No abstract

Disorders in verbal and emotional communication and imitation, social reciprocity and higher order cognition observed in individuals with autism spectrum disorders (ASD) are presented here as phenotypic expressions of temporo-spatial processing disorders (TSPDs). TSPDs include various degrees of disability in (i) processing multi-sensory dynamic stimuli online, (ii) associating them into meaningful and coherent patterns and (iii) producing real-time sensory-motor adjustments and motor outputs. In line with this theory, we found that slowing down the speed of facial and vocal events enhanced imitative, verbal and cognitive abilities in some ASD children, particularly those with low functioning autism. We then argue that TSPDs may result from Multi-system Brain Disconnectivity-Dissynchrony (MBD), defined as an increase or decrease in functional connectivity and neuronal synchronization within/between multiple neurofunctional territories and pathways. Recent functional magnetic resonance imaging (fMRI) and electrophysiological studies supporting MBD are outlined. Finally, we review the suspected underlying neurobiological mechanisms of MBD as evidenced in neuroimaging, genetic, environmental and epigenetic studies. Overall, our TSPD/MBD approach to ASD may open new promising avenues for a better understanding of neuro-physio-psychopathology of ASD and clinical rehabilitation of people affected by these syndromes.

Several recent studies suggest that autism may result from abnormal communication between brain regions. We directly assessed this hypothesis by testing the presence of abnormalities in a model of the functional cerebral network engaged during explicit emotion processing in adults with high functioning autism or Asperger syndrome. Comparison of structural equation models revealed abnormal patterns of effective connectivity, with the prefrontal cortex as a key site of dysfunction. These findings provide evidence that abnormal long-range connectivity between structures of the 'social brain' could explain the socio-emotional troubles that characterize the autistic pathology.

BackgroundAutism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples.MethodsmiRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions.ResultsWe identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients’ cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities.ConclusionsWhile independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0064-6) contains supplementary material, which is available to authorized users.