Genetic aspects of autism spectrum disorders: insights from animal models

Autism spectrum disorders (ASDs) are a complex neurodevelopmental disorder that display a triad of core behavioral deficits including restricted interests, often accompanied by repetitive behavior, deficits in language and communication, and an inability to engage in reciprocal social interactions. ASD is among the most heritable disorders but is not a simple disorder with a singular pathology and has a rather complex etiology. It is interesting to note that perturbations in synaptic growth, development, and stability underlie a variety of neuropsychiatric disorders, including ASD, schizophrenia, epilepsy, and intellectual disability. Biological characterization of an increasing repertoire of synaptic mutants in various model organisms indicates synaptic dysfunction as causal in the pathophysiology of ASD. Our understanding of the genes and genetic pathways that contribute toward the formation, stabilization, and maintenance of functional synapses coupled with an in-depth phenotypic analysis of the cellular and behavioral characteristics is therefore essential to unraveling the pathogenesis of these disorders. In this review, we discuss the genetic aspects of ASD emphasizing on the well conserved set of genes and genetic pathways implicated in this disorder, many of which contribute to synapse assembly and maintenance across species. We also review how fundamental research using animal models is providing key insights into the various facets of human ASD.

[1]  Jens Frahm,et al.  Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism , 2008, Proceedings of the National Academy of Sciences.

[2]  John J. Connolly,et al.  The Genetics of Autism Spectrum Disorders , 2011 .

[3]  G. Feng,et al.  SnapShot: Autism and the Synapse , 2011, Cell.

[4]  P. Rodier,et al.  Linking etiologies in humans and animal models: studies of autism. , 1997, Reproductive toxicology.

[5]  A. Well,et al.  Stereotypic and self‐injurious behavior in rhesus macaques: A survey and retrospective analysis of environment and early experience , 2003, American journal of primatology.

[6]  David G. Amaral,et al.  Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism , 2008, Brain, Behavior, and Immunity.

[7]  L. Freund,et al.  Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. , 2001, American journal of medical genetics.

[8]  Guosong Liu,et al.  Regulation of Dendritic Spine Morphology and Synaptic Function by Shank and Homer , 2001, Neuron.

[9]  Anne-Marie Le Sourd,et al.  Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2 , 2012, Nature.

[10]  T. Südhof,et al.  Activity-Dependent Validation of Excitatory versus Inhibitory Synapses by Neuroligin-1 versus Neuroligin-2 , 2007, Neuron.

[11]  A. El-Husseini,et al.  A Preformed Complex of Postsynaptic Proteins Is Involved in Excitatory Synapse Development , 2006, Neuron.

[12]  D. Pinto,et al.  Structural variation of chromosomes in autism spectrum disorder. , 2008, American journal of human genetics.

[13]  G. Feng,et al.  Shank3 mutant mice display autistic-like behaviours and striatal dysfunction , 2011, Nature.

[14]  H. McDermid,et al.  Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms , 2003, Journal of medical genetics.

[15]  K. Davis,et al.  Linkage and Association of the Mitochondrial Aspartate / Glutamate Carrier SLC 25 A 12 Gene With Autism , 2004 .

[16]  Andrew Menzies,et al.  X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment , 2008, Nature Genetics.

[17]  Takeshi Sakurai,et al.  The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders , 2009, Trends in Neurosciences.

[18]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[19]  Robert P. Carson,et al.  Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin , 2012, Neurobiology of Disease.

[20]  R. Huganir,et al.  Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism , 2011, Proceedings of the National Academy of Sciences.

[21]  Bradley P. Coe,et al.  Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations , 2012, Nature.

[22]  Robert Pinard,et al.  High-Throughput Sequencing of mGluR Signaling Pathway Genes Reveals Enrichment of Rare Variants in Autism , 2012, PloS one.

[23]  A. Bailey,et al.  Autism as a strongly genetic disorder: evidence from a British twin study , 1995, Psychological Medicine.

[24]  Christos G. Gkogkas,et al.  Autism-related deficits via dysregulated eIF4E-dependent translational control , 2012, Nature.

