acad Sci USA 107:13129–13134. doi: 10.1073/pnas.1002285107 source

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  • May combine two claims.

    Premisecitation

    Tbr1−/− mice have defective cortical morphology, neuronal migration, and axonal projections, which are not detected in Tbr1+/− mice.

    “Tbr1−/− mice have defective cortical morphology, neuronal migration, and axonal projections [156, 157], which are not detected in Tbr1+/− mice that model the haploinsufficiency observed in patients more faithfully.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Hevner RF, Miyashita-Lin E, Rubenstein JL (2002) J Comp Neurol 447:8–17. doi: 10.1002/cne.10219 source

      Not checked in the free run.

    • cites [157] Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M, Smiga S, Bulfone A, Goffinet AM, Campagnoni AT, Rubenstein JL (2001) Neuron 29:353–366 source

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  • May combine two claims.

    Premisecitation

    In Angelman syndrome, dendrites in layer III and V neurons of the visual cortex are shorter, less complex, and have fewer spines.

    “Dendrites in layer III and V neurons of the visual cortex are shorter, less complex, and have fewer spines [176].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Jay V, Becker LE, Chan FW, Perry TL Sr (1991) Neurology 41:416–422 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SynGAP1 is a Ras-GTPase activating protein located in the postsynaptic density of glutamatergic neurons and participates in dendritic spine maturation, glutamate receptor trafficking, and synaptic function.

    “Synaptic GTPase activating protein 1 (SynGAP1) is a Ras-GTPase activating protein localized in the PSD in glutamatergic neurons [66, 197] and involved in dendritic spine maturation, glutamate receptor trafficking and synaptic function [11].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB (1998) Neuron 20:895–904 source

      Not checked in the free run.

    • cites [197] Kim JH, Liao D, Lau LF, Huganir RL (1998) Neuron 20:683–691 source

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    • cites [11] Araki Y, Zeng M, Zhang M, Huganir RL (2015) Neuron 85:173–189. doi: 10.1016/j.neuron.2014.12.023 source

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  • May combine two claims.

    Premisecitation

    MRI and diffusion tensor imaging studies have revealed impaired white matter integrity in subjects with Angelman syndrome, likely due to a delay in myelination.

    “MRI and diffusion tensor imaging studies have revealed impaired white matter integrity in subjects with Angelman’s syndrome [281, 354, 388], likely due to a delay in myelination [146].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [281] Peters SU, Kaufmann WE, Bacino CA, Anderson AW, Adapa P, Chu Z, Yallampalli R, Traipe E, Hunter JV, Wilde EA (2011) Dev Med Child Neurol 53:361–367. doi: 10.1111/j.1469-8749.2010.03838.x source

      Not checked in the free run.

    • cites [354] Tiwari VN, Jeong JW, Wilson BJ, Behen ME, Chugani HT, Sundaram SK (2012) Neuroimage 59:349–355. doi: 10.1016/j.neuroimage.2011.07.067 source

      Not checked in the free run.

    • cites [388] Wilson BJ, Sundaram SK, Huq AH, Jeong JW, Halverson SR, Behen ME, Bui DQ, Chugani HT (2011) Pediatr Neurol 44:350–356. doi: 10.1016/j.pediatrneurol.2010.12.002 source

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    • cites [146] Harting I, Seitz A, Rating D, Sartor K, Zschocke J, Janssen B, Ebinger F, Wolf NI (2009) Eur J Paediatr Neurol 13:271–276. doi: 10.1016/j.ejpn.2008.04.005 source

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    Premisecitation

    Dscamdel17 mutant mice show altered dendritic morphology of layer V pyramidal neurons compared with wild-type, with an early increase in apical dendritic branching, reduced dendritic length, and higher spine density that normalize by adulthood.

    “These mice also showed altered dendritic morphology of layer V pyramidal neurons compared to WT controls, starting with an early increase in apical dendritic branching, reduced dendritic length and higher spine density, which were normalized by adulthood.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] Maynard KR, Stein E (2012) J Neurosci 32:16637–16650. doi: 10.1523/JNEUROSCI.2811-12.2012 source

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    Premisecitation

    Grin2b full knockout mice lack a suckling response and die shortly after birth.

    “Grin2b full KOs have no suckling response and therefore die shortly after birth [208].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] Kutsuwada T, Sakimura K, Manabe T, Takayama C, Katakura N, Kushiya E, Natsume R, Watanabe M, Inoue Y, Yagi T et al (1996) Neuron 16:333–344 source

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    Premisecitation

    In mice mimicking the Syngap1 deficit, layer V pyramidal neurons of the somatosensory cortex show precocious dendritic arborization, early spine formation and premature pruning, and enlarged spines during a critical developmental period compared with wild-type mice.

    “Studies using genetically modified mice that mimic the Syngap1 deficit have revealed precocious dendritic arborization, early formation and premature pruning of dendritic spines as well as enlarged dendritic spines in layer V pyramidal neurons of the somatosensory cortex during a critical period of development, compared to WT mice [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Aceti M, Creson TK, Vaissiere T, Rojas C, Huang WC, Wang YX, Petralia RS, Page DT, Miller CA, Rumbaugh G (2015) Biol Psychiatry 77:805–815. doi: 10.1016/j.biopsych.2014.08.001 source

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    Premisecitation

    In the hippocampal dentate gyrus of Syngap1 heterozygous mice, spine maturation and size follow a similar trend to the somatosensory cortex, but dendritic complexity is unaffected.

    “Maturation and size of spines in the hippocampal dentate gyrus of Syngap1 heterozygous mice follow a similar trend to that observed in the somatosensory cortex, although dendritic complexity is not affected in this cortical area [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA et al (2012) Cell 151:709–723. doi: 10.1016/j.cell.2012.08.045 source

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    Premisecitation

    Tbr1+/− mice exhibit a small or absent posterior region of the anterior commissure, possibly due to defective neuronal differentiation in amygdala neurons.

    “Tbr1+/− mice exhibit a small or absent posterior region of the anterior commissure, possibly a result of defective neuronal differentiation in amygdala neurons [161].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Huang TN, Chuang HC, Chou WH, Chen CY, Wang HF, Chou SJ, Hsueh YP (2014) Nat Neurosci 17:240–247. doi: 10.1038/nn.3626 source

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    Premisecitation

    TBR1 is a T-box transcription factor expressed specifically in the brain, and its expression increases in response to neuronal activity.

    “T-brain-1 (TBR1) is a T-box transcription factor expressed specifically in the brain, and its expression is increased in response to neuronal activity [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Chuang HC, Huang TN, Hsueh YP (2014) Front Cell Neurosci 8:280. doi: 10.3389/fncel.2014.00280 source

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    Premisecitation

    SynGAP expression is inversely correlated with synaptic AMPA receptor levels but not with NMDA receptor levels.

    “Studies using in vitro systems and KO mice have shown that SynGAP expression is inversely correlated to the levels of AMPA receptors, but not NMDA receptors, at the synapse [306].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [306] Rumbaugh G, Adams JP, Kim JH, Huganir RL (2006) Proc Natl Acad Sci USA 103:4344–4351. doi: 10.1073/pnas.0600084103 source

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    Premisecitation

    Syngap1 deficiency selectively in GABAergic neurons decreases presynaptic bouton density on the soma and reduces terminal axon branching on cortical interneurons.

