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| Open AccessTRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+
Mutations in the TRPV4 channel cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here the authors reveal that TRPV4 activation causes dose-dependent, CaMKII-mediated neuronal dysfunction and axonal degeneration via disruption of mitochondrial axonal transport.
- Brian M. Woolums
- , Brett A. McCray
- & Thomas E. Lloyd
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Article
| Open AccessGenome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants
Cerebral small vessel disease (CSVD) is a major cause of stroke and associated with structural changes of the brain. Here, Persyn et al. perform genome-wide association studies for magnetic resonance imaging (MRI) markers of CSVD, explore genetic correlations and prioritize candidate genes.
- Elodie Persyn
- , Ken B. Hanscombe
- & Hugh S. Markus
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Article
| Open AccessMulti-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction
Mutations in PTEN have been associated with various human disease, including autism spectrum disorder (ASD) and cancer. Here, the authors assess the function of 106 PTEN variants in yeast, invertebrate models and cell culture and report that PTEN variants generally decrease protein stability.
- Kathryn L. Post
- , Manuel Belmadani
- & Kurt Haas
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Article
| Open AccessIncreased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
Common variants identified by large-scale genomewide association studies cannot account fully account for the heritability of schizophrenia (SCZ). Here, the authors report high-coverage whole-genome sequencing of 1162 SCZ cases and 936 controls and explore the contribution of different types of variants to SCZ.
- Matthew Halvorsen
- , Ruth Huh
- & Jin P. Szatkiewicz
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Article
| Open AccessFemale copulation song is modulated by seminal fluid
Male fruitflies sing a patterned wing song during courtship. Here, the authors show that females sing a distinct song during copulation, which is controlled by sex-specific neurons, depends on seminal fluid from the male accessory gland and modulates latency of female remating with subsequent males.
- Peter Kerwin
- , Jiasheng Yuan
- & Anne C. von Philipsborn
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Article
| Open AccessMolecular and cellular determinants of motor asymmetry in zebrafish
Many animals show individual left/right biases in motor behaviour, but underlying neural substrates have proven elusive. Here the authors describe neurons that maintain individual, context-dependent lateralisation of swimming behaviour in zebrafish.
- Eric J. Horstick
- , Yared Bayleyen
- & Harold A. Burgess
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Article
| Open AccessTranscriptomic evidence that von Economo neurons are regionally specialized extratelencephalic-projecting excitatory neurons
Little is known about von Economo neurons, which have been described in a subset of mammals and appear to be selectively lost in several human neurological diseases. Here, authors reveal the gene expression profile of these cells and show that they are likely long-distance projection neurons.
- Rebecca D. Hodge
- , Jeremy A. Miller
- & Ed S. Lein
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Article
| Open AccessRegulatory sites for splicing in human basal ganglia are enriched for disease-relevant information
Regulation of gene expression and splicing are thought to be tissue-specific. Here, the authors obtain genomic and transcriptomic data from putamen and substantia nigra of 117 neurologically healthy human brains and find that splicing eQTLs are enriched for neuron-specific regulatory information.
- Sebastian Guelfi
- , Karishma D’Sa
- & Mina Ryten
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Article
| Open AccessA molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems
The human hippocampus plays a role in many different cognitive systems. Here the authors find that a single pattern of brain gene expression can predict how different parts of the hippocampus interact with the rest of the brain.
- Jacob W. Vogel
- , Renaud La Joie
- & Alan C. Evans
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Article
| Open AccessImprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development
How the imprinted Cdkn1c locus regulates corticogenesis is unclear. Here, the authors dissect the level of cell-autonomy of imprinted Cdkn1c gene function in mouse corticogenesis and identify this as regulating radial glial progenitor cell and projection neuron survival.
- Susanne Laukoter
- , Robert Beattie
- & Simon Hippenmeyer
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Article
| Open AccessGenetic mapping and evolutionary analysis of human-expanded cognitive networks
Several cortical association areas have rapidly expanded in size during human evolution, including elements of the central cognitive default mode network (DMN). Here, the authors show that genes highly divergent between humans and other primates (HAR genes) are particularly expressed in these brain regions.
- Yongbin Wei
- , Siemon C. de Lange
- & Martijn P. van den Heuvel
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Article
| Open AccessDisruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders
Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.
- Hui Guo
- , Elisa Bettella
- & Evan E. Eichler
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Article
| Open AccessInternational meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.
- Caroline M. Nievergelt
- , Adam X. Maihofer
- & Karestan C. Koenen
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Article
| Open AccessSensory cortex wiring requires preselection of short- and long-range projection neurons through an Egr-Foxg1-COUP-TFI network
Layer 4 spiny stellate cells project locally while pyramidal neurons have long-range projections yet the molecular program that determines their specificity is not yet known. Here, the authors demonstrate that Egr, Foxg1 and COUP-TFI transcription factors play causal role in the specification of these cell types.
- Pei-Shan Hou
- , Goichi Miyoshi
- & Carina Hanashima
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| 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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Article
| 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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Article
| 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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Article
| Open AccessNon-coding variability at the APOE locus contributes to the Alzheimer’s risk
Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.