[25]  Shiaoching Gong,et al.  Minimal aberrant behavioral phenotypes of neuroligin‐3 R451C knockin mice , 2008, Autism research : official journal of the International Society for Autism Research.

[26]  T. Südhof,et al.  Neuroligin 1: a splice site-specific ligand for beta-neurexins. , 1995, Cell.

[27]  Thomas Bourgeron,et al.  Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders , 2007, Nature Genetics.

[28]  Laurie R Santos,et al.  Primate brains in the wild: the sensory bases for social interactions , 2004, Nature Reviews Neuroscience.

[29]  Menachem Fromer,et al.  Rare Structural Variants , 2015 .

[30]  Eunjoon Kim,et al.  Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses , 2013, Front. Mol. Neurosci..

[31]  L. Weiss,et al.  Sodium channels SCN1A, SCN2A and SCN3A in familial autism , 2003, Molecular Psychiatry.

[32]  Wei Zhang,et al.  Pharmacological Inhibition of mTORC1 Suppresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-Specific Pten Knock-Out Mice , 2009, The Journal of Neuroscience.

[33]  Pamela J Lein,et al.  Immunologic and neurodevelopmental susceptibilities of autism. , 2008, Neurotoxicology.

[34]  R. Huganir,et al.  The Role of Synaptic GTPase-Activating Protein in Neuronal Development and Synaptic Plasticity , 2003, The Journal of Neuroscience.

[35]  T. Südhof,et al.  α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis , 2003, Nature.

[36]  Albert J. Vilella,et al.  The genome of a songbird , 2010, Nature.

[37]  R. Stevenson,et al.  AGTR2 Mutations in X-Linked Mental Retardation , 2002, Science.

[38]  Mark F. Bear,et al.  The Autistic Neuron: Troubled Translation? , 2008, Cell.

[39]  T. Südhof,et al.  Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Perrett,et al.  Imitation, mirror neurons and autism , 2001, Neuroscience & Biobehavioral Reviews.

[41]  C. Redies,et al.  Cadherins and neuropsychiatric disorders , 2012, Brain Research.

[42]  Eden R Martin,et al.  Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways. , 2012, Human molecular genetics.

[43]  Yiping Shen,et al.  Disruption of neurexin 1 associated with autism spectrum disorder. , 2008, American journal of human genetics.

[44]  D. Geschwind,et al.  Advances in autism genetics: on the threshold of a new neurobiology , 2008, Nature Reviews Genetics.

[45]  L. Gallagher,et al.  Copy-number variants in neurodevelopmental disorders: promises and challenges. , 2009, Trends in genetics : TIG.

[46]  S. C. Panaitof,et al.  A Songbird Animal Model for Dissecting the Genetic Bases of Autism Spectrum Disorder , 2012, Disease markers.

[47]  S. Rogers,et al.  The Behavioral Phenotype in Fragile X: Symptoms of Autism in Very Young Children with Fragile X Syndrome, Idiopathic Autism, and Other Developmental Disorders , 2001, Journal of developmental and behavioral pediatrics : JDBP.

[48]  M. Labouesse [Caenorhabditis elegans]. , 2003, Medecine sciences : M/S.

[49]  Andreas Buja,et al.  Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism , 2011, Proceedings of the National Academy of Sciences.

[50]  S. Folstein,et al.  Genetics of austim: complex aetiology for a heterogeneous disorder , 2001, Nature Reviews Genetics.

[51]  F. Calahorro,et al.  Functional Phenotypic Rescue of Caenorhabditis elegans Neuroligin-Deficient Mutants by the Human and Rat NLGN1 Genes , 2012, PloS one.

[52]  G. Ming,et al.  Neuronal Activity–Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis , 2009, Science.

[53]  M. Natowicz,et al.  Epigenetics in Autism , 2014 .

[54]  T. Südhof,et al.  Common circuit defect of excitatory-inhibitory balance in mouse models of autism , 2009, Journal of Neurodevelopmental Disorders.

[55]  J. Kaplan,et al.  Neurexin and Neuroligin Mediate Retrograde Synaptic Inhibition in C. elegans , 2012, Science.

[56]  M. Daly,et al.  Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders , 2008, Journal of Medical Genetics.