    “Syngap1 deficiency selectively induced in GABAergic neurons results in decreased density of presynaptic boutons terminating on the soma as well as reduced terminal branching of axons on interneurons of the cortex [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Berryer MH, Chattopadhyaya B, Xing P, Riebe I, Bosoi C, Sanon N, Antoine-Bertrand J, Levesque M, Avoli M, Hamdan FF et al (2016) Nat Commun 7:13340. doi: 10.1038/ncomms13340 source

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    Premisecitation

    Young Dscamdel17 mutant mice have fewer long spines and more spines with small head size, and the number of long and large spines increases with age.

    “Although young Dscamdel17 mutant mice have fewer long spines and more spines with small head size, the number of long and large spines increases with age [230].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] Maynard KR, Stein E (2012) J Neurosci 32:16637–16650. doi: 10.1523/JNEUROSCI.2811-12.2012 source

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    Premisecitation

    Imaging studies in 22q11.2 syndrome have revealed smaller brain volume, decreased cortical thickness in the superior parietal, right parietooccipital and inferior frontal gyrus, heterotopias and fewer gyri, and reduced volume in the hippocampus, cerebellum and amygdala, some of which varies based on the presence of schizophrenia or cognitive deficits.

    “Imaging studies in 22q11.2 syndrome have revealed smaller brain volume [361], decreased cortical thickness in the superior parietal, right parietooccipital and inferior frontal gyrus, heterotopias and fewer gyri [27, 193, 314], and reduced volume in the hippocampus [84, 85], cerebellum [49] and amygdala [85], some of which varies based on the presence of schizophrenia or cognitive deficits [20, 31”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [361] van Amelsvoort T, Daly E, Henry J, Robertson D, Ng V, Owen M, Murphy KC, Murphy DG (2004) Arch Gen Psychiatry 61:1085–1096. doi: 10.1001/archpsyc.61.11.1085 source

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    • cites [27] Bearden CE, van Erp TG, Dutton RA, Tran H, Zimmermann L, Sun D, Geaga JA, Simon TJ, Glahn DC, Cannon TD et al (2007) Cereb Cortex 17:1889–1898. doi: 10.1093/cercor/bhl097 source

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    • cites [193] Kiehl TR, Chow EW, Mikulis DJ, George SR, Bassett AS (2009) Cereb Cortex 19:153–164. doi: 10.1093/cercor/bhn066 source

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    • cites [314] Schaer M, Schmitt JE, Glaser B, Lazeyras F, Delavelle J, Eliez S (2006) Psychiatry Res 146:1–11. doi: 10.1016/j.pscychresns.2005.10.002 source

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    • cites [84] Debbane M, Schaer M, Farhoumand R, Glaser B, Eliez S (2006) Neuropsychologia 44:2360–2365. doi: 10.1016/j.neuropsychologia.2006.05.006 source

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    • cites [85] Deboer T, Wu Z, Lee A, Simon TJ (2007) Behav Brain Funct 3:54. doi: 10.1186/1744-9081-3-54 source

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    Premisecitation

    Another 16p11.2 deletion model, the 16p11.2del mouse, shows reduced brain weight and decreased cortical size with perturbed cortical lamination.

    “However, another model of the deletion, the 16p11.2del mouse, shows reduced brain weight and decreased cortical size with perturbed cortical lamination [291].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [291] Pucilowska J, Vithayathil J, Tavares EJ, Kelly C, Karlo JC, Landreth GE (2015) J Neurosci 35:3190–3200. doi: 10.1523/JNEUROSCI.4864-13.2015 source

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    Premisecitation

    In D/+ mice, no gross differences were observed, although neuron number and dendritic morphology were not quantified.

    “Although neuron number and dendritic morphology were not quantified in the D/+ mice, no gross differences were observed [204].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Kogan JH, Gross AK, Featherstone RE, Shin R, Chen Q, Heusner CL, Adachi M, Lin A, Walton NM, Miyoshi S et al (2015) J Neurosci 35:16282–16294. doi: 10.1523/JNEUROSCI.3967-14.2015 source

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    Premisecitation

    In the cerebellum of Ube3am−/p+ mice, cell density and dendritic complexity are unaffected.

    “In the cerebellum, cell density and dendritic complexity are unaffected in Ube3am−/p+ mice [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL (2008) Hum Mol Genet 17:111–118. doi: 10.1093/hmg/ddm288 source

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    Premisecitation

    Neither matDp/+ nor patDp/+ mice have gross morphological or histological brain abnormalities.

    “Neither of these mice have any gross morphological or histological abnormalities in the brain [253].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y, Chung YJ, Banerjee R et al (2009) Cell 137:1235–1246. doi: 10.1016/j.cell.2009.04.024 source

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    Premisecitation

    In a mouse model with maternal Ube3a deleted (Ube3am−/p+), total brain weight and cortex and cerebellum weights are lower than in wild-type.

    “Similar to the observation of small brain size in human samples from Angelman’s syndrome, the total brain weight, as well as the weight of the cortex and cerebellum, is lower in a mouse model with maternal Ube3a deleted (Ube3am−/p+) [181].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, Eichele G, Sweatt JD, Beaudet AL (1998) Neuron 21:799–811 source

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  • May combine two claims.

    Premisecitation

    In the 16p11+/− mouse model, brain weight is comparable to controls, but relative volumes of the nucleus accumbens and globus pallidus are increased.

    “In a third model (the 16p11+/− mice) brain weight is comparable to controls, although relative volumes of the nucleus accumbens and globus pallidus are increased.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [289] Portmann T, Yang M, Mao R, Panagiotakos G, Ellegood J, Dolen G, Bader PL, Grueter BA, Goold C, Fisher E et al (2014) Cell Rep 7:1077–1092. doi: 10.1016/j.celrep.2014.03.036 source

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    Premisecitation

    Necdin-deficient mice have small brainstem nuclei and disorganized axonal tracts in the medulla.

    “Necdin-deficient mice have small brainstem nuclei and disorganized axonal tracts in the medulla [271].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [271] Pagliardini S, Ren J, Wevrick R, Greer JJ (2005) Am J Pathol 167:175–191. doi: 10.1016/S0002-9440(10)62964-1 source

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  • May combine two claims.

    Interpretationreasoning

    Although relative brain volume changes in some mouse models do not reflect those seen in people with CNVs of this chromosomal region, the cellular mechanisms leading to altered brain volumes can be uncovered using these models.

    “Although the relative brain volume changes in some of the mouse models do not reflect those seen in people with CNVs of this chromosomal region, the cellular mechanisms leading to altered brain volumes can be uncovered using these models.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Neuropathological findings in Prader-Willi syndrome subjects include abnormal distribution of cells in the dentate and olivary nuclei, nerve degeneration in the dentate nucleus, cerebellar heterotopia, enlarged ventricles, reduced parieto-occipital lobe volume, multiple small gyri in the sylvian fissure, incompletely operculated insula, and smaller cerebellum and brainstem.

