Article

Brain Transcriptional and Epigenetic Associations with Autism

University of Insubria, Italy
PLoS ONE (Impact Factor: 3.23). 09/2012; 7(9):e44736. DOI: 10.1371/journal.pone.0044736
Source: PubMed

ABSTRACT

Autism is a common neurodevelopmental syndrome. Numerous rare genetic etiologies are reported; most cases are idiopathic.
To uncover important gene dysregulation in autism we analyzed carefully selected idiopathic autistic and control cerebellar and BA19 (occipital) brain tissues using high resolution whole genome gene expression and whole genome DNA methylation microarrays. No changes in DNA methylation were identified in autistic brain but gene expression abnormalities in two areas of metabolism were apparent: down-regulation of genes of mitochondrial oxidative phosphorylation and of protein translation. We also found associations between specific behavioral domains of autism and specific brain gene expression modules related to myelin/myelination, inflammation/immune response and purinergic signaling.
This work highlights two largely unrecognized molecular pathophysiological themes in autism and suggests differing molecular bases for autism behavioral endophenotypes.

Download full-text

Full-text

Available from: Robert Rubin, Mar 04, 2014
  • Source
    • "Several studies have examined changes in the expression of mitochondrial genes in brain samples of individuals with autism. Decreased mitochondrial ETC complex gene expression was found in the cerebellum and BA19 (occipital) brain tissue from 9 individuals with autism compared to 9 controls (Ginsberg et al., 2012). In another study, reduced expression of mitochondrial ETC genes, including 11 genes of complex I, five genes of complex III, five genes of complex IV, and seven genes of complex V were reported in the anterior cingulate gyrus, thalamus, and motor cortex derived from 8 patients with autism compared to 10 controls (Anitha et al., 2013). "

    Full-text · Dataset · Nov 2014
  • Source
    • "The effect produced by partial 6-OHDA lesion on depressivelike behavior was examined in the forced swim and tail suspension tests (Castagne et al., 2009; Ginsberg et al., 2012). We found that, in the forced swim test, 6-OHDA- lesioned mice displayed a longer immobility time (considered an index of depression) in comparison to sham mice (p < 0.0001, Student's t-test) (Figure 3A). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals.
    Full-text · Article · Aug 2014 · Frontiers in Behavioral Neuroscience
  • Source
    • "Several studies have examined changes in the expression of mitochondrial genes in brain samples of individuals with autism. Decreased mitochondrial ETC complex gene expression was found in the cerebellum and BA19 (occipital) brain tissue from 9 individuals with autism compared to 9 controls (Ginsberg et al., 2012). In another study, reduced expression of mitochondrial ETC genes, including 11 genes of complex I, five genes of complex III, five genes of complex IV, and seven genes of complex V were reported in the anterior cingulate gyrus, thalamus, and motor cortex derived from 8 patients with autism compared to 10 controls (Anitha et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are defined solely on the basis of behavioral observations. Therefore, ASD has traditionally been framed as a behavioral disorder. However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation. While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals. A majority of these brain tissue studies have been published since 2010. The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination. This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders. This understanding may lead to new testing and treatment strategies in individuals with ASD.
    Full-text · Article · Apr 2014 · Frontiers in Physiology
Show more