1. Boersma M, Kemner C, De Reus M, Collin G, Snijders T, Hofman D, Buitelaar J, Stam C, van den Heuvel M. {{Disrupted functional brain networks in autistic toddlers}}. {Brain connectivity}. 2012 Dec 23.
Communication and integration of information between brain regions plays a key role in healthy brain function. Conversely, disruption in brain communication may lead to cognitive and behavioral problems. Autism is a neurodevelopmental disorder that is characterized by impaired social interactions and aberrant basic information processing. Aberrant brain connectivity patterns have indeed been hypothesized to be a key neural underpinning of autism. In this study, graph analytical tools are used to explore the possible deviant functional brain network organization in autism at a very early stage of brain development. Electroencephalography (EEG) recordings in 12 toddlers with autism (mean age 3.5 years) and 19 control subjects were used to assess interregional functional brain connectivity, with functional brain networks constructed at the level of temporal synchronization between brain regions underlying the EEG electrodes. Children with autism showed significantly increased normalized path length and reduced normalized clustering, suggesting a reduced global communication capacity already during early brain development. In addition, whole brain connectivity was found to be significantly reduced in these young patients suggesting an overall under-connectivity of functional brain networks in autism. Our findings support the hypothesis of abnormal neural communication in autism, with deviating effects already present at the early stages of brain development.
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2. Renda MM, Voigt RG, Babovic-Vuksanovic D, Highsmith WE, Vinson SS, Sadowski CM, Hagerman RJ. {{Neurodevelopmental Disabilities in Children With Intermediate and Premutation Range Fragile X Cytosine-Guanine-Guanine Expansions}}. {Journal of child neurology}. 2012 Dec 23.
To determine the range of neurodevelopmental diagnoses associated with intermediate (45-54 repeats) and premutation (55-200 repeats) range cytosine-guanine-guanine fragile X expansions, the medical records of children with intermediate or premutation range expansions were retrospectively reviewed, and all neurodevelopmental diagnoses were abstracted. Twenty-nine children (9 female, 20 male; age, 13 months to 17 years) with intermediate (n = 25) or premutation (n = 4) range expansions were identified with neurodevelopmental diagnoses, including global developmental delay/intellectual disability (n = 15), language and learning disorders (n = 9), attention-deficit hyperactivity disorder (n = 5), epilepsy (n = 5), and motor disorders (n = 12), including 2 boys younger than 4 years of age with tremor and ataxia. Thus, children with intermediate or premutation range fragile X cytosine-guanine-guanine expansions may be more susceptible than children without such expansions to other processes, both genetic and environmental, that contribute to neurodevelopmental disability.
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3. Santini E, Huynh TN, Macaskill AF, Carter AG, Pierre P, Ruggero D, Kaphzan H, Klann E. {{Exaggerated translation causes synaptic and behavioural aberrations associated with autism}}. {Nature}. 2012 Dec 23.
Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.
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4. Stamou M, Streifel KM, Goines PE, Lein PJ. {{Neuronal connectivity as a convergent target of gene-environment interactions that confer risk for Autism Spectrum Disorders}}. {Neurotoxicology and teratology}. 2012 Dec 23.
Evidence implicates environmental factors in the pathogenesis of Autism Spectrum Disorders (ASD). However, the identity of specific environmental chemicals that influence ASD risk, severity or treatment outcome remains elusive. The impact of any given environmental exposure likely varies across a population according to individual genetic substrates, and this increases the difficulty of identifying clear associations between exposure and ASD diagnoses. Heritable genetic vulnerabilities may amplify adverse effects triggered by environmental exposures if genetic and environmental factors converge to dysregulate the same signaling systems at critical times of development. Thus, one strategy for identifying environmental risk factors for ASD is to screen for environmental factors that modulate the same signaling pathways as ASD susceptibility genes. Recent advances in defining the molecular and cellular pathology of ASD point to altered patterns of neuronal connectivity in the developing brain as the neurobiological basis of these disorders. Studies of syndromic ASD and rare highly penetrant mutations or CNVs in ASD suggest that ASD risk genes converge on several major signaling pathways linked to altered neuronal connectivity in the developing brain. This review briefly summarizes the evidence implicating dysfunctional signaling via Ca(2+)-dependent mechanisms, extracellular signal-regulated kinases (ERK)/phosphatidylinositol-3-kinases (PI3K) and neuroligin-neurexin-SHANK as convergent molecular mechanisms in ASD, and then discusses examples of environmental chemicals for which there is emerging evidence of their potential to interfere with normal neuronal connectivity via perturbation of these signaling pathways.