    “Neuropathological findings in subjects with Prader-Willi syndrome include abnormal distribution of cells in the dentate and olivary nuclei, nerve degeneration in the dentate nucleus, cerebellar heterotopia [150], enlarged ventricles, reduced volume of parieto-occipital lobe, multiple small gyri in the sylvian fissure, incompletely operculated insula [239], and smaller cerebellum and brainstem [222”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [150] Hayashi M, Itoh M, Kabasawa Y, Hayashi H, Satoh J, Morimatsu Y (1992) Brain Dev 14:58–62 source

      Not checked in the free run.

    • cites [239] Miller JL, Couch JA, Schmalfuss I, He G, Liu Y, Driscoll DJ (2007) Am J Med Genet A 143A:476–483. doi: 10.1002/ajmg.a.31508 source

      Not checked in the free run.

    • cites [222] Lukoshe A, White T, Schmidt MN, van der Lugt A, Hokken-Koelega AC (2013) J Neurodev Disord 5:31. doi: 10.1186/1866-1955-5-31 source

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  • May combine two claims.

    Premisecitation

    Expression of the UBE3A T485A variant, identified in a patient with ASD, abolishes phosphorylation at the mutated site, increases protein activity, and causes increased spine density on basal dendrites in the somatosensory cortex.

    “Expression of the UBE3A T485A variant, identified in a patient with ASD abolishes phosphorylation of UBE3A at the mutated site, results in increased activity of the protein and causes increased spine density on basal dendrites in the somatosensory cortex [396].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [396] Yi JJ, Berrios J, Newbern JM, Snider WD, Philpot BD, Hahn KM, Zylka MJ (2015) Cell 162:795–807. doi: 10.1016/j.cell.2015.06.045 source

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    Premisecitation

    In 16p11+/− mice, the number of cells expressing dopamine receptor D2 is increased in the striatum, with no change in dendritic complexity or spine density, and fewer dopaminergic cells are found in cortical layers V and VI.

    “The number of cells expressing dopamine receptor D2 is increased in the striatum, with no change in dendritic complexity or spine density, and fewer dopaminergic cells in cortical layers V and VI are found in these mice [289].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [289] Portmann T, Yang M, Mao R, Panagiotakos G, Ellegood J, Dolen G, Bader PL, Grueter BA, Goold C, Fisher E et al (2014) Cell Rep 7:1077–1092. doi: 10.1016/j.celrep.2014.03.036 source

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  • May combine two claims.

    Premisecitation

    In hippocampal CA1 neurons of Ube3am−/p+ mice, presynaptic vesicle density, spine density, and spine length are lower than in wild-type controls.

    “Also, the density of presynaptic vesicles, as well as spine density and length, in hippocampal CA1 neurons is lower compared to WT controls [342].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [342] Su H, Fan W, Coskun PE, Vesa J, Gold JA, Jiang YH, Potluri P, Procaccio V, Acab A, Weiss JH et al (2011) Neurosci Lett 487:129–133. doi: 10.1016/j.neulet.2009.06.079 source

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    Premisecitation

    Macrocephaly is observed in subjects with the 16p11.2 microdeletion, whereas carriers of the duplication show microcephaly.

    “Macrocephaly is observed in subjects with the 16p11.2 microdeletion, whereas carriers of the duplication show microcephaly [227, 292, 326, 337].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [227] Maillard AM, Ruef A, Pizzagalli F, Migliavacca E, Hippolyte L, Adaszewski S, Dukart J, Ferrari C, Conus P, Mannik K et al (2015) Mol Psychiatry 20:140–147. doi: 10.1038/mp.2014.145 source

      Not checked in the free run.

    • cites [292] Qureshi AY, Mueller S, Snyder AZ, Mukherjee P, Berman JI, Roberts TP, Nagarajan SS, Spiro JE, Chung WK, Sherr EH et al (2014) J Neurosci 34:11199–11211. doi: 10.1523/JNEUROSCI.1366-14.2014 source

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    • cites [326] Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, Scott DA, Probst FJ, Craigen WJ, Graham BH, Pursley A et al (2010) J Med Genet 47:332–341. doi: 10.1136/jmg.2009.073015 source

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    • cites [337] Steinman KJ, Spence SJ, Ramocki MB, Proud MB, Kessler SK, Marco EJ, Green Snyder L, D’Angelo D, Chen Q, Chung WK et al (2016) Am J Med Genet A 170:2943–2955. doi: 10.1002/ajmg.a.37820 source

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  • May combine two claims.

    Premisecitation

    In vitro overexpression of Snrpn reduces dendrite length, increases spine density, and alters spine distribution on cortical neurons.

    “In vitro studies using overexpression of Snrpn show that the gene reduces dendrite length, increases spine density and alters spine distribution on cortical neurons [215].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [215] Li H, Zhao P, Xu Q, Shan S, Hu C, Qiu Z, Xu X (2016) Sci Rep 6:29878. doi: 10.1038/srep29878 source

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    Premisecitation

    PatDp/+ mice, but not matDp/+ mice, show increased postnatal turnover of excitatory spines in the somatosensory and anterior frontal cortex.

    “PatDp/+ mice, but not matDp/+ mice, show increased postnatal turnover of excitatory spines in the somatosensory and anterior frontal cortex [172].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Isshiki M, Tanaka S, Kuriu T, Tabuchi K, Takumi T, Okabe S (2014) Nat Commun 5:4742. doi: 10.1038/ncomms5742 source

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    Premisecitation

    In Ube3am−/p+ mice, there are more thin spines and fewer stubby spines than in wild-type.

    “with more thin spines and fewer stubby spines in the disease model than in the WT [196]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Kim H, Kunz PA, Mooney R, Philpot BD, Smith SL (2016) J Neurosci 36:4888–4894. doi: 10.1523/JNEUROSCI.4204-15.2016 source

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  • May combine two claims.

    Premisecitation

    VPA exposure leads to decreased thickness of the PFC and basolateral amygdala at early ages, and of the hippocampal CA1 at all ages.

    “VPA exposure leads to decreased thickness of the PFC and the basolateral amygdala at early ages, and of the hippocampal CA1 at all ages [332].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [332] Sosa-Diaz N, Bringas ME, Atzori M, Flores G (2014) Synapse 68:468–473. doi: 10.1002/syn.21759 source

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  • May combine two claims.

    Premisecitation

    Acute high-dose VPA exposure reduces cortical thickness, whereas chronic low-dose exposure increases cortical thickness.

    “Acute exposure at a high dose reduces cortical thickness [250], whereas chronic exposure to a low dose increases cortical thickness [307].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [250] Mychasiuk R, Richards S, Nakahashi A, Kolb B, Gibb R (2012) Dev Neurosci 34:268–276. doi: 10.1159/000341786 source

      Not checked in the free run.

    • cites [307] Sabers A, Bertelsen FC, Scheel-Kruger J, Nyengaard JR, Moller A (2014) Neurosci Lett 580:12–16. doi: 10.1016/j.neulet.2014.07.036 source

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    Premisecitation

    The most striking neuroanatomical features of BTBR mice are the absence of corpus callosum and the extremely reduced hippocampal commissure, observed by diffusion tensor tractography and on histologic preparations.