- Xiaopu Zhou
- , Yu Chen
- & Nancy Y. Ip
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Article
| Open AccessActivation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors
DNA methylation plays an important role in silencing transposable elements. Here the authors find that loss of DNMT1 and DNA methylation leads to transcriptional activation and chromatin remodelling of evolutionarily young—hominoid-specific —LINE-1 elements which then act as alternative promoters for neuronal genes.
- Marie E Jönsson
- , Per Ludvik Brattås
- & Johan Jakobsson
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Article
| Open AccessPlasticity versus stability across the human cortical visual connectome
It is thought that higher cortical areas are more plastic than lower ones, but there is little direct evidence for this. Here, the authors show that plasticity (defined as lower heritability) of functional connectivity decreases from early to mid-level visual cortex, and then increases further up the visual hierarchy.
- Koen V. Haak
- & Christian F. Beckmann
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Article
| Open AccessPaternal-age-related de novo mutations and risk for five disorders
Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.
- Jacob L. Taylor
- , Jean-Christophe P. G. Debost
- & Elise B. Robinson
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Article
| Open AccessA frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy
Genetic variants in RP1 can cause hereditary retinal degeneration (HRD). Here, in a genomic screen of 331 Japanese HRD patients, the authors identify a near-polymorphic RP1 variant that causes Mendelian HRD in trans with an Alu insertion and otherwise is associated with HRD according to a complex model of inheritance.
- Konstantinos Nikopoulos
- , Katarina Cisarova
- & Carlo Rivolta
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| Open AccessIn vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function
Despite the known role of midbrain dopaminergic (mDA) signaling in the homeostatic control of mood and motor functions, little is known about how gene expression in these neurons is regulated. Here, authors develop an in vivo nuclear tagging and capture technique for low-input chromatin accessibility and transcriptome profiling of genetically-defined neuron populations to identify Gmeb1 as a novel transcriptional regulator of mDA neurons, whose loss of function impairs motor control in mice.
- Luis M. Tuesta
- , Mohamed N. Djekidel
- & Yi Zhang
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Article
| Open AccessComprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy
Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.
- Atsushi Takata
- , Mitsuko Nakashima
- & Naomichi Matsumoto
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| Open AccessHuman evolved regulatory elements modulate genes involved in cortical expansion and neurodevelopmental disease susceptibility
Different classes of human evolved regulatory elements are located in non-coding regions of the genome. The authors connect the expansion of the cortical surface and connectivity with human evolved elements and show that their target genes are involved in neurodevelopmental disease susceptibility.
- Hyejung Won
- , Jerry Huang
- & Daniel H. Geschwind
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Article
| Open AccessDifferential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis
Dopamine dysregulation is centrally linked to major psychosis. Here, the authors characterise the hypomethylation of an enhancer within the insulin-like growth factor 2 gene in neurons of patients with major psychosis and provide evidence that this enhancer targets the tyrosine hydroxylase gene, responsible for dopamine synthesis.
- Shraddha Pai
- , Peipei Li
- & Viviane Labrie
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Article
| Open AccessHomozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly
Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.
- Najim Lahrouchi
- , Aman George
- & Abdelaziz Sefiani
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Article
| Open AccessGenome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates
Sleep is essential for homeostasis and insufficient or excessive sleep are associated with adverse outcomes. Here, the authors perform GWAS for self-reported habitual sleep duration in adults, supported by accelerometer-derived measures, and identify genetic correlation with psychiatric and metabolic traits
- Hassan S. Dashti
- , Samuel E. Jones
- & Richa Saxena
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Article
| Open AccessA genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome
Carpal tunnel syndrome (CTS) is caused by entrapment of the median nerve at the wrist. Here, Wiberg et al. perform a GWAS for CTS in the UK Biobank cohort and identify 16 genetic loci, and find a causal relationship between short stature and CTS risk using Mendelian randomisation.
- Akira Wiberg
- , Michael Ng
- & Dominic Furniss
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Article
| Open AccessPrioritizing Parkinson’s disease genes using population-scale transcriptomic data
GWAS have identified over 41 susceptibility loci for Parkinson’s disease (PD). Here, the authors integrate PD GWAS summary statistics with transcriptome data from monocytes and DLFPC tissue in a TWAS approach and find 66 significant associations with PD risk highlighting lysosomal and innate immune functions.
- Yang I. Li
- , Garrett Wong
- & Towfique Raj
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Article
| Open AccessLow-frequency variation in TP53 has large effects on head circumference and intracranial volume
Size and shape of the brain are, among others, influenced by the dimensions of the skull. Here, the authors report genome-wide association studies for head circumference and intracranial volume in children and adults and the identification of nine common or low-frequency variants associated with these traits.
- Simon Haworth
- , Chin Yang Shapland
- & Beate St Pourcain
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| Open AccessGenome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Epilepsies are common brain disorders and are classified based on clinical phenotyping, imaging and genetics. Here, the authors perform genome-wide association studies for 3 broad and 7 subtypes of epilepsy and identify 16 loci - 11 novel - that are further annotated by eQTL and partitioned heritability analyses.
