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| Open AccessLongitudinal EEG power in the first postnatal year differentiates autism outcomes
Brain oscillations may be disrupted in children with autism spectrum disorder. The authors performed a longitudinal study of electroencephalography recordings and found that EEG recordings from the first year after birth can distinguish healthy children from children with autism spectrum disorder.
- Laurel J. Gabard-Durnam
- , Carol Wilkinson
- & Charles A. Nelson
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Article
| Open AccessHaploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome
Understanding of the genetic factors and molecular mechanisms underlying neurodevelopmental disorders remains incomplete. In this study, authors show that microdeletions in the gene ANKS1B lead to loss of the neuronal synapse-enriched protein AIDA-1 and to a novel neurodevelopmental syndrome
- Abigail U. Carbonell
- , Chang Hoon Cho
- & Bryen A. Jordan
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| Open AccessThe autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour
In humans, copy-number variants of the CYFIP1 gene have been associated with autism spectrum disorders and schizophrenia. Here, the authors characterize Cyfip1-heterozygous mice, revealing that they display deficits in brain white matter structure and functional connectivity along with abnormal behaviours.
- Nuria Domínguez-Iturza
- , Adrian C. Lo
- & Claudia Bagni
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| Open AccessCyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility
People with a genetic deletion of the 15q11.2 locus are at increased risk for psychiatric disorders and white matter disturbances, but the gene(s) responsible are unclear. Here, the authors show that low dosage of CYFIP1, present in the human 15q11.2 region, alters white matter structure and cognition in rats.
- Ana I. Silva
- , Josephine E. Haddon
- & Lawrence S. Wilkinson
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| Open AccessA genome-wide scan statistic framework for whole-genome sequence data analysis
Whole-genome sequencing data reveals a large number of variants for testing their associations with phenotypic traits and diseases. Here, the authors develop WGScan, a statistical method for detecting the existence and estimating the locations of the association signal at genome-wide scale.
- Zihuai He
- , Bin Xu
- & Iuliana Ionita-Laza
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| Open AccessAbnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice
GPRASP2 plays a role in trafficking of GPCRs and mutations in this gene have been linked to neurodevelopmental disorders. Here the authors study the role of Gprasp2 in the CNS and show that it regulates the surface availability of mGluR5 receptors and that knockout mice for this protein show autistic-like behavioural abnormalities.
- Mohamed Edfawy
- , Joana R. Guedes
- & João Peça
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| Open AccessAtypical functional connectome hierarchy in autism
Autism spectrum disorder (ASD) is associated with symptoms ranging from sensory hypersensitivity to social difficulties. Here, the authors provide evidence of atypical connectivity transitions between sensory and higher-order cortical areas in people with ASD, which could underlie the diverse symptoms.
- Seok-Jun Hong
- , Reinder Vos de Wael
- & Boris C. Bernhardt
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| Open AccessHaploinsufficiency of autism spectrum disorder candidate gene NUAK1 impairs cortical development and behavior in mice
Nuak1 is an autism spectrum disorder candidate gene. Here the authors report behavioral and cortical development in mice heterozygous for Nuak1, suggesting loss of function mutations in one copy of Nuak1 may contribute to neurodevelopmental disorders.
- Virginie Courchet
- , Amanda J. Roberts
- & Julien Courchet
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| Open AccessRole of VTA dopamine neurons and neuroligin 3 in sociability traits related to nonfamiliar conspecific interaction
Individuals with autism spectrum disorder have alteration in social and novelty behaviors. Here, Bellone and colleagues show that chemogenetic inhibition of mouse dopamine neurons in the ventral tegmental area can blunt exploration towards unfamiliar conspecifics, and that these behavioral deficits are recapitulated in mice lacking neuroligin3 gene product.
- Sebastiano Bariselli
- , Hanna Hörnberg
- & Camilla Bellone
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| Open AccessPervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster
The 16p11.2 deletion leads to a range of neurodevelopmental phenotypes, but to date, sequencing studies have not been able to pinpoint individual genes that are causative for the disease on their own. Here, using Drosophila homologs of 14 16p11.2 genes, the authors take a combinatorial approach to show that gene interactions contribute to a neurological phenotype.
- Janani Iyer
- , Mayanglambam Dhruba Singh
- & Santhosh Girirajan
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Article
| Open AccessReducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome
Loss of fragile X mental retardation protein (FMRP) leads to fragile X syndrome, associated with cognitive dysfunction. Here the authors show that mice lacking FMRP show reduced hippocampal neurogenesis and cognitive deficits, which can be rescued by reducing histone acetylation.
- Yue Li
- , Michael E. Stockton
- & Xinyu Zhao
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| Open AccessEnhanced pupillary light reflex in infancy is associated with autism diagnosis in toddlerhood
Previous studies showed that children with autism spectrum disorder (ASD) have atypicalities in the pupillary light reflex (PLR). This study uses longitudinal monitoring of infants at risk for ASD to show that PLR magnitude at 10 months of age is associated with later ASD diagnosis and symptom severity.