    “The most striking neuroanatomical features of BTBR mice are the absence of corpus callosum and the extremely reduced hippocampal commissure, observed by diffusion tensor tractography and on histologic preparations [87, 96, 367].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [87] Dodero L, Damiano M, Galbusera A, Bifone A, Tsaftsaris SA, Scattoni ML, Gozzi A (2013) PLoS One 8:e76655. doi: 10.1371/journal.pone.0076655 source

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    • cites [96] Ellegood J, Babineau BA, Henkelman RM, Lerch JP, Crawley JN (2013) Neuroimage 70:288–300. doi: 10.1016/j.neuroimage.2012.12.029 source

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    • cites [367] Wahlsten D, Metten P, Crabbe JC (2003) Brain Res 971:47–54 source

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  • May combine two claims.

    Premisecitation

    When 22q11 deletion cases with ASD were compared to those without, volumes of the whole brain, prefrontal cortex, cerebellum, and left amygdala were unchanged, but the right amygdala was enlarged.

    “When cases with 22q11 deletion with ASD were compared to those without, volumes of the whole brain as well as prefrontal cortex, cerebellum and left amygdala were unchanged, but that of the right amygdala was enlarged [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Antshel KM, Aneja A, Strunge L, Peebles J, Fremont WP, Stallone K, Abdulsabur N, Higgins AM, Shprintzen RJ, Kates WR (2007) J Autism Dev Disord 37:1776–1786. doi: 10.1007/s10803-006-0308-6 source

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    Premisecitation

    Other white matter changes in BTBR mice include abnormal posterior interhemispheric connectivity and skewed orientation of glial cells in some affected white matter tracts.

    “Other white matter changes in BTBR mice include abnormal posterior interhemispheric connectivity [240] and skewed orientation of glial cells in some of the affected white matter tracts [338].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [240] Miller VM, Gupta D, Neu N, Cotroneo A, Boulay CB, Seegal RF (2013) Brain Res 1513:26–33. doi: 10.1016/j.brainres.2013.04.001 source

      Not checked in the free run.

    • cites [338] Stephenson DT, O’Neill SM, Narayan S, Tiwari A, Arnold E, Samaroo HD, Du F, Ring RH, Campbell B, Pletcher M et al (2011) Mol Autism 2:7. doi: 10.1186/2040-2392-2-7 source

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  • May combine two claims.

    Premisecitation

    Neuropathology in prenatal VPA models depends on the dose of VPA or the age at which neuropathology was assessed.

    “Neuropathology in prenatal VPA models depends on the dose of VPA or the age at which neuropathology was assessed [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Bringas ME, Carvajal-Flores FN, Lopez-Ramirez TA, Atzori M, Flores G (2013) Neuroscience 241:170–187. doi: 10.1016/j.neuroscience.2013.03.030 source

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  • May combine two claims.

    Premisecitation

    In vitro cultures of hippocampal neurons from Df(16)A+/− mice show fewer mushroom spines, decreased spine head diameter and length, fewer glutamatergic synapses, and decreased presynaptic vesicle density.

    “Other studies show fewer mushroom spines, decreased spine head diameter and length, fewer glutamatergic synapses and decreased presynaptic vesicle density using in vitro cultures of hippocampal neurons from Df(16)A+/− mice [249].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [249] Mukai J, Dhilla A, Drew LJ, Stark KL, Cao L, MacDermott AB, Karayiorgou M, Gogos JA (2008) Nat Neurosci 11:1302–1310. doi: 10.1038/nn.2204 source

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    Premisecitation

    In vivo analyses of Df(16)A+/− mice show reduced total and mushroom spine density and decreased spine head diameter but not length.

    “In vivo analyses show reduced total and mushroom spine density and decreased spine head diameter but not length [336].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M et al (2008) Nat Genet 40:751–760. doi: 10.1038/ng.138 source

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    Premisecitation

    Dgcr8+/− mice have fewer layer II and III cortical neurons and reduced spine width, but not spine length, on basal dendrites in prefrontal cortical neurons.

    “Some examples include fewer layer II and III cortical neurons and reduced spine width, but not spine length, on basal dendrites in prefrontal cortical neurons of Dgcr8+/− mice [111]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Fenelon K, Mukai J, Xu B, Hsu PK, Drew LJ, Karayiorgou M, Fischbach GD, Macdermott AB, Gogos JA (2011) Proc Natl Acad Sci USA 108:4447–4452. doi: 10.1073/pnas.1101219108 source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    As multiple factors may contribute to ASD, genetic models expressing a single mutation cannot perfectly model all the pathological features of ASD.

    “As multiple factors may contribute to ASD, genetic models expressing a single mutation cannot perfectly model all the pathological features of ASD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Multiple factors may contribute to ASD.

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    Premisecitation

    In prenatal VPA models, the cerebellum decreases in size and the amygdala increases in size.

    “Other brain areas that are affected include the cerebellum which decreases in size [247], and the amygdala which increases in size [265].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [247] Mowery TM, Wilson SM, Kostylev PV, Dina B, Buchholz JB, Prieto AL, Garraghty PE (2015) Int J Dev Neurosci 40:15–23. doi: 10.1016/j.ijdevneu.2014.10.003 source

      Not checked in the free run.

    • cites [265] Olde Loohuis NF, Kole K, Glennon JC, Karel P, Van der Borg G, Van Gemert Y, Van den Bosch D, Meinhardt J, Kos A, Shahabipour F et al (2015) Neurobiol Dis 80:42–53. doi: 10.1016/j.nbd.2015.05.006 source

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  • May combine two claims.

    Premisecitation

    In the medial prefrontal cortex of Df(16)A+/− mice, there is a decrease in cell numbers in layers II and V, with fewer inhibitory neurons in layer V; cell size is normal, basal dendritic length and complexity are decreased, and the length of the primary apical dendrite is reduced.

    “In the medial prefrontal cortex of Df(16)A+/− mice, there is a decrease in cell numbers in layers II and V, with fewer inhibitory neurons in layer V. Cell size is normal, basal dendritic length and complexity is decreased [391] and length of the primary apical dendrite is reduced in these animals.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [391] Xu B, Hsu PK, Stark KL, Karayiorgou M, Gogos JA (2013) Cell 152:262–275. doi: 10.1016/j.cell.2012.11.052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuropathological observations in 22q11.2 deletion include more numerous medium spiny neurons in the caudate and interstitial neurons in subcortical white matter.

    “Neuropathological observations include more numerous medium spiny neurons in the caudate and interstitial neurons in subcortical white matter [390].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [390] Wu P, Teot L, Murdoch G, Monaghan-Nichols AP, McFadden K (2014) Pediatr Dev Pathol 17:386–392. doi: 10.2350/13-11-1399-CR.1 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cell density is increased in the neocortex with low-dose VPA and decreased in the prefrontal and somatosensory cortex with high-dose VPA.

    “Cell density is increased in the neocortex with a low dose [307] and decreased in the prefrontal and somatosensory cortex with a high dose of VPA [186].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [307] Sabers A, Bertelsen FC, Scheel-Kruger J, Nyengaard JR, Moller A (2014) Neurosci Lett 580:12–16. doi: 10.1016/j.neulet.2014.07.036 source

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    • cites [186] Kataoka S, Takuma K, Hara Y, Maeda Y, Ago Y, Matsuda T (2013) Int J Neuropsychopharmacol 16:91–103. doi: 10.1017/S1461145711001714 source

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  • May combine two claims.