[57]  E. Klann,et al.  mTOR signaling: At the crossroads of plasticity, memory and disease , 2010, Trends in Neurosciences.

[58]  S. Hyman,et al.  Can Autism Speak to Neuroscience? , 2006, The Journal of Neuroscience.

[59]  T. Soong,et al.  CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency , 2010, Pflügers Archiv - European Journal of Physiology.

[60]  S. J. Martin,et al.  SynGAP Regulates ERK/MAPK Signaling, Synaptic Plasticity, and Learning in the Complex with Postsynaptic Density 95 and NMDA Receptor , 2002, The Journal of Neuroscience.

[61]  J. Sebat,et al.  CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics , 2012, Cell.

[62]  A. Addington,et al.  Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. , 2009, The New England journal of medicine.

[63]  Pat Levitt,et al.  The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. , 2009, The Journal of clinical investigation.

[64]  Elvira Bramon,et al.  Disruption of the neurexin 1 gene is associated with schizophrenia. , 2009, Human molecular genetics.

[65]  I. Scheffer,et al.  The spectrum of SCN1A-related infantile epileptic encephalopathies. , 2007, Brain : a journal of neurology.

[66]  P. Ashwood,et al.  The role of immune dysfunction in the pathophysiology of autism , 2012, Brain, Behavior, and Immunity.

[67]  Daisuke Hattori,et al.  DNA Methylation-Related Chromatin Remodeling in Activity-Dependent Bdnf Gene Regulation , 2003, Science.

[68]  Albert David,et al.  X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. , 2004, American journal of human genetics.

[69]  Andrew Dunsire,et al.  Tipping the Balance , 1996 .

[70]  R. Ebstein,et al.  Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills , 2006, Molecular Psychiatry.

[71]  A. Beaudet Autism: highly heritable but not inherited , 2007, Nature Medicine.

[72]  Chih-Chieh Wang,et al.  SynGAP Regulates Protein Synthesis and Homeostatic Synaptic Plasticity in Developing Cortical Networks , 2013, PloS one.

[73]  Kiyoshi Inoue,et al.  Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism , 2009, Cell.

[74]  Juan I. Young,et al.  Mice with Truncated MeCP2 Recapitulate Many Rett Syndrome Features and Display Hyperacetylation of Histone H3 , 2002, Neuron.

[75]  Michael L Platt,et al.  Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders , 2012, Journal of Neurodevelopmental Disorders.

[76]  M. Rieder,et al.  Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations , 2011, Nature Genetics.

[77]  Jing Liu,et al.  Positive Association of the Oxytocin Receptor Gene (OXTR) with Autism in the Chinese Han Population , 2005, Biological Psychiatry.

[78]  Russell S. Kirby,et al.  Advanced Parental Age and the Risk of Autism Spectrum Disorder , 2008, American journal of epidemiology.

[79]  E. Bacchelli,et al.  Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene , 2003, Molecular Psychiatry.

[80]  Andrew J. Schroeder,et al.  Drosophila Fragile X Protein, DFXR, Regulates Neuronal Morphology and Function in the Brain , 2002, Neuron.

[81]  Hugo J. Bellen,et al.  Axon-Glia Interactions and the Domain Organization of Myelinated Axons Requires Neurexin IV/Caspr/Paranodin , 2001, Neuron.

[82]  P. Scheiffele,et al.  Control of Excitatory and Inhibitory Synapse Formation by Neuroligins , 2005, Science.

[83]  Ravinesh A. Kumar,et al.  Novel Submicroscopic Chromosomal Abnormalities Detected in Autism Spectrum Disorder , 2008, Biological Psychiatry.

[84]  John A. Sweeney,et al.  Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes , 2009, PLoS genetics.

[85]  D. Conrad,et al.  Recurrent 16p11.2 microdeletions in autism. , 2007, Human molecular genetics.

[86]  Valentino Romano,et al.  Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. , 2006, The American journal of psychiatry.

[87]  J. Piven,et al.  Autism and Tuberous Sclerosis Complex: Prevalence and Clinical Features , 1998, Journal of autism and developmental disorders.

[88]  S. Christian,et al.  Disruption of contactin 4 in three subjects with autism spectrum disorder , 2008, Journal of Medical Genetics.