- Bassel Abou-Khalil
- , Pauls Auce
- & Fritz Zimprich
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Article
| Open AccessGenome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume
An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume.
- Dina Vojinovic
- , Hieab H. Adams
- & Myriam Fornage
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| Open AccessNeurogenetic profiles delineate large-scale connectivity dynamics of the human brain
Attractor dynamics have been discovered in neural circuits, but it is not clear if they exist at the level of whole-brain activity. Here, the authors show that certain brain regions act as nodes in which many activity ‘streams’ converge, regardless of brain state. These regions show distinctive gene expression.
- Ibai Diez
- & Jorge Sepulcre
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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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Article
| Open AccessIdentifying gene targets for brain-related traits using transcriptomic and methylomic data from blood
To comprehend the genetic regulatory mechanisms underlying brain-related traits in humans, Qi et al. estimate the correlation of expression and DNA methylation QTL effects in cis between blood and brain and show that using blood eQTL/mQTL data of large sample size can increase power in gene discovery for brain-related traits and diseases.
- Ting Qi
- , Yang Wu
- & Jian Yang
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Article
| Open AccessStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.
- Gail Davies
- , Max Lam
- & Ian J. Deary
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Article
| Open AccessLarge-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors
TMT is a chemical that evokes innate defensive behaviors yet the molecular mechanisms are not well understood. Here the authors perform a large-scale forward genetics screen in mice and identify Trpa1, a pungency/irritancy receptor, as a chemosensor for predator odor-evoked innate fear and defensive behaviors.
- Yibing Wang
- , Liqin Cao
- & Qinghua Liu
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Article
| Open AccessThirty loci identified for heart rate response to exercise and recovery implicate autonomic nervous system
Genome-wide association studies have identified multiple loci for resting heart rate (HR) but the genetic factors associated with HR increase during and HR recovery after exercise are less well studied. Here, the authors examine both traits in a two-stage GWAS design in up to 67,257 individuals from UK Biobank.
- Julia Ramírez
- , Stefan van Duijvenboden
- & Patricia B. Munroe
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Article
| Open AccessCross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
- Adriana I. Iglesias
- , Aniket Mishra
- & Stuart MacGregor
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Article
| Open AccessGene expression links functional networks across cortex and striatum
The functional connectivity of brain regions can be reflected in a shared molecular architecture. This cross-modal study demonstrates correspondence of spatial patterns of gene expression to limbic and somato/motor cortico-striatal networks in human and non-human primates.
- Kevin M. Anderson
- , Fenna M. Krienen
- & Avram J. Holmes
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Article
| Open AccessGenetic study links components of the autonomous nervous system to heart-rate profile during exercise
Response of the heart rate (HR) to exercise is associated with cardiac fitness and risk of cardiac death. Here, in a genome-wide association study, Verweij et al. identify 23 loci for HR increase during exercise or HR recovery, and highlight pleiotropy with blood pressure by polygenic risk score analysis.
- Niek Verweij
- , Yordi J. van de Vegte
- & Pim van der Harst
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Article
| Open AccessComprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes
More than 100 risk loci for schizophrenia have been identified by genome-wide association studies. Here, the authors apply an integrative genomic approach to prioritize risk genes and validate GLT8D1 and CSNK2B as candidate causal genes by in vitro studies in neural stem cells.
- Cui-Ping Yang
- , Xiaoyan Li
- & Xiong-Jian Luo
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Article
| Open AccessRAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response
A nucleotide repeat expansion in C9orf72 is a common genetic cause of neurodegenerative disorders. Here, the authors provide insight into the molecular mechanism by which this repeat undergoes Repeat-Associated Non-AUG (RAN) translation, implicating the integrated stress response and eIF2α phosphorylation.
- Katelyn M. Green
- , M. Rebecca Glineburg
- & Peter K. Todd
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Article
| 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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Article
| Open AccessVariation in a range of mTOR-related genes associates with intracranial volume and intellectual disability
The mTOR pathway is a key regulator of normal brain development. Here, the authors identify de novo mutations in RHEB, an mTOR activator protein, in patients with intellectual disability associated with megalencephaly and find a role for RHEB in regulating neuronal soma size and migration in vitro and in vivo.
- M. R. F. Reijnders
- , M. Kousi
- & H. G. Brunner
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Article
| Open AccessDevelopmental activities of the complement pathway in migrating neurons
Emerging evidence suggests that immune molecules play an important role in regulating brain development. Goreliket al. show that molecules in the lectin arm of the complement pathway are expressed in the developing mouse cortex, and regulate radial migration of excitatory neurons.
- Anna Gorelik
- , Tamar Sapir
- & Orly Reiner
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Article
| Open AccessHeritability of the shape of subcortical brain structures in the general population
The volume of subcortical brain structures is known to be heritable. Here, Roshchupkin and colleagues studied seven different subcortical brain structures in the general population and show that the genetic contributions go beyond these volumetric measurements, and also extend to their shapes.
- Gennady V. Roshchupkin
- , Boris A. Gutman
- & Hieab H. H. Adams