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


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.

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Available from: Peter R. Mouton, Jun 25, 2014
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    • "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. "
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    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.
    Neuroscience Letters 01/2015; 589. DOI:10.1016/j.neulet.2015.01.021 · 2.03 Impact Factor
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    • "Explanations for this early growth pattern, and attempts at localizing specifically affected areas of the brain have proven controversial. Increase in the number of neurons [9], increase in neuronal dendritic volume and synapses [10], and increase in the number and size of microglial cells [11] are three posited explanations for the unusual growth pattern in ASD. In addition, important findings of increased numbers and size of microglia and excessive microglial activation has been shown in wide age range of individuals with ASD [12] [13] [14]. "
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    ABSTRACT: Recent studies of Autism Spectrum Disorders (ASD) highlight hyperactivity of the immune system, irregular neuronal growth and increased size and number of microglia. Though the small sample size in many of these studies limits extrapolation to all individuals with ASD, there is mounting evidence of both immune and nervous system related pathogenesis in at least a subset of patients with ASD. Given the disturbing rise in incidence rates for ASD, and the fact that no pharmacological therapy for ASD has been approved by the Food and Drug Administration (FDA), there is an urgent need for new therapeutic options. Research in the therapeutic effects of mesenchymal stem cells (MSC) for other immunological and neurological conditions has shown promising results in preclinical and even clinical studies. MSC have demonstrated the ability to suppress the immune system and to promote neurogenesis with a promising safety profile. The working hypothesis of this paper is that the potentially synergistic ability of MSC to modulate a hyperactive immune system and its ability to promote neurogenesis make it an attractive potential therapeutic option specifically for ASD. Theoretical mechanisms of action will be suggested, but further research is necessary to support these hypothetical pathways. The choice of tissue source, type of cell, and most appropriate ages for therapeutic intervention remain open questions for further consideration. Concern over poor regulatory control of stem cell studies or treatment, and the unique ethical challenges that each child with ASD presents, demands that future research be conducted with particular caution before widespread use of the proposed therapeutic intervention is implemented.
    Medical Hypotheses 12/2014; 84(3). DOI:10.1016/j.mehy.2014.12.016 · 1.07 Impact Factor
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    • "Experimental studies in rhesus monkey show that they are key elements in the circuitry involved in working memory and other prefrontal cortex-dependent associative cognitive functions (Wang et al., 2006; Verduzco-Flores et al., 2009). Data from various psychiatric disorders showed that selective alteration of large layer III pyramidal cells correlates with a decline in higher cognitive functions (Morrison and Hof, 2002; Selemon et al., 2003; Dean, 2009; Dorph-Petersen et al., 2009; Courchesne et al., 2011; Jacot-Descombes et al., 2012; Teffer and Semendeferi, 2012; Selemon et al., 2013) and developmental studies found that prominence in size of neurons in the upper cortical layers and peak in synaptic number appear by the end of infancy, stage when human specific mental capacities appear (Petanjek et al., 2008, 2011). Altogether, it can be concluded that large layer III pyramidal neurons in the high order associative areas are the main integrative elements (“associative” neurons) between different cortical areas (Goldman-Rakic, 1999; see discussion from Petanjek et al., 2008). "
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    ABSTRACT: In this article we first point at the expansion of associative cortical areas in primates, as well as at the intrinsic changes in the structure of the cortical column. There is a huge increase in proportion of glutamatergic cortical projecting neurons located in the upper cortical layers (II/III). Inside this group, a novel class of associative neurons becomes recognized for its growing necessity in both inter-areal and intra-areal columnar integration. Equally important to the changes in glutamatergic population, we found that literature data suggest a 50% increase in the proportion of neocortical GABAergic neurons between primates and rodents. This seems to be a result of increase in proportion of calretinin interneurons in layers II/III, population which in associative areas represents 15% of all neurons forming those layers. Evaluating data about functional properties of their connectivity we hypothesize that such an increase in proportion of calretinin interneurons might lead to supra-linear growth in memory capacity of the associative neocortical network. An open question is whether there are some new calretinin interneuron subtypes, which might substantially change micro-circuitry structure of the primate cerebral cortex.
    Frontiers in Neuroanatomy 09/2014; 8:103. DOI:10.3389/fnana.2014.00103 · 3.54 Impact Factor
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