Article

Neuron Number and Size in Prefontal Cortex of Children With Autism

Department of Neuroscience, NIH-UCSD Autism Center of Excellence, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 11/2011; 306(18):2001-10. DOI: 10.1001/jama.2011.1638
Source: PubMed

ABSTRACT

Autism often involves early brain overgrowth, including the prefrontal cortex (PFC). Although prefrontal abnormality has been theorized to underlie some autistic symptoms, the cellular defects that cause abnormal overgrowth remain unknown.
To investigate whether early brain overgrowth in children with autism involves excess neuron numbers in the PFC. DESIGN, SETTING, AND CASES: Postmortem prefrontal tissue from 7 autistic and 6 control male children aged 2 to 16 years was examined by expert anatomists who were blinded to diagnostic status. Number and size of neurons were quantified using stereological methods within the dorsolateral (DL-PFC) and mesial (M-PFC) subdivisions of the PFC. Cases were from the eastern and southeastern United States and died between 2000 and 2006.
Mean neuron number and size in the DL-PFC and M-PFC were compared between autistic and control postmortem cases. Correlations of neuron number with deviation in brain weight from normative values for age were also performed.
Children with autism had 67% more neurons in the PFC (mean, 1.94 billion; 95% CI, 1.57-2.31) compared with control children (1.16 billion; 95% CI, 0.90-1.42; P = .002), including 79% more in DL-PFC (1.57 billion; 95% CI, 1.20-1.94 in autism cases vs 0.88 billion; 95% CI, 0.66-1.10 in controls; P = .003) and 29% more in M-PFC (0.36 billion; 95% CI, 0.33-0.40 in autism cases vs 0.28 billion; 95% CI, 0.23-0.34 in controls; P = .009). Brain weight in the autistic cases differed from normative mean weight for age by a mean of 17.6% (95% CI, 10.2%-25.0%; P = .001), while brains in controls differed by a mean of 0.2% (95% CI, -8.7% to 9.1%; P = .96). Plots of counts by weight showed autistic children had both greater total prefrontal neuron counts and brain weight for age than control children.
In this small preliminary study, brain overgrowth in males with autism involved an abnormal excess number of neurons in the PFC.

Download full-text

Full-text

Available from: Peter R. Mouton, Jun 25, 2014
  • Source
    • "As in Alzheimer's disease, interneuron and pyramidal enrichments were found in down-regulated genes, while enrichments of glial and endothelial cells were present in the up-regulated gene sets. The cellular changes expected to correspond to decreased expression of neuronal transcripts is unclear, with no consensus in the literature about how neurons are affected in autistic patients (van Kooten et al., 2008; Courchesne et al., 2011; Casanova et al., 2013). Up-regulation of astro-and micro-glial genes, which indicates activation in those cell types, is broadly supported by past studies which have shown elevated expression of glial marker genes, increased cell densities and altered morphologies for both cell types (Laurence and Fatemi, 2005; Vargas et al., 2005; Morgan et al., 2012; Tetreault et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cell types that trigger the primary pathology in many brain diseases remain largely unknown. One route to understanding the primary pathological cell type for a particular disease is to identify the cells expressing susceptibility genes. Although this is straightforward for monogenic conditions where the causative mutation may alter expression of a cell type specific marker, methods are required for the common polygenic disorders. We developed the Expression Weighted Cell Type Enrichment (EWCE) method that uses single cell transcriptomes to generate the probability distribution associated with a gene list having an average level of expression within a cell type. Following validation, we applied EWCE to human genetic data from cases of epilepsy, Schizophrenia, Autism, Intellectual Disability, Alzheimer’s disease, Multiple Sclerosis and anxiety disorders. Genetic susceptibility primarily affected microglia in Alzheimer’s and Multiple Sclerosis; was shared between interneurons and pyramidal neurons in Autism and Schizophrenia; while intellectual disabilities and epilepsy were attributable to a range of cell-types, with the strongest enrichment in interneurons. We hypothesised that the primary cell type pathology could trigger secondary changes in other cell types and these could be detected by applying EWCE to transcriptome data from diseased tissue. In Autism, Schizophrenia and Alzheimer’s disease we find evidence of pathological changes in all of the major brain cell types. These findings give novel insight into the cellular origins and progression in common brain disorders. The methods can be applied to any tissue and disorder and have applications in validating mouse models.
    Full-text · Article · Jan 2016 · Frontiers in Neuroscience
  • Source
    • "Brain weight at autopsy is also shifted upward with heavier than the normal mean for an estimated 80% of 2–16 year olds, but lighter for a minority (Redcay & Courchesne, 2005; Courchesne et al, 2011b). A small sample of young ASD boys with heavy brain weight exhibited an excess of 67% neurons in the prefrontal cortex, which mediates social, communication and cognitive development (Courchesne et al, 2011b). The excess of neurons in enlarged brains points to potential dysregulation of mechanisms that govern cerebral cortical neuron number during second trimester development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic mechanisms underlying abnormal early neural develop- ment in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi-tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored rela- tionships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregu- lated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candi- date genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/ S and G2/M phase transition. Finally, analyses of the CHD8 subnet- work and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.
    Full-text · Article · Dec 2015 · Molecular Systems Biology
  • Source
    • "children with autism [1] [2] [3] that is localized to specific areas, such as frontal cortex [3] [4]. Postmortem studies of autistic brains have also revealed abnormalities in cellular number and morphology in some brain areas including the cerebral cortex, amygdala, cerebellum, and brainstem [5] [6] [7]. An alteration in the number of cortical cell subtypes or in the soma volume of neurons in specific layers of the cortex would likely alter the pattern of connections between cortical areas and could produce disturbances in cognitive functioning similar to those seen in autism. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the cytoarchitecture of the anterior superior temporal area (TA2) of the postmortem cerebral cortex in 9 subjects with autism and 9 age-matched typically developing subjects between the ages of 13 and 56 years. The superior temporal gyrus is involved in auditory processing and social cognition and its pathology has been correlated with autism. We quantified the number and soma volume of pyramidal neurons in the supragranular layers and pyramidal neurons in the infragranular layers in each subject. We did not find significant differences in the number or volume of supragranular or infragranular neurons in the cerebral cortex of subjects with autism compared to typically developing subjects. This report does not support an alteration of supragranular to infragranular neurons in autism. However, further stereological analysis of the number of cells and cell volumes in specific cortical areas is needed to better establish the cellular phenotype of the autistic cerebral cortex and to understand its clinical relevance in autism. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Jan 2015 · Neuroscience Letters
Show more