Le numéro de mai 2018 de la revue Developmental Neurobiology est consacré à l’autisme :

Developmental Neuroscience of Autism Spectrum Disorders

1. Muotri AR. Autism spectrum disorders : Challenges and perspectives. Dev Neurobiol ;2018 (May) ;78(5):431-433.

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2. Suarez NA, Macia A, Muotri AR. LINE-1 retrotransposons in healthy and diseased human brain. Dev Neurobiol ;2018 (May) ;78(5):434-455.

Long interspersed element-1 (LINE-1 or L1) is a transposable element with the ability to self-mobilize throughout the human genome. The L1 elements found in the human brain is hypothesized to date back 56 million years ago and has survived evolution, currently accounting for 17% of the human genome. L1 retrotransposition has been theorized to contribute to somatic mosaicism. This review focuses on the presence of L1 in the healthy and diseased human brain, such as in autism spectrum disorders. Throughout this exploration, we will discuss the impact L1 has on neurological disorders that can occur throughout the human lifetime. With this, we hope to better understand the complex role of L1 in the human brain development and its implications to human cognition. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78 : 434-455, 2018.

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3. Mash LE, Reiter MA, Linke AC, Townsend J, Muller RA. Multimodal approaches to functional connectivity in autism spectrum disorders : An integrative perspective. Dev Neurobiol ;2018 (May) ;78(5):456-473.

Atypical functional connectivity has been implicated in autism spectrum disorders (ASDs). However, the literature to date has been largely inconsistent, with mixed and conflicting reports of hypo- and hyper-connectivity. These discrepancies are partly due to differences between various neuroimaging modalities. Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG) measure distinct indices of functional connectivity (e.g., blood-oxygenation level-dependent [BOLD] signal vs. electrical activity). Furthermore, each method has unique benefits and disadvantages with respect to spatial and temporal resolution, vulnerability to specific artifacts, and practical implementation. Thus far, functional connectivity research on ASDs has remained almost exclusively unimodal ; therefore, interpreting findings across modalities remains a challenge. Multimodal integration of fMRI, EEG, and MEG data is critical in resolving discrepancies in the literature, and working toward a unifying framework for interpreting past and future findings. This review aims to provide a theoretical foundation for future multimodal research on ASDs. First, we will discuss the merits and shortcomings of several popular theories in ASD functional connectivity research, using examples from the literature to date. Next, the neurophysiological relationships between imaging modalities, including their relationship with invasive neural recordings, will be reviewed. Finally, methodological approaches to multimodal data integration will be presented, and their future application to ASDs will be discussed. Analyses relating transient patterns of neural activity (« states ») are particularly promising. This strategy provides a comparable measure across modalities, captures complex spatiotemporal patterns, and is a natural extension of recent dynamic fMRI research in ASDs. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78 : 456-473, 2018.

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4. Needham BD, Tang W, Wu WL. Searching for the gut microbial contributing factors to social behavior in rodent models of autism spectrum disorder. Dev Neurobiol ;2018 (May) ;78(5):474-499.

Social impairment is one of the major symptoms in multiple psychiatric disorders, including autism spectrum disorder (ASD). Accumulated studies indicate a crucial role for the gut microbiota in social development, but these mechanisms remain unclear. This review focuses on two strategies adopted to elucidate the complicated relationship between gut bacteria and host social behavior. In a top-down approach, researchers have attempted to correlate behavioral abnormalities with altered gut microbial profiles in rodent models of ASD, including BTBR mice, maternal immune activation (MIA), maternal valproic acid (VPA) and maternal high-fat diet (MHFD) offspring. In a bottom-up approach, researchers use germ-free (GF) animals, antibiotics, probiotics or pathogens to manipulate the intestinal environment and ascertain effects on social behavior. The combination of both approaches will hopefully pinpoint specific bacterial communities that control host social behavior. Further discussion of how brain development and circuitry is impacted by depletion of gut microbiota is also included. The converging evidence strongly suggests that gut microbes affect host social behavior through the alteration of brain neural circuits. Investigation of intestinal microbiota and host social behavior will unveil any bidirectional communication between the gut and brain and provide alternative therapeutic targets for ASD. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78 : 474-499, 2018.

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5. Fernandes IR, Cruz ACP, Ferrasa A, Phan D, Herai RH, Muotri AR. Genetic variations on SETD5 underlying autistic conditions. Dev Neurobiol ;2018 (May) ;78(5):500-518.