- Pär Nyström
- , Teodora Gliga
- & Terje Falck-Ytter
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| Open AccessA mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry
The Na+/H+ exchanger NHE9 is proposed to regulate the H+ electrochemical gradient across endosomal membranes. Here, the authors find that NHE9 knockout mice show autism spectrum disorder-like behaviors and disrupted synaptic vesicle exocytosis due to impaired presynaptic calcium entry.
- Julie C. Ullman
- , Jing Yang
- & Robert H. Edwards
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| Open AccessNitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
Human MEF2C haploinsufficiency results in Autism Spectrum Disorder (ASD), but it is unclear if the same is true in mice. Here, the authors show that Mef2c +/− mice have behavioral defects and neuronal abnormalities similar to ASD, and symptoms can be ameliorated with the new drug, NitroSynapsin.
- Shichun Tu
- , Mohd Waseem Akhtar
- & Nobuki Nakanishi
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| Open AccessAltered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice
Dysfunction of mGluR5 has been implicated in Fragile X syndrome. Here, using a single-molecule tracking technique, the authors found an increased lateral mobility of mGluR5 at the synaptic site in Fmr1 KO hippocampal neurons, leading to abnormal NMDAR-mediated synaptic plasticity and cognitive deficits.
- Elisabetta Aloisi
- , Katy Le Corf
- & Andreas Frick
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| Open AccessCross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder
“There have been a number of recent epigenetic studies on autism spectrum disorder. Here, the authors integrate genetic and epigenetic data from cord and peripheral blood and also from brain tissues to show the potential of blood-based epigenetic data to provide insights into psychiatric disorders.”
- Shan V. Andrews
- , Shannon E. Ellis
- & M. Daniele Fallin
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| Open AccessAn autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio
Trio is a RhoGEF protein that promotes actin polymerization and is implicated in the regulation of glutamatergic synapses in autism spectrum disorder (ASD). Here the authors identify a large cluster of de novo mutations in the GEF1 domain of Trio in whole-exome sequencing data from individuals with ASD, and confirm that some of these mutations lead to glutamatergic dysregulation in vitro.
- Anastasiia Sadybekov
- , Chen Tian
- & Bruce E. Herring
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| Open AccessReproductive fitness and genetic risk of psychiatric disorders in the general population
Why genetic variants that confer risk for psychiatric disorders persist in the genome is an evolutionary conundrum. Here, Mullinset al. report association of polygenic risk for autism with having fewer children and polygenic risk for ADHD with higher reproductive fitness.
- Niamh Mullins
- , Andrés Ingason
- & Kari Stefansson
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| Open AccessEnhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model
Fragile X syndrome (FXS) is a leading cause of autism and neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, the authors show that neurons from Fmr1 knockout mice have increased levels of ADCY1 protein, producing abnormal ERK1/2 signalling, dysregulated protein synthesis and behavioural symptoms associated with FXS.
- Ferzin Sethna
- , Wei Feng
- & Hongbing Wang
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| Open AccessMECP2 regulates cortical plasticity underlying a learned behaviour in adult female mice
Rett syndrome is associated with impaired synaptic connectivity beginning in early development. Here the authors show in female mice heterozygous forMecp2, a model of Rett syndrome, that during adulthood, auditory cortex plasticity associated with a learned maternal behaviour is also impaired.
- Keerthi Krishnan
- , Billy Y. B. Lau
- & Stephen D. Shea
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| Open AccessHyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome
Dysregulation of mTOR signaling has been implicated in autism spectrum disorders. Here authors show that hyperconnectivity and hyperactivity of the mPFC–BLA circuitry inPten+/−mice underlies their social impairments, and that reducing mTORC1 signaling during early postnatal development rescues these deficits.
- Wen-Chin Huang
- , Youjun Chen
- & Damon T. Page
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Article
| Open AccessDe novo genic mutations among a Chinese autism spectrum disorder cohort
Recurrent sporadic mutations are important risk factors for autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, Eichler, Xia and colleagues analyse risk genes in a large Chinese ASD cohort and find novel recurrences of potential pathogenic significance.
- Tianyun Wang
- , Hui Guo
- & Evan E. Eichler
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| Open AccessDysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice
Mutations in SHANK2 are associated with autism spectrum disorders (ASD). Here, Peter et al. show that selective loss of Shank2in Purkinje cells of the mouse cerebellum leads to deficits in plasticity, motor behaviour, and a social behaviour phenotype similar to that seen in ASD.
- Saša Peter
- , Michiel M. ten Brinke
- & Chris I. De Zeeuw
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| Open AccessAltered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism
SHANK3 mutations have been linked to autism spectrum disorders, although the underlying mechanisms remain unclear. Here, the authors generate a complete knockout Shank3 mouse model, identifying ASD-like behaviours associated with impaired mGluR5-Homer scaffolding and abnormal brain connectivity.
- Xiaoming Wang
- , Alexandra L. Bey
- & Yong-hui Jiang
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| Open AccessA small number of abnormal brain connections predicts adult autism spectrum disorder
Autism spectrum disorder (ASD) is manifested by subtle but significant changes in the brain. Here, Yahata and colleagues devise a novel machine learning algorithm and develop a reliable ASD classifier based on brain functional connectivity, with which they quantitatively measure neuroimaging dimensions between ASD and other mental disorders.