[89]  Eric M. Morrow,et al.  Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry , 2008, Science.

[90]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[91]  Joshua M. Korn,et al.  Integrated detection and population-genetic analysis of SNPs and copy number variation , 2008, Nature Genetics.

[92]  P. Worley,et al.  Disrupted mGluR5-Homer scaffolds mediate abnormal mGluR5 signaling, circuit function and behavior in a mouse model of Fragile X Syndrome , 2012, Nature Neuroscience.

[93]  M. Cuccaro,et al.  Autism and maternally derived aberrations of chromosome 15q. , 1998, American journal of medical genetics.

[94]  Eric C. Griffith,et al.  Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2 , 2003, Science.

[95]  T. Tully,et al.  A Drosophila model for Angelman syndrome , 2008, Proceedings of the National Academy of Sciences.

[96]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[97]  Matthew W. State,et al.  The Emerging Biology of Autism Spectrum Disorders , 2012, Science.

[98]  T. Murphy,et al.  Proteins That Promote Filopodia Stability, but Not Number, Lead to More Axonal-Dendritic Contacts , 2011, PloS one.

[99]  Yuan Tian,et al.  Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders. , 2012, American journal of human genetics.

[100]  Thomas Bourgeron,et al.  Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism , 2003, Nature Genetics.

[101]  E. Hatchwell,et al.  Autism and environmental genomics. , 2006, Neurotoxicology.

[102]  B. Abrahams,et al.  Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation. , 2012, Human molecular genetics.

[103]  Sarah E. London,et al.  Integrating Genomes, Brain and Behavior in the Study of Songbirds , 2009, Current Biology.

[104]  M. Kennedy,et al.  A Synaptic Ras-GTPase Activating Protein (p135 SynGAP) Inhibited by CaM Kinase II , 1998, Neuron.

[105]  N. Kato,et al.  Association of the neuronal cell adhesion molecule (NRCAM) gene variants with autism. , 2009, The international journal of neuropsychopharmacology.

[106]  M. Schachner,et al.  Analysis of Interactions of the Adhesion Molecule TAG-1 and Its Domains with Other Immunoglobulin Superfamily Members , 2002, Molecular and Cellular Neuroscience.

[107]  Ute Moog,et al.  Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation , 2010, Nature Genetics.

[108]  D. Avramopoulos,et al.  β2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort , 2007, Molecular Psychiatry.

[109]  J. Sebat,et al.  Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. , 2008, American journal of human genetics.

[110]  D. Amaral,et al.  The amygdala and autism: implications from non‐human primate studies , 2003, Genes, brain, and behavior.

[111]  Richard P Lifton,et al.  Disruption of Contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. , 2004, American journal of human genetics.

[112]  Gary D Bader,et al.  Functional impact of global rare copy number variation in autism spectrum disorders , 2010, Nature.

[113]  T. Bourgeron,et al.  Linkage and association of the glutamate receptor 6 gene with autism , 2002, Molecular Psychiatry.

[114]  B. Leventhal,et al.  Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. , 1997, American journal of human genetics.

[115]  Kathryn Roeder,et al.  Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism , 2011, Neuron.

[116]  R. Dolmetsch,et al.  Molecular mechanisms of autism: a possible role for Ca2+ signaling , 2007, Current Opinion in Neurobiology.

[117]  S. Priori,et al.  CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism , 2004, Cell.

[118]  W. Reik,et al.  Genomic imprinting: parental influence on the genome , 2001, Nature Reviews Genetics.

[119]  H. Zoghbi,et al.  Learning and Memory and Synaptic Plasticity Are Impaired in a Mouse Model of Rett Syndrome , 2006, The Journal of Neuroscience.

[120]  T. Südhof Neuroligins and neurexins link synaptic function to cognitive disease , 2008, Nature.

[121]  F. Santorelli,et al.  Autism with Seizures and Intellectual Disability: Possible Causative Role of Gain-of-function of the Inwardly-Rectifying K+ Channel Kir4.1 , 2011, Neurobiology of Disease.

[122]  Jyothi Arikkath,et al.  Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity , 2008, Trends in Neurosciences.