The prevalence of autism spectrum disorders (ASD) and the number of identified ASD-related genes have increased in recent years. The SETD5 gene encodes a SET-containing-domain 5 protein, a likely reader enzyme. Genetic evidences suggest that SETD5 malfunction contributes to ASD phenotype, such as on intellectual disability (ID) and facial dysmorphism. In this review, we mapped the clinical phenotypes of individuals carrying mutations on the SETD5 gene that are associated with ASD and other chromatinopathies (mutation in epigenetic modifiers that leads to the development of neurodevelopmental disorders such as ASD). After a detailed systematic literature review and analysis of public disease-related databank, we found so far 42 individuals carrying mutations on the SETD5 gene, with 23.8% presenting autistic-like features. Furthermore, most of mutations occurred between positions 9,480,000-9,500,000 bp on chromosome 3 (3p25.3) at the SETD5 gene locus. In all males, mutations in SETD5 presented high penetrance, while in females the clinical phenotype seems more variable with two reported cases showing normal female carriers and not presenting ASD or any ID-like symptoms. At the molecular level, SETD5 interacts with proteins of PAF1C and N-CoR complexes, leading to a possible involvement with chromatin modification pathway, which plays important roles for brain development. Together, we propose that mutations on the SETD5 gene could lead to a new syndromic condition in males, which is linked to 3p25 syndrome, and can leads to ASD-related intellectual disability and facial dysmorphism. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78 : 500-518, 2018.

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6. Deshpande A, Weiss LA. Recurrent reciprocal copy number variants : Roles and rules in neurodevelopmental disorders. Dev Neurobiol ;2018 (May) ;78(5):519-530.

Deletions and duplications, called reciprocal CNVs when they occur at the same locus, are implicated in neurodevelopmental phenotypes ranging from morphological to behavioral. In this article, we propose three models of how differences in gene expression in deletion and duplication genotypes may result in deleterious phenotypes. To explore these models, we use examples of the similarities and differences in clinical phenotypes of five reciprocal CNVs known to cause neurodevelopmental disorders : 1q21.1, 7q11.23, 15q13.3, 16p11.2, and 22q11.2. These models and examples may inform some insights into better understanding of gene-phenotype relationships. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78 : 519-530, 2018.

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7. Hanson KL, Lew CH, Hrvoj-Mihic B, Groeniger KM, Halgren E, Bellugi U, Semendeferi K. Increased glia density in the caudate nucleus in williams syndrome : Implications for frontostriatal dysfunction in autism. Dev Neurobiol ;2018 (May) ;78(5):531-545.

Williams syndrome (WS) is a rare neurodevelopmental disorder with a well-described, known genetic etiology. In contrast to Autism Spectrum Disorders (ASD), WS has a unique phenotype characterized by global reductions in IQ and visuospatial ability, with relatively preserved language function, enhanced reactivity to social stimuli and music, and an unusual eagerness to interact socially with strangers. A duplication of the deleted region in WS has been implicated in a subset of ASD cases, defining a spectrum of genetic and behavioral variation at this locus defined by these opposite extremes in social behavior. The hypersociability characteristic of WS may be linked to abnormalities of frontostriatal circuitry that manifest as deficits in inhibitory control of behavior. Here, we examined the density of neurons and glia in associative and limbic territories of the striatum including the caudate, putamen, and nucleus accumbens regions in Nissl stained sections in five pairs of age, sex, and hemisphere-matched WS and typically-developing control (TD) subjects. In contrast to what is reported in ASD, no significant increase in overall neuron density was observed in this study. However, we found a significant increase in the density of glia in the dorsal caudate nucleus, and in the ratio of glia to neurons in the dorsal and medial caudate nucleus in WS, accompanied by a significant increase in density of oligodendrocytes in the medial caudate nucleus. These cellular abnormalities may underlie reduced frontostriatal activity observed in WS, with implications for understanding altered connectivity and function in ASD. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78 : 531-545, 2018.

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8. Chukoskie L, Westerfield M, Townsend J. A novel approach to training attention and gaze in ASD : A feasibility and efficacy pilot study. Dev Neurobiol ;2018 (May) ;78(5):546-554.

In addition to the social, communicative and behavioral symptoms that define the disorder, individuals with ASD have difficulty re-orienting attention quickly and accurately. Similarly, fast re-orienting saccadic eye movements are also inaccurate and more variable in both endpoint and timing. Atypical gaze and attention are among the earliest symptoms observed in ASD. Disruption of these foundation skills critically affects the development of higher level cognitive and social behavior. We propose that interventions aimed at these early deficits that support social and cognitive skills will be broadly effective. We conducted a pilot clinical trial designed to demonstrate the feasibility and preliminary efficacy of using gaze-contingent video games for low-cost in-home training of attention and eye movement. Eight adolescents with ASD participated in an 8-week training, with pre-, mid- and post-testing of eye movement and attention control. Six of the eight adolescents completed the 8 weeks of training and all six showed improvement in attention (orienting, disengagement) and eye movement control or both. All game systems remained intact for the duration of training and all participants could use the system independently. We delivered a robust, low-cost, gaze-contingent game system for home use that, in our pilot training sample, improved the attention orienting and eye movement performance of adolescent participants in 8 weeks of training. We are currently conducting a clinical trial to replicate these results and to examine what, if any, aspects of training transfer to more real-world tasks. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78 : 546-554, 2018.

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