    Premisecitation

    Exposure of pregnant women to VPA, but not other anti-epileptic treatments, nearly triples their risk for having a child with ASD, and ASD-like behavioral phenotypes have been replicated in rodent models of prenatal VPA exposure.

    “Exposure of pregnant women to VPA, but not other anti-epileptic treatments, nearly triples their risk for having a child with ASD [44, 69] and ASD-like behavioral phenotypes have been replicated in rodent models of prenatal VPA exposure (see Supplementary Table 3).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [44] Bromley RL, Mawer G, Clayton-Smith J, Baker GA, Liverpool, Manchester Neurodevelopment G (2008) Neurology 71:1923–1924. doi: 10.1212/01.wnl.0000339399.64213.1a source

      Not checked in the free run.

    • cites [69] Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M (2013) JAMA 309:1696–1703. doi: 10.1001/jama.2013.2270 source

      Not checked in the free run.

    • cites Supplementary Table 3

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher dose VPA exposure in rodents results in reduced brain weight, whereas lower dose does not affect brain weight.

    “Exposure to a higher dose of VPA in rodents results in reduced brain weight [250, 265], whereas a lower dose does not affect brain weight [331].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [250] Mychasiuk R, Richards S, Nakahashi A, Kolb B, Gibb R (2012) Dev Neurosci 34:268–276. doi: 10.1159/000341786 source

      Not checked in the free run.

    • cites [265] Olde Loohuis NF, Kole K, Glennon JC, Karel P, Van der Borg G, Van Gemert Y, Van den Bosch D, Meinhardt J, Kos A, Shahabipour F et al (2015) Neurobiol Dis 80:42–53. doi: 10.1016/j.nbd.2015.05.006 source

      Not checked in the free run.

    • cites [331] Snow WM, Hartle K, Ivanco TL (2008) Dev Psychobiol 50:633–639 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with agenesis of corpus callosum show difficulties in language and social communication, and decreased volume of the corpus callosum has been found in ASD.

    “Patients with agenesis of corpus callosum show difficulties in language and social communication [45, 276, 357], and decreased volume of the corpus callosum has been found in ASD (see meta-analysis in [114]).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [45] Brown WS, Paul LK, Symington M, Dietrich R (2005) Neuropsychologia 43:906–916. doi: 10.1016/j.neuropsychologia.2004.09.008 source

      Not checked in the free run.

    • cites [276] Paul LK, Van Lancker-Sidtis D, Schieffer B, Dietrich R, Brown WS (2003) Brain Lang 85:313–324 source

      Not checked in the free run.

    • cites [357] Turk AA, Brown WS, Symington M, Paul LK (2010) Neuropsychologia 48:43–50. doi: 10.1016/j.neuropsychologia.2009.08.009 source

      Not checked in the free run.

    • cites [114] Frazier TW, Hardan AY (2009) Biol Psychiatry 66:935–941. doi: 10.1016/j.biopsych.2009.07.022 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These findings agree with the reduction of gray matter volume over time in ASD, which is associated with increased severity of symptoms.

    “These findings agree with the reduction of gray matter volume over time in ASD, which is associated with increased severity of symptoms [143].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Hardan AY, Libove RA, Keshavan MS, Melhem NM, Minshew NJ (2009) Biol Psychiatry 66:320–326. doi: 10.1016/j.biopsych.2009.04.024 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Df(16)1/+ mouse model of the 22q11.2 deletion, dendritic complexity, spine length, spine width, spine density, and PSD length are unaffected in the hippocampal CA1.

    “In the Df(16)1/+ mouse model of the 22q11.2 deletion, dendritic complexity, spine length, spine width, spine density and PSD length are unaffected in the hippocampal CA1 [92].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Earls LR, Bayazitov IT, Fricke RG, Berry RB, Illingworth E, Mittleman G, Zakharenko SS (2010) J Neurosci 30:15843–15855. doi: 10.1523/JNEUROSCI.1425-10.2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Df(16)A+/− mice, spine turnover is higher than in wild-type, with smaller spine width but comparable spine density and length on apical dendrites, and decreased spine density, increased spine width, and fewer mushroom spines on basal dendrites.

    “Spine turnover in these animals is higher than in WT, with smaller spine width but comparable spine density and length on apical dendrites [112] and decreased spine density, increased spine width and fewer mushroom spines on the basal dendrites [391].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Fenelon K, Xu B, Lai CS, Mukai J, Markx S, Stark KL, Hsu PK, Gan WB, Fischbach GD, MacDermott AB et al (2013) J Neurosci 33:14825–14839. doi: 10.1523/JNEUROSCI.1611-13.2013 source

      Not checked in the free run.

    • cites [391] Xu B, Hsu PK, Stark KL, Karayiorgou M, Gogos JA (2013) Cell 152:262–275. doi: 10.1016/j.cell.2012.11.052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ranbp1−/− embryos show reduced proliferation of basal progenitor cells, leading to fewer layer II and III projection neurons.

    “and reduced proliferation of basal progenitor cells, leading to fewer layer II and III projection neurons in Ranbp1−/− embryos [274].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [274] Paronett EM, Meechan DW, Karpinski BA, LaMantia AS, Maynard TM (2015) Cereb Cortex 25:3977–3993. doi: 10.1093/cercor/bhu285 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MRI studies have revealed decreased gray matter volume in the dorsofrontal, cingulate, retrosplenial, occipital and parietal cortex, as well as in subcortical areas including lateral and posterior thalamus, posterior hypothalamus and ventral hippocampus, but increased volume in the olfactory bulbs, medial prefrontal and insular cortex, amygdala and dorsal hippocampus in BTBR mice.

    “MRI studies have revealed decreased gray matter volume in the dorsofrontal, cingulate, retrosplenial, occipital and parietal cortex, as well as in subcortical areas including lateral and posterior thalamus, posterior hypothalamus and ventral hippocampus, but increased volume in the olfactory bulbs, medial prefrontal and insular cortex, amygdala and dorsal hippocampus [87, 270].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Dodero L, Damiano M, Galbusera A, Bifone A, Tsaftsaris SA, Scattoni ML, Gozzi A (2013) PLoS One 8:e76655. doi: 10.1371/journal.pone.0076655 source

      Not checked in the free run.

    • cites [270] Pagani M, Damiano M, Galbusera A, Tsaftaris SA, Gozzi A (2016) J Neurosci Methods 267:62–73. doi: 10.1016/j.jneumeth.2016.04.007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTBR mice have more serotonin-expressing neurons in the caudal portions of the median and dorsal raphe but decreased axon terminals in the hippocampal CA1, decreased adult neurogenesis in the dentate gyrus, upregulation of postnatal turnover of excitatory synapses in the anterior frontal cortex, and unaltered synaptic density and PSD thickness in the somatosensory cortex.