[123]  J. Gogos,et al.  Modeling Madness in Mice: One Piece at a Time , 2006, Neuron.

[124]  R. Benayed,et al.  Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder , 2004, Molecular Psychiatry.

[125]  J. Bender DNA methylation and epigenetics. , 2004, Annual review of plant biology.

[126]  D. Geschwind,et al.  Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits , 2011, Cell.

[127]  Y. Giwercman Copy number variants , 2010 .

[128]  Sathyanarayanan V. Puthanveettil,et al.  Neurexin-Neuroligin Transsynaptic Interaction Mediates Learning-Related Synaptic Remodeling and Long-Term Facilitation in Aplysia , 2011, Neuron.

[129]  J. Buxbaum,et al.  Association analysis of the NrCAM gene in autism and in subsets of families with severe obsessive–compulsive or self-stimulatory behaviors , 2006, Psychiatric genetics.

[130]  T. Boeckers,et al.  Scaffold proteins at the postsynaptic density. , 2012, Advances in experimental medicine and biology.

[131]  D. Stephan,et al.  Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. , 2006, The New England journal of medicine.

[132]  M. Ehlers,et al.  Microanatomy of dendritic spines: emerging principles of synaptic pathology in psychiatric and neurological disease , 2004, Biological Psychiatry.

[133]  H. Zoghbi Postnatal Neurodevelopmental Disorders: Meeting at the Synapse? , 2003, Science.

[134]  Christian R Marshall,et al.  Contribution of SHANK3 mutations to autism spectrum disorder. , 2007, American journal of human genetics.

[135]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[136]  R. Martienssen,et al.  DNA methylation and epigenetic inheritance in plants and filamentous fungi. , 2001, Science.

[137]  J. Shim,et al.  Association of the Neuronal Cell Adhesion Molecule (NrCAM) Gene Variants with Personality Traits and Addictive Symptoms in Methamphetamine Use Disorder , 2012, Psychiatry investigation.

[138]  E. Mugnaini,et al.  Ataxia and Abnormal Cerebellar Microorganization in Mice with Ablated Contactin Gene Expression , 1999, Neuron.

[139]  Evan T. Geller,et al.  Patterns and rates of exonic de novo mutations in autism spectrum disorders , 2012, Nature.

[140]  Steven Petrou,et al.  SCN1A mutations and epilepsy , 2005, Human mutation.

[141]  Paula Krakowiak,et al.  Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome , 2011, Brain, Behavior, and Immunity.

[142]  J M Friedman,et al.  A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1α , 2007, Journal of Medical Genetics.

[143]  S. Eichler,et al.  E-I Balance and Human Diseases – from Molecules to Networking , 2008, Frontiers in molecular neuroscience.

[144]  J. Gilbert,et al.  A Genome‐wide Association Study of Autism Reveals a Common Novel Risk Locus at 5p14.1 , 2009, Annals of human genetics.

[145]  M. Herbert Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders , 2010, Current opinion in neurology.

[146]  Mark F Bear,et al.  Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. , 2012, Cold Spring Harbor perspectives in biology.

[147]  Sarah Curran,et al.  A Common Variant in DRD3 Receptor Is Associated with Autism Spectrum Disorder , 2009, Biological Psychiatry.

[148]  B. Philpot,et al.  Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes , 2011, Trends in Neurosciences.

[149]  T. Südhof,et al.  A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins. , 2005, Neuron.

[150]  G. Oliveira,et al.  Autoantibody repertoires to brain tissue in autism nuclear families , 2004, Journal of Neuroimmunology.

[151]  Ronald W. Alfa,et al.  Mouse model of Timothy syndrome recapitulates triad of autistic traits , 2011, Proceedings of the National Academy of Sciences.

[152]  D. Sabatini,et al.  mTOR signaling at a glance , 2009, Journal of Cell Science.

[153]  Peter A. Jones,et al.  Epigenetics in human disease and prospects for epigenetic therapy , 2004, Nature.

[154]  Charles E. Schwartz,et al.  High frequency of neurexin 1β signal peptide structural variants in patients with autism , 2006, Neuroscience Letters.

[155]  S. Grant,et al.  Genome Variation and Complexity in the Autism Spectrum , 2010, Neuron.

