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| Open AccessAutologous cell transplantation for treatment of colorectal aganglionosis in mice
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. Here, authors perform autologous cell transplantation of enteric neural stem cells in a mouse model of colonic aganglionosis and report restoration of colonic contractile activity.
- Weikang Pan
- , Ahmed A. Rahman
- & Ryo Hotta
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Article
| Open AccessiPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity
PACS1 syndrome is a neurodevelopmental disorder resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). Here the authors use cortical organoids to investigate the impact of this variant on neurodevelopment.
- Lauren Rylaarsdam
- , Jennifer Rakotomamonjy
- & Alicia Guemez-Gamboa
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| Open AccessHigh-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
Using an unbiased phenotypic cell-based high-throughput screen, the authors identify and characterize a small molecule, BCH-HSP-C01, that restores aberrant protein trafficking in neuronal models of adapter protein complex 4 deficiency.
- Afshin Saffari
- , Barbara Brechmann
- & Mustafa Sahin
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| Open AccessNeural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy
PACS1 syndrome is caused by an Arg203Trp mutation in PACS1. Here, the authors show that PACS1R203Wdysregulates HDAC6 to disturb neuronal structure and function in a mouse model, and that silencing PACS1R203W/HDAC6 reverses these deficits.
- Sabrina Villar-Pazos
- , Laurel Thomas
- & Gary Thomas
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Article
| Open AccessKDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors
Zhang et al. report that KDM2B-∆CxxC activated Wnt signaling in the developing hippocampi, where the migration and differentiation of neural progenitors were blocked. KDM2B-∆CxxC mice exhibited defects of hippocampal morphology and related behaviors.
- Bo Zhang
- , Chen Zhao
- & Yan Zhou
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Article
| Open AccessBuffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional modulator MECP2. Here, the authors measured transcription rate and mRNA half-life changes in RTT patient-derived neurons to show transcription rate buffered by mRNA half-life changes.
- Deivid C. Rodrigues
- , Marat Mufteev
- & James Ellis
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Article
| Open AccessCBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.
- Aurélie de Thonel
- , Johanna K. Ahlskog
- & Valérie Mezger
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| Open AccessDevelopmental disruption and restoration of brain synaptome architecture in the murine Pax6 neurodevelopmental disease model
Brain-wide mapping of synapse molecular composition in Pax6 mutant mice shows remodelling and restoration of synaptome architecture during development, a possible means of conferring resilience to genetic disorders.
- Laura Tomas-Roca
- , Zhen Qiu
- & Seth G. N. Grant
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| Open AccessRescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
The molecular mechanisms underlying deficits in Down syndrome remain unclear. Here, the authors show that copy number restoration of a chromatin remodeler in trisomic mice is sufficient to rescue epigenomic, physiological and cognitive deficits.
- Sasha L. Fulton
- , Wendy Wenderski
- & Ian Maze
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| Open AccessModeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes
Our understanding of human brain development in health and disease is limited. The authors generated human brain organoids from stem cell-derived isolated single neural rosettes to study human cortico-striatal development and deficits caused by an autism-associated genetic abnormality in SHANK3.
- Yueqi Wang
- , Simone Chiola
- & Aleksandr Shcheglovitov
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Article
| Open AccessRaptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex
Karalis et al show that genetic reduction of the mTORC1 component Raptor improves multiple phenotypes in mouse models of TSC. Their findings suggest that Raptor could be a potential therapeutic target for treating the neurological aspects of TSC.
- Vasiliki Karalis
- , Franklin Caval-Holme
- & Helen S. Bateup
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Article
| Open AccessPattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2
Impaired sociability is often interpreted as social avoidance. Here, the authors show that the problem is actually failure to distinguish social from nonsocial stimuli, caused by indistinguishable coactivity patterns in the medial prefrontal cortex.
- Pan Xu
- , Yuanlei Yue
- & Hui Lu
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Article
| Open AccessAltered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders
Lysosomal storage disorders, characterized by altered metabolism of heparan sulfate, cause autistic symptoms followed by dementia in children. Here, the authors show that embryonic dopaminergic neurodevelopmental defects due to altered function of heparan sulfate cause autistic behaviours in mice.
- Maria De Risi
- , Michele Tufano
- & Elvira De Leonibus
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Article
| Open AccessLoss of function mutations in GEMIN5 cause a neurodevelopmental disorder
GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder.
