1. Barth L, Sutterlin R, Nenniger M, Vogt KE. {{Reduced synaptic activity in neuronal networks derived from embryonic stem cells of murine Rett syndrome model}}. {Front Cell Neurosci};2014;8:79.
Neurodevelopmental diseases such as the Rett syndrome (RTT) have received renewed attention, since the mechanisms involved may underlie a broad range of neuropsychiatric disorders such as schizophrenia and autism. In vertebrates early stages in the functional development of neurons and neuronal networks are difficult to study. Embryonic stem cell-derived neurons provide an easily accessible tool to investigate neuronal differentiation and early network formation. We used in vitro cultures of neurons derived from murine embryonic stem cells missing the methyl-CpG-binding protein 2 (MECP2) gene (MeCP2-/y) and from wild type cells of the corresponding background. Cultures were assessed using whole-cell patch-clamp electrophysiology and immunofluorescence. We studied the functional maturation of developing neurons and the activity of the synaptic connections they formed. Neurons exhibited minor differences in the developmental patterns for their intrinsic parameters, such as resting membrane potential and excitability; with the MeCP2-/y cells showing a slightly accelerated development, with shorter action potential half-widths at early stages. There was no difference in the early phase of synapse development, but as the cultures matured, significant deficits became apparent, particularly for inhibitory synaptic activity. MeCP2-/y embryonic stem cell-derived neuronal cultures show clear developmental deficits that match phenotypes observed in slice preparations and thus provide a compelling tool to further investigate the mechanisms behind RTT pathophysiology.
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2. Corominas R, Yang X, Lin GN, Kang S, Shen Y, Ghamsari L, Broly M, Rodriguez M, Tam S, Trigg SA, Fan C, Yi S, Tasan M, Lemmens I, Kuang X, Zhao N, Malhotra D, Michaelson JJ, Vacic V, Calderwood MA, Roth FP, Tavernier J, Horvath S, Salehi-Ashtiani K, Korkin D, Sebat J, Hill DE, Hao T, Vidal M, Iakoucheva LM. {{Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism}}. {Nat Commun};2014;5:3650.
Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases.
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3. Correia CT, Conceicao IC, Oliveira B, Coelho J, Sousa I, Sequeira AF, Almeida J, Cafe C, Duque F, Mouga S, Roberts W, Gao K, Lowe JK, Thiruvahindrapuram B, Walker S, Marshall CR, Pinto D, Nurnberger JI, Scherer SW, Geschwind DH, Oliveira G, Vicente AM. {{Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders}}. {Mol Autism};2014 (Apr 10);5(1):28.
BACKGROUND: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. METHODS: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. RESULTS: The ANXA1 duplication, overlapping the last four exons and 3’UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3’UTR identified 11 novel changes, but no obvious variants with clinical significance. CONCLUSIONS: We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.
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4. Meyer BJ, Gardiner JM, Bowler DM. {{Directed Forgetting in High-Functioning Adults with Autism Spectrum Disorders}}. {J Autism Dev Disord};2014 (Apr 11)
Rehearsal strategies of adults with autism spectrum disorders (ASDs) and demographically matched typically developed (TD) adults were strategically manipulated by cueing participants to either learn, or forget each list word prior to a recognition task. Participants were also asked to distinguish between autonoetic and noetic states of awareness using the Remember/Know paradigm. The ASD group recognised a similar number of to-be-forgotten words as the TD group, but significantly fewer to-be-learned words. This deficit was only evident in Remember responses that reflect autonoetic awareness, or episodic memory, and not Know responses. These findings support the elaborative encoding deficit hypothesis and provide a link between the previously established mild episodic memory impairments in adults with high functioning autism and the encoding strategies employed.
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5. Pankert A, Pankert K, Herpertz-Dahlmann B, Konrad K, Kohls G. {{Responsivity to familiar versus unfamiliar social reward in children with autism}}. {J Neural Transm};2014 (Apr 12)
In autism spectrum disorders (ASD), social motivation theories suggest that the core social communication problems seen in children with ASD arise from diminished responsiveness to social reward. Although clinical and experimental data support these theories, the extent to which the reward deficit in ASD is unique for social rewards remains unclear. With the present investigation, we aimed to provide insight into the degree to which sociality as well as familiarity of reward incentives impact motivated goal-directed behavior in children with ASD. To do so, we directly compared the influence of familiar versus unfamiliar social reward relative to nonsocial, monetary reward in children with ASD relative to age- and IQ-matched typically developing controls (TDC) using a visual and auditory incentive go/nogo task with reward contingencies for successful response inhibitions. We found that children with ASD responded stronger to visual familiar and unfamiliar social reward as well as to nonsocial, monetary reward than TDC. While the present data are at odds with predictions made by social motivation theories, individual variations beyond clinical diagnosis, such as reward exposure across various social settings, help explain the pattern of results. The findings of this study stress the necessity for additional research on intra-individual as well as environmental factors that contribute to social reward responsiveness in individuals with ASD versus other neuropsychiatric disorders such as ADHD or conduct disorder.
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6. Prontera P, Serino D, Caldini B, Scarponi L, Merla G, Testa G, Muti M, Napolioni V, Mazzotta G, Piccirilli M, Donti E. {{Brief Report: Functional MRI of a Patient with 7q11.23 Duplication Syndrome and Autism Spectrum Disorder}}. {J Autism Dev Disord};2014 (Apr 11)
The duplication of the Williams-Beuren syndrome (WBS) region (7q11.23) is a copy number variant associated with autism spectrum disorder (ASD). One of the most intriguing aspects is that the reciprocal microdeletion causes WBS, characterized by hypersociability, marked empathy, and a relative capacity in verbal short-term memory and language. Herein, we studied, by using functional morphological and volumetric magnetic resonance, a 17-year-old male patient who displays a de novo 7q11.23 duplication and ASD. The limbic system of the patient appeared hypo-functional, while the total brain volume was increased, thus contrasting, in an opposite and intriguing manner, with the global brain volume reduction reported in WBS. Even if these findings come from the analysis of a single patient and, therefore, have to be considered preliminary results, they encourage carrying on further functional and volumetric studies in patients with 7q11.23 duplication, to fully elucidate the role of this gene-dosage alteration on brain development and limbic system function.
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7. Schaaf RC, Leiby B, Benevides T, Hunt J, van Hooydonk E, Faller P, Mailloux Z. {{Response from Authors to Comments on « An Intervention for Sensory Difficulties in Children with Autism: A Randomized Trial »}}. {J Autism Dev Disord};2014 (Apr 11)
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8. Wang H. {{Lipid rafts: a signaling platform linking cholesterol metabolism to synaptic deficits in autism spectrum disorders}}. {Front Behav Neurosci};2014;8:104.