    “The presence of more serotonin-expressing neurons in the caudal portions of the median and dorsal raphe but decreased axon terminals in the hippocampal CA1 [134], decreased adult neurogenesis in the dentate gyrus [338], upregulation of postnatal turnover of excitatory synapses in the anterior frontal cortex [172], and unaltered synaptic density and PSD thickness in the somatosensory cortex [381]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [134] Guo YP, Commons KG (2017) Autism Res 10:66–77. doi: 10.1002/aur.1665 source

      Not checked in the free run.

    • cites [338] Stephenson DT, O’Neill SM, Narayan S, Tiwari A, Arnold E, Samaroo HD, Du F, Ring RH, Campbell B, Pletcher M et al (2011) Mol Autism 2:7. doi: 10.1186/2040-2392-2-7 source

      Not checked in the free run.

    • cites [172] Isshiki M, Tanaka S, Kuriu T, Tabuchi K, Takumi T, Okabe S (2014) Nat Commun 5:4742. doi: 10.1038/ncomms5742 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In syndromic cases where genetic information was assessed, cases were rarely separated based on presence or absence of ASD or only qualitative neuropathology was provided.

    “In the syndromic cases where genetic information was assessed, cases were rarely separated based on presence or absence of ASD or only qualitative neuropathology was provided [128, 340].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [128] Greco CM, Navarro CS, Hunsaker MR, Maezawa I, Shuler JF, Tassone F, Delany M, Au JW, Berman RF, Jin LW et al (2011) Mol Autism 2:2. doi: 10.1186/2040-2392-2-2 source

      Not checked in the free run.

    • cites [340] Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, Morton DH (2006) N Engl J Med 354:1370–1377. doi: 10.1056/NEJMoa052773 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased glial proliferation and altered astrocyte and microglial densities are observed in the hippocampus and cerebellum following VPA exposure.

    “Increased glial proliferation [213] and altered astrocyte and microglial densities are observed in the hippocampus and cerebellum following VPA exposure [189].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [213] Lee HJ, Dreyfus C, DiCicco-Bloom E (2016) Dev Neurobiol 76:780–798. doi: 10.1002/dneu.22359 source

      Not checked in the free run.

    • cites [189] Kazlauskas N, Campolongo M, Lucchina L, Zappala C, Depino AM (2016) Psychoneuroendocrinology 72:11–21. doi: 10.1016/j.psyneuen.2016.06.001 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Several neuropathologic abnormalities have been reported in postmortem brain of ASD subjects, including altered size of neuronal cell bodies, changes in neuronal density, and abnormal distribution of neurons during development.

    “To date, several neuropathologic abnormalities have been reported in postmortem brain of ASD subjects, including altered size of neuronal cell bodies, changes in neuronal density, and abnormal distribution of neurons during development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a rhesus monkey model of maternal autoantibody exposure, brain volume is increased, as has been described in children with autism born to mothers with the autoantibodies.

    “In a similar model generated in rhesus monkeys, brain volume is increased [24], as has been described in children with autism born to mothers with the autoantibodies [259].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J, Amaral DG (2013) Transl Psychiatry 3:e278. doi: 10.1038/tp.2013.47 source

      Not checked in the free run.

    • cites [259] Nordahl CW, Braunschweig D, Iosif AM, Lee A, Rogers S, Ashwood P, Amaral DG, Van de Water J (2013) Brain Behav Immun 30:61–65. doi: 10.1016/j.bbi.2013.01.084 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ectopic cells and reduced size and complexity of dendritic branching of Purkinje cells are seen in VPA-exposed rodents.

    “Ectopic cells and reduced size and complexity of dendritic branching of Purkinje cells are seen in VPA-exposed rodents [228].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Main SL, Kulesza RJ (2017) Neuroscience 340:34–47. doi: 10.1016/j.neuroscience.2016.10.052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following prenatal VPA exposure, cell density is increased in the hippocampus but decreased in the cerebellum and the superior olivary nuclei of the brainstem.

    “Cell density is increased in the hippocampus [94], but it is decreased in the cerebellum [164] and the superior olivary nuclei of the brainstem [221] following prenatal VPA exposure.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [94] Edalatmanesh MA, Nikfarjam H, Vafaee F, Moghadas M (2013) Brain Res 1526:15–25. doi: 10.1016/j.brainres.2013.06.024 source

      Not checked in the free run.

    • cites [164] Ingram JL, Peckham SM, Tisdale B, Rodier PM (2000) Neurotoxicol Teratol 22:319–324 source

      Not checked in the free run.

    • cites [221] Lukose R, Schmidt E, Wolski TP Jr, Murawski NJ, Kulesza RJ Jr (2011) Brain Res 1398:102–112. doi: 10.1016/j.brainres.2011.05.013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodent models of prenatal VPA exposure, basal dendrites show no change in length on layer II pyramidal neurons in the motor cortex, decreased length and complexity in the medial PFC and hippocampal CA1, and increased length and complexity in the nucleus accumbens and basolateral amygdala.

    “Basal dendrites in rodent models of prenatal VPA exposure show no change in length on layer II pyramidal neurons in the motor cortex [331], decreased length and complexity in the medial PFC [297] and the hippocampal CA1, and increased length and complexity in the nucleus accumbens and basolateral amygdala [42].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [331] Snow WM, Hartle K, Ivanco TL (2008) Dev Psychobiol 50:633–639 source

      Not checked in the free run.

    • cites [297] Raza S, Harker A, Richards S, Kolb B, Gibb R (2015) Behav Brain Res 282:25–36. doi: 10.1016/j.bbr.2014.12.055 source

      Not checked in the free run.

    • cites [42] Bringas ME, Carvajal-Flores FN, Lopez-Ramirez TA, Atzori M, Flores G (2013) Neuroscience 241:170–187. doi: 10.1016/j.neuroscience.2013.03.030 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    VPA exposure in utero leads to fewer parvalbumin-expressing interneurons in the parietal and occipital cortex, fewer glutamate decarboxylase 67-immunoreactive interneurons in the dentate gyrus, cerebellum, and cortex, and loss of motor neurons in some motor nerve nuclei in the brainstem.

    “VPA exposure in utero leads to fewer parvalbumin-expressing interneurons in the parietal and occipital cortex [127], fewer glutamate decarboxylase 67-immunoreactive interneurons in the dentate gyrus, in the cerebellum and in the cortex [374], and loss of motor neurons in some of the motor nerve nuclei in the brainstem [303].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [127] Gogolla N, Leblanc JJ, Quast KB, Südhof TC, Fagiolini M, Hensch TK (2009) J Neurodev Disord 1:172–181. doi: 10.1007/s11689-009-9023-x source

      Not checked in the free run.

    • cites [374] Watanabe Y, Murakami T, Kawashima M, Hasegawa-Baba Y, Mizukami S, Imatanaka N, Akahori Y, Yoshida T, Shibutani M (2017) Neurotox Res 31:46–62. doi: 10.1007/s12640-016-9660-2 source

      Not checked in the free run.

    • cites [303] Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996) J Comp Neurol 370:247–261. doi: 10.1002/(SICI)1096-9861(19960624)370:2<247:AID-CNE8>3.0.CO;2-2 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In prenatal VPA models, apical dendrite complexity but not length is increased on layer II pyramidal neurons in the motor cortex, decreased in the medial PFC, or unchanged in layer V pyramidal neurons of the somatosensory cortex.