- Sukhleen Kour
- , Deepa S. Rajan
- & Udai Bhan Pandey
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Article
| Open AccessAAV2/9-mediated silencing of PMP22 prevents the development of pathological features in a rat model of Charcot-Marie-Tooth disease 1 A
Charcot-Marie-Tooth disease 1 A (CMT1A) results from PMP22 gene duplication and is characterized by peripheral nerve myelination deficits. Here, the authors prevent the development of pathological features in a rat model of CMT1A through the local delivery of AAV2/9 expressing shRNAs against PMP22.
- Benoit Gautier
- , Helene Hajjar
- & Nicolas Tricaud
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Article
| Open AccessPharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation
Previous work has shown in iPSC derived neurons that synaptic impairments are associated with a 4bp DISC1 deletion. Here the authors demonstrate a role for the PDE4 signalling pathway in these synaptic impairments.
- Nam-Shik Kim
- , Zhexing Wen
- & Guo-li Ming
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Article
| Open AccessMutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia
The impact of neurodevelopmental mutations on functional brain connectivity is poorly understood. Here the authors identify thalamo-sensorimotor dysconnectivity dimensions shared across 16p11.2 and 22q11.2 copy number variants, autism and schizophrenia, but not ADHD.
- Clara A. Moreau
- , Sebastian G. W. Urchs
- & Sebastien Jacquemont
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| Open AccessTranscriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders
How neurodevelopmental disorder-associated risk genes are translated into spatially patterned brain vulnerabilities is unclear. Here, the authors show that disorder-specific patterns of neuroanatomical changes are aligned to brain expression maps of disease risk genes in healthy subjects.
- Jakob Seidlitz
- , Ajay Nadig
- & Armin Raznahan
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| Open AccessLong-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques
The consequences of postnatal Zika infection are not fully understood. Here, the authors show that postnatal Zika infection in infant rhesus macaques alters neurodevelopment resulting in social, cognitive and motor impairments, as well as structural and functional changes in the brain.
- Jessica Raper
- , Zsofia Kovacs-Balint
- & Ann Chahroudi
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Article
| Open AccessDALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification
METTL2 methyltransferase is responsible for 3-methylcytosine modification of arginine tRNAs in mammals. Here the authors show that DALR anticodon binding domain containing 3 (DALRD3) forms a complex with METTL2 to recognize specific arginine tRNAs and find DALRD3 mutations in patients with developmental delay and early-onset epileptic encephalopathy.
- Jenna M. Lentini
- , Hessa S. Alsaif
- & Dragony Fu
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| Open AccessP2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice
P2X7 receptors are purinergic receptors with pro-inflammatory functions. Here, the authors show that inhibition of leukocyte P2X7 receptors reduces dendritic spine pathology and social behavioral deficits in a mouse model of Rett syndrome.
- Juan Mauricio Garré
- , Hernandez Moura Silva
- & Guang Yang
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Article
| Open AccessInhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome
Birk-Barel intellectual disability is an imprinting syndrome due to maternally-only transmitted mutations of KCNK9/TASK3. Here authors are using a heterozygous deletion of the active maternal Kcnk9 allele to model the disease and show phenotypic rescue by HDAC inhibition.
- Alexis Cooper
- , Tamer Butto
- & Susann Schweiger
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Article
| Open AccessTsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility
Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which negatively regulate mTORC1 signalling. Here the authors selectively delete Tsc1 from dopamine neurons in mice and find impairments in striatal dopamine release that are sufficient to reduce cognitive flexibility.
- Polina Kosillo
- , Natalie M. Doig
- & Helen S. Bateup
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| Open AccessNeuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
Kleefstra syndrome is a neurodevelopmental disorder associated with hapoinsufficiency of the histone methyltransferase EHMT1. Here the authors show using induced pluripotent cells-derived neurons from patients that network dysfunction occurs and is due to dysfunction of the NMDA receptor.