[156]  S. Jamain,et al.  Neuroligin 2 is exclusively localized to inhibitory synapses. , 2004, European journal of cell biology.

[157]  Daniel E Weeks,et al.  Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. , 2005, American journal of human genetics.

[158]  J. Crawley Designing mouse behavioral tasks relevant to autistic-like behaviors. , 2004, Mental retardation and developmental disabilities research reviews.

[159]  Cori Bargmann,et al.  GFP Reconstitution Across Synaptic Partners (GRASP) Defines Cell Contacts and Synapses in Living Nervous Systems , 2008, Neuron.

[160]  J. Weiner,et al.  Protocadherins, not prototypical: a complex tale of their interactions, expression, and functions , 2013, Front. Mol. Neurosci..

[161]  M. Herbert,et al.  Autism and Environmental Genomics: Synergistic Systems Approaches to Autism Complexity , 2011 .

[162]  Jacqueline Blundell,et al.  A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice , 2007, Science.

[163]  Tsuyoshi Koide,et al.  Epigenetics in autism and other neurodevelopmental diseases. , 2012, Advances in experimental medicine and biology.

[164]  Tanya M. Teslovich,et al.  A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. , 2008, American journal of human genetics.

[165]  Cathleen K. Yoshida,et al.  Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. , 2005, Archives of pediatrics & adolescent medicine.

[166]  P. Williams,et al.  Brief Report: The Association of Neurofibromatosis Type 1 and Autism , 1998, Journal of autism and developmental disorders.

[167]  L. Zon,et al.  Zebrafish: a model system for the study of human disease. , 2000, Current opinion in genetics & development.

[168]  G. Pampiglione,et al.  Clinical and EEG Studies on a Group of 35 Psychotic Children , 1969, Developmental medicine and child neurology.

[169]  A. Breman,et al.  SHANK3 overexpression causes manic-like behavior with unique pharmacogenetic properties , 2013, Nature.

[170]  Robert T. Schultz,et al.  Common genetic variants on 5p14.1 associate with autism spectrum disorders , 2009, Nature.

[171]  F. Calahorro,et al.  Caenorhabditis elegans as an experimental tool for the study of complex neurological diseases: Parkinson’s disease, Alzheimer’s disease and autism spectrum disorder , 2011, Invertebrate Neuroscience.

[172]  M. Pownall Tipping the balance. , 1989, Nursing times.

[173]  J. Buxbaum,et al.  An analysis of candidate autism loci on chromosome 2q24–q33: Evidence for association to the STK39 gene , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[174]  Jan Bressler,et al.  Epigenetics and human disease. , 2004, Annual review of genomics and human genetics.

[175]  William A Catterall,et al.  Autistic behavior in Scn1a+/− mice and rescue by enhanced GABAergic transmission , 2012, Nature.

[176]  J. Price,et al.  The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. , 2000, Cerebral cortex.

[177]  P. Scheiffele,et al.  Disorder-associated mutations lead to functional inactivation of neuroligins. , 2004, Human molecular genetics.

[178]  Laurent Mottron,et al.  Novel de novo SHANK3 mutation in autistic patients , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[179]  Colin L. Stewart,et al.  Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1 , 2003, The Journal of cell biology.

[180]  X. Estivill,et al.  Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability , 2007, Nature Reviews Genetics.

[181]  D. Pinto,et al.  Rare deletions at the neurexin 3 locus in autism spectrum disorder. , 2012, American journal of human genetics.

[182]  Katarzyna Chawarska,et al.  Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. , 2008, American journal of human genetics.

[183]  A. Hartemink,et al.  Computational and experimental identification of novel human imprinted genes. , 2007, Genome research.

[184]  C. Gillberg,et al.  A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. , 1989, Journal of child psychology and psychiatry, and allied disciplines.

[185]  W. Dreyer,et al.  Binding between the neural cell adhesion molecules axonin-1 and Nr- CAM/Bravo is involved in neuron-glia interaction , 1995, The Journal of cell biology.

[186]  Irva Hertz-Picciotto,et al.  Tipping the Balance of Autism Risk: Potential Mechanisms Linking Pesticides and Autism , 2012, Environmental health perspectives.

