A synaptic trek to autism.

Human Genetics and Cognitive Functions, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France.
Current opinion in neurobiology (Impact Factor: 7.21). 07/2009; 19(2):231-4. DOI: 10.1016/j.conb.2009.06.003
Source: PubMed

ABSTRACT Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.

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    ABSTRACT: Background: Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. The metabolic pathology of autism is relatively unexplored although metabolic imbalance is implicated in the pathogenesis of multiple other neurobehavioral disorders. An abnormal accumulation or deficit of specific metabolites in a defined pathway can provide clues into relevant candidate genes and/or environmental exposures. In addition, the identification of precursor-product metabolite imbalance can inform targeted intervention strategies to restore metabolic balance and potentially improve symptoms of autism. We have investigated metabolic pathways essential for cellular methylation and antioxidant capacity and the functional impact of metabolic imbalance on genome-wide DNA hypomethylation and protein/DNA oxidative damage in children with autism. These metabolic pathways regulate the distribution of precursors for DNA synthesis (proliferation), DNA methylation (epigenetic regulation of gene expression) and glutathione synthesis (redox/antioxidant defense capacity). Previously, we reported that the metabolic profile of many children with autism is consistent with reduced methylation capacity and a more oxidized microenvironment. Objectives: To determine whether methylation and antioxidant metabolic profile differs between case children, unaffected siblings, and age-matched control children and to determine whether the metabolic imbalance is accompanied by DNA hypomethylation and protein/DNA oxidative damage. Methods: Subjects included 162 children, ages 3-10, who were participants in the autism IMAGE study (Integrated Metabolic And Genomic Endeavor) at Arkansas Children’s Hospital Research Institute. The IMAGE cohort is comprised of 162 children including of 68 case children, 54 age-matched controls and 40 unaffected siblings. Children with autistic disorder were diagnosed using DSM-IV (299.0), ADOS and/or CARS >30. Fasting plasma samples were analyzed for folate-dependent transmethylation and transsulfuration metabolites and 3-nitrotyrosine (oxidized protein derivative) using HPLC with electrochemical detection. Genome-wide DNA methylation (as %5-methylcytosine) and the oxidized DNA adduct 8-oxo-deoxyguanine were quantified with Dionex HPLC-UV system coupled to an electrospray ionization (ESI) tandem mass spectrometer. Results: In a pair-wise comparison, the overall metabolic profile of the unaffected siblings differed significantly from their autistic siblings but was not different from unrelated control children. In addition, we report new evidence of genome-wide DNA hypomethylation (epigenetic dysregulation) and oxidative protein/DNA damage in children with autism that was not present in their paired siblings or in unaffected control children. Conclusions: These data indicate that the deficit in antioxidant and methylation capacity is autism-specific and is associated with DNA hypomethylation (epigenetic dysregulation) and oxidative damage. Further, these results suggest a plausible mechanism by which environmental stressors might modulate the genetic predisposition to autism. Acknowledgement: This research was supported with funding from the National Institute of Child Health and Development (RO1 HD051873; SJJ) and Department of Defense (AS073218P1; SJJ)
    International Meeting for Autism Research 2011; 05/2011
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    ABSTRACT: Autism has been described as a disorder of general neural processing, but the particular processing characteristics that might be abnormal in autism have mostly remained obscure. Here, we present evidence of one such characteristic: poor evoked response reliability. We compared cortical response amplitude and reliability (consistency across trials) in visual, auditory, and somatosensory cortices of high-functioning individuals with autism and con-trols. Mean response amplitudes were statistically indistinguishable across groups, yet trial-by-trial response reliability was significantly weaker in autism, yielding smaller signal-to-noise ratios in all sensory systems. Response reliability differences were evident only in evoked cortical responses and not in ongoing resting-state activity. These findings reveal that abnormally unreliable cortical responses, even to elementary nonsocial sensory stimuli, may represent a fundamental physiological alteration of neural processing in autism. The results motivate a critical expansion of autism research to determine whether (and how) basic neural processing proper-ties such as reliability, plasticity, and adaptation/ habituation are altered in autism.
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    ABSTRACT: Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2-based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2-associated neurodevelopmental disorders.
    Frontiers in Neuroanatomy 09/2014; 8:97. · 4.18 Impact Factor


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