- Monica Frega
- , Katrin Linda
- & Nael Nadif Kasri
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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 AccessLarge-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis
Brain morphogenesis is an important process contributing to higher-order cognition, however our knowledge about its biological basis is largely incomplete. Here, authors analyzed 118 neuroanatomical parameters in 1,566 mutant mouse lines to identify 198 genes whose disruptions yield neuroanatomical phenotypes
- Stephan C. Collins
- , Anna Mikhaleva
- & Binnaz Yalcin
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| Open AccessAltered steady state and activity-dependent de novo protein expression in fragile X syndrome
Elevated protein synthesis, and dysregulated mGluR signalling, are documented in fragile X syndrome (FXS) Here the authors use proteomic analysis in a mouse model of FXS, and following mGluR5 stimulation, to identify potential biomarkers for the disease.
- Heather Bowling
- , Aditi Bhattacharya
- & Eric Klann
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Article
| Open AccessMAP1B mutations cause intellectual disability and extensive white matter deficit
Intellectual disability (ID) is characterized by an intelligence quotient of below 70 and impaired adaptive skills. Here, analyzing whole genome sequences from 31,463 Icelanders, Walters et al. identify variants in MAP1B associated with ID and extensive brain-wide white matter deficits.
- G. Bragi Walters
- , Omar Gustafsson
- & Kari Stefansson
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| Open AccessNeonatal brain injury causes cerebellar learning deficits and Purkinje cell dysfunction
Premature infants are vulnerable to hypoxia and thus white matter injury, especially in the cerebellum, which develops during late gestation. Here, the authors test the effects of perinatal hypoxia on motor performance and rescue behavioral deficits using the GABA reuptake inhibitor Tiagabine.
- Aaron Sathyanesan
- , Srikanya Kundu
- & Vittorio Gallo
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| Open AccessIdentification of genes associated with cortical malformation using a transposon-mediated somatic mutagenesis screen in mice
Cortical malformations have a variety of causes. Here the authors use transposon mutagenesis to insert mutations into neural stem cells in the developing mouse cortex to screen for new candidate genes for cortical malformation, and validate some targets in human brain tissue.
- I-Ling Lu
- , Chien Chen
- & Jin-Wu Tsai
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| Open AccessUncovering inherent cellular plasticity of multiciliated ependyma leading to ventricular wall transformation and hydrocephalus
Multiciliated ependymal cells (ECs) in the mammalian brain are glial cells facilitating cerebral spinal fluid movement. This study describes an inherent cellular plasticity of ECs as maintained by Foxj1 and IKK2 signaling, and shows resulting hydrocephalus when EC de-differentiation is triggered.
- Khadar Abdi
- , Chun-Hsiang Lai
- & Chay T. Kuo
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| Open AccessAutism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice
Lrfn2/SALM1 is a synaptic adhesion molecule, and is known to interact with PSD-95. Here the authors show that Lrfn2 regulates excitatory synapse maturation and maintenance, and that Lrfn2 knockout mice exhibit autism-like behaviours as well as enhanced learning and memory.
- Naoko Morimura
- , Hiroki Yasuda
- & Jun Aruga
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| Open AccessDisrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells
Angelman syndrome (AS) is characterized by developmental delay and intellectual disability, but the underlying pathophysiology is not well understood. Here the authors use induced pluripotent stem cell-derived neurons from AS patients and find impaired maturation of resting membrane potential and action potential firing, and defects in synaptic activity associated with the disease.
- James J. Fink
- , Tiwanna M. Robinson
- & Eric S. Levine
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| Open AccessBrain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
Glut1-deficiency syndrome is a severe neurodevelopmental disorder characterized by low brain glucose and epileptic seizures. Tanget al. show that in model mice, low Glut1 leads to defects of the brain vasculature, and that AAV9-based gene therapy at pre- or early-symptomatic stages prevents the defects and mitigates disease.
- Maoxue Tang
- , Guangping Gao
- & Umrao R. Monani
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| Open AccessDecrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function
Glutamatergic signalling regulation by Syngap1 has been linked to intellectual disabilities. Here, the authors find Syngap1 also regulates cortical GABAergic synaptic signalling development and that this reduced inhibitory signalling contributes to cognitive deficits in a mouse model.
- Martin H. Berryer
- , Bidisha Chattopadhyaya
- & Graziella Di Cristo
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| Open AccessDisrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome
Cerebro–costo–mandibular syndrome, CCMS, is a severe human multiple malformation disorder. Here, the authors report that mutations in SNRPBdisrupt the normal regulation of alternative splicing at this gene, and in so doing, may be responsible for the development of CCMS.
- Danielle C. Lynch
- , Timothée Revil
- & Francois P. Bernier