Age-Dependent Brain Gene Expression and Copy Number Anomalies in Autism Suggest Distinct Pathological Processes at Young Versus Mature Ages

Department of Neuroscience, NIH-UCSD Autism Center of Excellence, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS Genetics (Impact Factor: 7.53). 03/2012; 8(3):e1002592. DOI: 10.1371/journal.pgen.1002592
Source: PubMed


Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism.

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Available from: Lauren A Weiss, Oct 10, 2015
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    • "We chose to investigate the DLPFC as dysfunction or lack of normal maturation of the DLPFC is heavily implicated in ASD and is thought to underpin many ASD symptoms, including behavioural deficits (Bachevalier and Loveland, 2006), with neuroimaging studies also supporting this hypothesis (Schmitz et al., 2007; Sun et al., 2012). This part of our investigation was carried out utilising recently published microarray gene expression data patients with ASD and controls (Chow et al., 2012). We then investigated whether mGluR5 protein levels were altered in the DLPFC of individuals with ASD utilising post-mortem stereological quantitation and investigating the number of mGluR5-positive neurons and glia within the DLPFC of individuals with ASD versus normal controls. "
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    ABSTRACT: Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, while activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p = 0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p = 0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 06/2015; 49. DOI:10.1016/j.bbi.2015.05.009 · 5.89 Impact Factor
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    • "Prior studies have shown differentially expressed genes and miRNAs in brain [48]–[52] and blood [15]–[23] samples from patients with ASD. This study further examines gene expression and demonstrates the capability of blood gene expression profiling to distinguish ASD patients from controls, with an average accuracy of 72.5% in one population (the P1 cohort) and 72.7% in an independently collected validation population (the P2 cohort). "
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    ABSTRACT: Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62-0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65-0.82), but not for female samples (AUC 0.51, 95% CI 0.36-0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58-0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.
    PLoS ONE 12/2012; 7(12):e49475. DOI:10.1371/journal.pone.0049475 · 3.23 Impact Factor
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    • "Imaging studies of the brains of autistic individuals have demonstrated abnormalities in the PFC (Herbert et al., 2003), which is a key area involved in social cognition. For example, toddlers and children with autism often exhibit early brain enlargement and excessive numbers of neurons in the PFC (Chow et al., 2012). According to Rinaldi et al. (2008) the social deficit in autism could be re-interpreted in the light of a hyperfunctional PFC. "
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    ABSTRACT: Research on autism has been gaining more and more attention. However, its aetiology is not entirely known and several factors are thought to contribute to the development of this neurodevelopmental disorder. These potential contributing factors range from genetic heritability to environmental effects. A significant number of reviews have already been published on different aspects of autism research as well as focusing on using animal models to help expand current knowledge around its aetiology. However, the diverse range of symptoms and possible causes of autism have resulted in as equally wide variety of animal models of autism. In this update article we focus only on the animal models with neurobehavioural characteristics of social deficit related to autism and present an overview of the animal models with alterations in brain regions, neurotransmitters, or hormones that are involved in a decrease in sociability.
    Neuroscience Research 11/2012; 74(3-4). DOI:10.1016/j.neures.2012.10.004 · 1.94 Impact Factor
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