- Noriaki Yahata
- , Jun Morimoto
- & Mitsuo Kawato
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| Open AccessIdentification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration
This study presents gene expression responses of cultured brain cells to hundreds of chemicals found in the environment and in food. The authors identified chemicals that induce transcriptomic profiles that overlap those seen in human brains affected with autism, aging, and neurodegeneration.
- Brandon L. Pearson
- , Jeremy M. Simon
- & Mark J. Zylka
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| Open AccessPX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking
The molecular underpinning of autism is unclear. Here the authors show PX-RICS deficient mice exhibit autism-like social behavioural abnormalities and impaired GABAA receptor trafficking, and enhancing inhibitory synaptic transmission with a GABAAreceptor agonist ameliorate the behavioural deficits.
- Tsutomu Nakamura
- , Fumiko Arima-Yoshida
- & Tetsu Akiyama
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| Open AccessGene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders
Autism spectrum disorder is approximately 4.5 times more likely to occur in boys than girls. Here, Werling, Geschwind and Parikshak characterized sexually dimorphic gene expression in the non-diseased, post-mortem, adult and prenatal human brain, and show genes expressed at higher levels in males are significantly enriched for genes upregulated in autistic brain.
- Donna M. Werling
- , Neelroop N. Parikshak
- & Daniel H. Geschwind
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| Open AccessTrans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation
Zinc is a nutritional factor implicated in autism spectrum disorders (ASDs), but evidence for a strong association and linking mechanism is largely lacking. Here, the authors report that trans-synaptic zinc mobilization rapidly rescues social interaction in two independent mouse models of ASD.
- Eun-Jae Lee
- , Hyejin Lee
- & Eunjoon Kim
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| Open AccessThe autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment
Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.
- Justin Cotney
- , Rebecca A. Muhle
- & James P. Noonan
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| Open AccessTranscriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism
Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. In this study, the authors use RNA sequencing analyses to characterize differences in the transcriptome between autistic and typically developing brains.
- Simone Gupta
- , Shannon E. Ellis
- & Dan E. Arking
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Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism
Impairments of cerebellar-dependent motor control and learning are implicated in some forms of autism spectrum disorder (ASD). In this study, the authors provide a characterization of the motor deficits and cerebellar function abnormalities in a transgenic mouse model of ASD.
- Claire Piochon
- , Alexander D. Kloth
- & Christian Hansel
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Recurrent de novo mutations implicate novel genes underlying simplex autism risk
Autism spectrum disorder (ASD) is a common disorder with a strong and complex genetic component. Here, the authors resequence 64 candidate neurodevelopmental disorder risk genes in almost 6,000 samples and identify novel genes associated with ASD.
- B. J. O'Roak
- , H. A. Stessman
- & E. E. Eichler
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De novo TBR1 mutations in sporadic autism disrupt protein functions
Autism spectrum disorders (ASD) are characterized by social impairments, communication deficits and repetitive stereotyped behaviours. Here, the authors show that de novo missense mutations, but not inherited missense mutations, in TBR1disrupt the protein function and contribute to ASD aetiology.
- Pelagia Deriziotis
- , Brian J. O’Roak
- & Simon E. Fisher
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Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology
The Wdfy3gene has been associated with autism spectrum disorders in children. Here, the authors examine two separate mutant alleles of this gene in mice and identify its role in cortical neurogenesis, reproducing pathological changes characteristic of the disorder.
- Lori A. Orosco
- , Adam P. Ross
- & Konstantinos S Zarbalis
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Enhanced synapse remodelling as a common phenotype in mouse models of autism
Impaired neuronal connectivity is implicated in autism spectrum disorder (ASD). In this study, the authors perform time-lapse imaging of brain neurons from different mouse models of ASD and provide evidence for enhanced turnover of excitatory synapses as a commonly occurring mechanism in ASD.
- Masaaki Isshiki
- , Shinji Tanaka
- & Shigeo Okabe
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| Open AccessThe impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
The autism spectrum disorders are complex genetic traits characterized by various neurodevelopmental deficits. Here, the authors analyse defective gene family interaction networks in autism cases and healthy controls and identify potential gene family interactions that may contribute to autism aetiology.
- Dexter Hadley
- , Zhi-liang Wu
- & Hakon Hakonarson
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| Open AccessProtein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism
Autism spectrum disorder (ASD) is a complex genetic trait that encompasses a range of neurodevelopmental disorders. Here, the authors clone brain-expressed alternatively-spliced isoforms of ASD risk factors and construct a network of protein interactions that provides further insight into the disease aetiology.
- Roser Corominas
- , Xinping Yang
- & Lilia M. Iakoucheva
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| Open AccessRapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex
Tuberous sclerosis complex is an autosomal dominant cognitive disorder caused by mutations affecting TSCgenes. Sato and colleagues examine tuberous sclerosis complex mutant mice and find that the behavioural and anatomical abnormalities can be reversed by inhibiting rapamycin-sensitive signalling pathways, even in adulthood.
- Atsushi Sato
- , Shinya Kasai
- & Masashi Mizuguchi