Patches of Disorganization in the Neocortex of Children with Autism
Open accessAbstract
BACKGROUND: Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development. METHODS: To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type-specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years. RESULTS: We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches. CONCLUSIONS: In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.).
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Neurobiological studies of both pathology and genetics suggest that the mechanisms behind autism are in place during fetal development.
“Second, neurobiological studies of both pathology and genetics suggest that the mechanisms behind autism are in place during fetal development (Stoner et al. 2014), so from a biological standpoint, onset may be before birth.”
From Recent Advances in Autism Research as Reflected in DSM-5 Criteria for Autism Spectrum Disorder (2015) · cites this paper as Stoner et al. 2014
Postmortem studies found focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from a majority of young children with autism.
“Postmortem studies have found focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from a majority of young children with autism, with the clearest signs of abnormal expression of excitatory neuronal markers in deep cortical layers 4 and 5 122.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [122]
Evidence from neuroanatomical, animal, and epidemiologic studies supports prenatal and early postnatal origins of autism.
“evidence from neuroanatomical, animal, and epidemiologic studies support the prenatal and early postnatal origins of autism.19–24”
From Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence (2014) · cites this paper as [24]
Excess cortical neuron numbers and patches of abnormal cortical organization and cell migration implicate mid-fetal development as crucial in ASD pathophysiology.
“Excess cortical neuron numbers and patches of abnormal cortical organization and cell migration are pathologies that also implicate mid-fetal development as being crucial in ASD pathophysiology16, 17.”
From Altered proliferation and networks in neural cells derived from idiopathic autistic individuals (2017) · cites this paper as [17]
Patches of focal laminar disorganization and nearby clusters of mis-migrated neurons were found in prefrontal and temporal cortices in 10 of 11 young ASD cases.
“Patches of focal laminar disorganization and nearby clusters of mis-migrated neurons were found in prefrontal and temporal cortices in 10 of 11 young ASD cases [34].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [34]
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 [34]
MIA can also induce more complex cortical phenotypes such as focal cortical dysplasia, similar to those found in ASD.
“MIA can also induce more complex cortical phenotypes such as focal cortical dysplasia [81, 132], similar to those found in ASD [34] (Fig. 7).”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [34]
Cytoarchitecture heterogeneity is seen in MIA models and is characteristic of ASD cases.
“Also, cytoarchitecture heterogeneity is seen that is characteristic of ASD cases [34, 132].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [34]
The same fetal MIA perturbation of littermates causes patches of focal cortical dysplasia that have marked heterogeneity, analogous to heterogeneity found in cortex in unrelated individual ASD cases postmortem.
“The Choi and colleagues [132, 81] MIA ASD mouse model study showed that the same fetal MIA perturbation of littermates causes patches of focal cortical dysplasia that have marked heterogeneity, analogous to heterogeneity found in cortex in unrelated individual ASD cases postmortem [34] (Fig. 7).”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [34]
Genetic and non-genetic factors and their interaction may act at very early periods of fetal brain development and potentially alter protein or gene expression regulation leading to shared pathways for complex ASD-related phenotypes.
“Recent evidence11, 12, 13, 14, 15, 16, 17, 18, 19, 20 has also catalyzed the concept that genetic and non-genetic factors and their interaction, may act at very early periods of fetal brain development and potentially alter protein or gene expression regulation leading to shared pathways for complex ASD-related phenotypes.”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [11]
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].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [339]
In the few human studies, a decrease in PV+ cells and/or PVALB mRNA was reported.
“Also in the few human studies, a decrease in PV+ cells and/or PVALB mRNA was reported [46, 86].”
A recent report in the New England Journal of Medicine describes structural brain abnormalities in autistic children that began during prenatal brain development.
“A recent report in the New England Journal of Medicine describes structural brain abnormalities in autistic children that began during prenatal brain development,116”
From The Gut Microbiome and the Brain (2014) · cites this paper as [116]
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- Authors
- Stoner, R., Chow, M. L., Boyle, M. P., Sunkin, S. M., Mouton, P. R., Roy, S., Wynshaw-Boris, A., Colamarino, S. A., Lein, E. S., & Courchesne, E.
- Affiliations
- Allen Institute for Brain Science (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-03-27
- Volume
- 370
- Issue
- 13
- Pages
- 1209-1219
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4499461
- OpenAlex
- W2142438562
- Cited by
- 722
- References
- 30
- Citations by year
- 2026: 25 · 2025: 33 · 2024: 37 · 2023: 41 · 2022: 59 · 2021: 68 · 2020: 78 · 2019: 46 · 2018: 65 · 2017: 84 · 2016: 65 · 2015: 74 · 2014: 46
- FWCI
- 50.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (P50MH081755)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01 HD 43383, N01-HD-4-3368)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- autism spectrum disorder, neocortex, prefrontal cortex, temporal cortex, occipital cortex, neuronal differentiation, fetal brain development, RNA in situ hybridization, postmortem brain, children
- MeSH terms
- Adolescent, Autistic Disorder, Cell Count, Child, Child, Preschool, Humans, Nerve Tissue Proteins, Neurons, RNA, Biomarkers, Gene Expression, Cryoultramicrotomy, Neurofilament Proteins, In Situ Hybridization, Neocortex, Imaging, Three-Dimensional, Cyclic Nucleotide Phosphodiesterases, Type 1, Neurogenesis, Nuclear Receptor Subfamily 1, Group F, Member 2, Calbindin 1
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