    “In the case of apical dendrites, complexity, but not length, is increased on layer II pyramidal neurons in the motor cortex [331], decreased in the medial PFC [297], or is unchanged in layer V pyramidal neurons of the somatosensory cortex following VPA exposure in rodents [301].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [331] Snow WM, Hartle K, Ivanco TL (2008) Dev Psychobiol 50:633–639 source

      Not checked in the free run.

    • cites [297] Raza S, Harker A, Richards S, Kolb B, Gibb R (2015) Behav Brain Res 282:25–36. doi: 10.1016/j.bbr.2014.12.055 source

      Not checked in the free run.

    • cites [301] Rinaldi T, Silberberg G, Markram H (2008) Cereb Cortex 18:763–770. doi: 10.1093/cercor/bhm117 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In prenatal VPA models, reduced dendritic branching but not length in the orbital PFC was reported in one study, whereas another showed decreased dendritic length in the same brain region.

    “Reduced dendritic branching but not length in the orbital PFC was reported in one study [297], whereas another showed decreased dendritic length in the same brain region [250].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [297] Raza S, Harker A, Richards S, Kolb B, Gibb R (2015) Behav Brain Res 282:25–36. doi: 10.1016/j.bbr.2014.12.055 source

      Not checked in the free run.

    • cites [250] Mychasiuk R, Richards S, Nakahashi A, Kolb B, Gibb R (2012) Dev Neurosci 34:268–276. doi: 10.1159/000341786 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Experimental mice exposed to maternal autoantibodies in utero show increased cell proliferation during cortical neurogenesis and increased neuronal and brain size in adulthood.

    “Experimental mice exposed to maternal autoantibodies in utero show increased cell proliferation during cortical neurogenesis [184, 229] and increased neuronal and brain size in adulthood [229].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [184] Kadam SD, French BM, Kim ST, Morris-Berry CM, Zimmerman AW, Blue ME, Singer HS (2013) J Exp Neurosci 7:93–99. doi: 10.4137/JEN.S12979 source

      Not checked in the free run.

    • cites [229] Martínez-Cerdeño V, Camacho J, Fox E, Miller E, Ariza J, Kienzle D, Plank K, Noctor SC, Van de Water J (2016) Cereb Cortex 26:374–383. doi: 10.1093/cercor/bhu291 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In VPA-exposed rodents, fewer postsynaptic densities are observed in the hippocampus, whereas more and thicker postsynaptic densities are present in the medial PFC.

    “Fewer postsynaptic densities are observed in the hippocampus of VPA exposed rodents [199], whereas more and thicker postsynaptic densities are present in the medial PFC [198].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [199] Kim KC, Kim P, Go HS, Choi CS, Park JH, Kim HJ, Jeon SJ, Dela Pena IC, Han SH, Cheong JH et al (2013) J Neurochem 124:832–843. doi: 10.1111/jnc.12147 source

      Not checked in the free run.

    • cites [198] Kim KC, Choi CS, Kim JW, Han SH, Cheong JH, Ryu JH, Shin CY (2016) Mol Neurobiol 53:40–56. doi: 10.1007/s12035-014-8987-z source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MIA mice have delayed cell development in the neocortex and reduced cell density and abnormal developmental migration in the cerebellum.

    “MIA mice have delayed cell development in the neocortex [333] and reduced cell density and abnormal developmental migration in the cerebellum [325].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [333] Soumiya H, Fukumitsu H, Furukawa S (2011) J Neurosci Res 89:1575–1585. doi: 10.1002/jnr.22704 source

      Not checked in the free run.

    • cites [325] Shi L, Smith SE, Malkova N, Tse D, Su Y, Patterson PH (2009) Brain Behav Immun 23:116–123. doi: 10.1016/j.bbi.2008.07.012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Analyses of ASD neuropathology using postmortem human brains face challenges related to the heterogeneous nature of the disorder, frequent confounding comorbid diagnoses, and small sample sizes.

    “However, analyses addressing the neuropathology of ASD using postmortem human brains face several challenges related to the heterogeneous nature of the disorder, the frequent presence of confounding comorbid diagnoses and the small sample sizes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    VPA rats have increased microglia in the medial PFC and more astrocytes in the hippocampus.

    “VPA rats have increased microglia in the medial PFC and more astrocytes in the hippocampus [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Codagnone MG, Podesta MF, Uccelli NA, Reines A (2015) Dev Neurosci 37:215–231. doi: 10.1159/000375489 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In prenatal VPA models, spine density is reduced in the PFC, orbital PFC, cerebellum, and dorsal hippocampus, but increased in the ventral hippocampus, basolateral amygdala, and nucleus accumbens.

    “Spine density is reduced in the PFC [42, 250, 297], orbital PFC [250, 297], cerebellum [250], and in the dorsal hippocampus [42, 346], but increased in the ventral hippocampus, basolateral amygdala and nucleus accumbens [42].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Bringas ME, Carvajal-Flores FN, Lopez-Ramirez TA, Atzori M, Flores G (2013) Neuroscience 241:170–187. doi: 10.1016/j.neuroscience.2013.03.030 source

      Not checked in the free run.

    • cites [250] Mychasiuk R, Richards S, Nakahashi A, Kolb B, Gibb R (2012) Dev Neurosci 34:268–276. doi: 10.1159/000341786 source

      Not checked in the free run.

    • cites [297] Raza S, Harker A, Richards S, Kolb B, Gibb R (2015) Behav Brain Res 282:25–36. doi: 10.1016/j.bbr.2014.12.055 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In Mecp2 mouse models, either too little or too much of the gene leads to autism-like phenotypes through separate pathways.

    “The Mecp2 mouse models make evident how deficiency or overexpression of the same gene can result in ASD phenotypes through very different mechanisms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Given the heterogeneity of ASD, no single model can be expected to recapitulate the entire spectrum of symptoms.

    “Given the heterogeneity of ASD, no single model can be expected to recapitulate the entire spectrum of symptoms.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Spine type distributions shift with neuronal activity, aging, and disease processes.

    “the distribution of various spine types, which changes in response to neuronal activity, aging or disease pathology”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Hering H, Sheng M (2001) Nat Rev Neurosci 2:880–888. doi: 10.1038/35104061 source

      Not checked in the free run.

    • cites [280] Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM (2011) Nat Neurosci 14:285–293. doi: 10.1038/nn.2741 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Animal models of genetic or idiopathic autism are pointing to treatments that may address core autistic behaviors and to disease mechanisms that could support more individualized diagnosis.

    “Complementary investigations using animal models that replicate genetic or idiopathic ASD are revealing possible therapies that can target core ASD behaviors as well as basic mechanisms underlying the disease that may enable more personalized diagnoses.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Animal models that reproduce genetic or idiopathic autism are valid enough models of the human condition to reveal therapies and disease mechanisms.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because autism is neurodevelopmental, the first diagnosis and treatment choices for a child may strongly and durably shape how symptoms unfold.

    “This is particularly relevant for the initial diagnosis and treatment plan that, given the neurodevelopmental character of the disorder, can have a major and long-lasting impact in the progression of the symptoms for each affected child.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Studies of the human brain are the most appropriate for understanding the cellular underpinnings of complex neuropsychiatric disorders.

    “Although studies of the human brain are the most appropriate for understanding the cellular underpinnings of complex neuropsychiatric disorders, supplementing studies using human samples with those in animal models of ASD provides a valuable tool to fill in some of the gaps in postmortem ASD studies and to eliminate heterogeneity, thus enabling a better understanding of the effect of a mutations”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Clarifying how suspected genetic risk interacts with cellular and molecular brain pathology should lead to improved diagnostic and treatment approaches.

    “understanding the interactions between putative genetic susceptibility in the context of neuropathologic abnormalities at the cellular and molecular levels will allow for better diagnostic and therapeutic tools”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Animal models that reproduce genetic or idiopathic autism are valid enough models of the human condition to reveal therapies and disease mechanisms.

  • May combine two claims.

    Interpretationreasoning

    Supplementing human studies with animal models of ASD provides a valuable tool to fill gaps in postmortem ASD studies and to eliminate heterogeneity, enabling better understanding of the effects of mutations in ASD-associated genes or loci on neurological and synaptic features.

    “supplementing studies using human samples with those in animal models of ASD provides a valuable tool to fill in some of the gaps in postmortem ASD studies and to eliminate heterogeneity, thus enabling a better understanding of the effect of a mutations in ASD-associated genes or genetic loci on neurological and synaptic features.”
    Quote in the paperSubstantial claim
134 of 134

  • The paper relies on this without support.

    Using current methods, only about 20% of ASD cases have an identified genetic cause.

    “Using current methods, only 20% of ASD cases have an identified genetic cause, often involving chromosomal rearrangements, CNVs or point mutations.”

  • The paper relies on this without support.

    Over 60% of patients with Rett syndrome meet criteria for ASD.

    “Over 60% of patients with Rett syndrome meet the criteria for ASD, with features such as repetitive hand movements, social withdrawal and loss of verbal communication.”

  • The paper relies on this without support.

    Approximately 22% of all carriers and 30% of males with FMR1 mutations meet diagnostic criteria for ASD.

    “Besides, approximately 22% of all carriers and 30% of males with FMR1 mutations meet the diagnostic criteria for ASD.”

  • The paper relies on this without support.

    The estimated prevalence of ASD in carriers of TSC mutations is 36%.

    “The estimated prevalence of ASD in carriers of TSC mutations is 36%.”

  • The paper relies on this without support.

    TSC is an autosomal dominant disorder characterized by benign tumors called tubers in multiple organs, including the brain and kidneys, and increased risk for malignant tumors.

    “Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by benign tumors called tubers in multiple organs, including the brain and kidneys, as well as increased risk for developing malignant tumors.”

  • The paper relies on this without support.

    TSC is caused by mutations in TSC1 or TSC2, resulting in loss of inhibitory action on mTOR and dysregulation of mTOR signaling.

    “TSC is caused by mutations in the TSC1 gene encoding the hamartin protein or the TSC2 gene encoding tuberin, resulting in the loss of their inhibitory action on the mammalian target of rapamycin (mTOR) protein and dysregulation of mTOR signaling.”

  • The paper relies on this without support.

    SCN2A mutations are associated with infantile seizures, epileptic encephalopathy, epileptic syndromes, intellectual disability, and ASD without epilepsy.

    “Sodium channel, voltage-gated type II α subunit (SCN2A) mutations have previously been associated with infantile seizures, epileptic encephalopathy, epileptic syndromes, as well as intellectual disability and ASD without epilepsy.”

  • The paper relies on this without support.

    The ASD-relevant behaviors of the inbred mouse and rat strains used as idiopathic autism models are not caused by known genetic mutations.

    “These inbred strains are considered to be models of idiopathic autism, as their ASD-relevant behaviors are not caused by known genetic mutations.”

  • The paper relies on this without support.

    Multiple factors may contribute to ASD.

    “As multiple factors may contribute to ASD, genetic models expressing a single mutation cannot perfectly model all the pathological features of ASD.”

  • The paper relies on this without support.

    Animal models that reproduce genetic or idiopathic autism are valid enough models of the human condition to reveal therapies and disease mechanisms.

    “Complementary investigations using animal models that replicate genetic or idiopathic ASD are revealing possible therapies that can target core ASD behaviors as well as basic mechanisms underlying the disease that may enable more personalized diagnoses.”
    “These experimental systems are proving to be invaluable in uncovering mechanisms whereby ASD genes contribute or regulate the pruning and turnover of dendritic spines during development.”

  • The paper relies on this without support.

    Changes in dendritic spine density in these models have functional consequences for autism.

    “To illuminate fully the functional implications of altered spine densities, further investigations are warranted in most of these models”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In ASD, neural migration and cortical laminar organization, stages that occur in second and third trimesters, are abnormal.

    “In ASD, neural migration and cortical laminar organization, stages that occur in second and third trimesters, are also abnormal (Fig. 2) [34, 45–48].”

    From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [46]

  • 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].”

    From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [46]

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.

  • Chd8 spine-density direction reverses in the discussion

    Minor

    The discussion lists increased neocortical spine density in Chd8 mice, but the earlier description of Chd8 knockdown in mouse cortical neurons reports reduced spine density.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Altemeier WA, Altemeier LE (2009) Pediatr Ann 38(167–170):172
  2. Broca P (1861) Bull Mem Soc Anat Paris. 36:330–357
  3. Committee on Children with Disabilities 2000–2001 (2000) Pediatrics 2001(108):192–196
  4. Gutstein SE (2009) Ann Clin Psychiatry 21:174–182

Cited by

Sorted by citations

Related

Authors
Varghese, M., Keshav, N., Jacot-Descombes, S., Warda, T., Wicinski, B., Dickstein, D. L., Harony-Nicolas, H., De Rubeis, S., Drapeau, E., Buxbaum, J. D., & Hof, P. R.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • University Hospital of Geneva (CH)
  • Uniformed Services University of the Health Sciences (US)
Corresponding author
Hof, Patrick R.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2017-06-05
Volume
134
Issue
4
Pages
537-566
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-017-1736-4
PMC
PMC5693718
OpenAlex
W2622311208
Semantic Scholar
f84e9a1e1d3dbd3ca8ce530722a80bea391fda4b
Cited by
536
References
399
Citations by year
2026: 43 · 2025: 68 · 2024: 86 · 2023: 75 · 2022: 79 · 2021: 60 · 2020: 47 · 2019: 36 · 2018: 27 · 2017: 10 · 2016: 1
FWCI
3.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Seaver Foundation
  • Simons Foundation (FA #345922)
  • Autism Speaks
  • Foundation for Prader-Willi Research
  • National Institutes of Health (MH093725, MH101584)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
autism spectrum disorder, neuropathology, animal models of autism, postmortem brain, dendritic spines, copy number variation, risk genes, idiopathic autism, valproic acid, maternal immune activation, maternal autoantibodies, neuronal morphology, glia, cerebral vasculature, 16p11.2, 15q11-q13
MeSH terms
Autism Spectrum Disorder, Animals, Brain, Disease Models, Animal, Humans, Neurons

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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