[187]  J. Sebat,et al.  Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. , 2009, Trends in genetics : TIG.

[188]  Thomas C. Südhof,et al.  Neuroligins Determine Synapse Maturation and Function , 2006, Neuron.

[189]  W. Brown,et al.  Increased activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in the frontal cortex and cerebellum of autistic individuals. , 2009, Life sciences.

[190]  S. Smalley,et al.  Autism and tuberous sclerosis , 1992, Journal of autism and developmental disorders.

[191]  G. P. Mullen,et al.  Neuroligin-deficient mutants of C. elegans have sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity , 2010, Disease Models & Mechanisms.

[192]  Peter Kirsch,et al.  Edinburgh Research Explorer Association of Mouse Dlg4 (PSD-95) Gene Deletion and Human DLG4 Gene Variation With Phenotypes Relevant to Autism Spectrum Disorders and Williams' Syndrome , 2022 .

[193]  Mark Ellisman,et al.  A single mutation near the C-terminus in alpha/beta hydrolase fold protein family causes a defect in protein processing. , 2005, Chemico-biological interactions.

[194]  D. Owald,et al.  Drosophila Neuroligin 1 Promotes Growth and Postsynaptic Differentiation at Glutamatergic Neuromuscular Junctions , 2010, Neuron.

[195]  M. Ehlers,et al.  Modeling Autism by SHANK Gene Mutations in Mice , 2013, Neuron.

[196]  T. Carew,et al.  Transsynaptic Coordination of Presynaptic and Postsynaptic Modifications underlying Enduring Synaptic Plasticity , 2011, Neuron.

[197]  Igor Tsigelny,et al.  The Arg451Cys-Neuroligin-3 Mutation Associated with Autism Reveals a Defect in Protein Processing , 2004, The Journal of Neuroscience.

[198]  S. Folstein,et al.  Genetic influences and infantile autism , 1977, Nature.

[199]  Jacqueline N. Crawley,et al.  Autistic-like behavior and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice , 2012, Nature.

[200]  Gang-yi Wu,et al.  Regulation of Dendritic Morphogenesis by Ras–PI3K–Akt–mTOR and Ras–MAPK Signaling Pathways , 2005, The Journal of Neuroscience.

[201]  C. Rieder,et al.  Greatwall kinase , 2004, The Journal of cell biology.

[202]  T. Bourgeron,et al.  Searching for ways out of the autism maze: genetic, epigenetic and environmental clues , 2006, Trends in Neurosciences.

[203]  Salvatore Currenti,et al.  Understanding and Determining the Etiology of Autism , 2010, Cellular and Molecular Neurobiology.

[204]  Kenny Q. Ye,et al.  De Novo Gene Disruptions in Children on the Autistic Spectrum , 2012, Neuron.

[205]  J. Kleinman,et al.  Spatiotemporal transcriptome of the human brain , 2011, Nature.

[206]  Min Goo Lee,et al.  Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function , 2012, Nature.

[207]  L. Kanner Autistic disturbances of affective contact. , 1968, Acta paedopsychiatrica.

[208]  E R Martin,et al.  Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. , 2005, American journal of human genetics.

[209]  H. Bellen,et al.  Drosophila Neuroligin 2 is Required Presynaptically and Postsynaptically for Proper Synaptic Differentiation and Synaptic Transmission , 2012, The Journal of Neuroscience.

[210]  E Maestrini,et al.  Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects , 2005, Journal of Medical Genetics.

[211]  Ryszard Przewłocki,et al.  Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism , 2005, Neuropsychopharmacology.

[212]  J. Sutcliffe,et al.  Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. , 2001, Genomics.

[213]  D. Geschwind,et al.  Genome-wide analyses of human perisylvian cerebral cortical patterning , 2007, Proceedings of the National Academy of Sciences.

[214]  A. Cowey,et al.  Sensitivity to eye gaze in prosopagnosic patients and monkeys with superior temporal sulcus ablation , 1990, Neuropsychologia.

[215]  Joshua M. Korn,et al.  Association between microdeletion and microduplication at 16p11.2 and autism. , 2008, The New England journal of medicine.

[216]  L. Van Aelst,et al.  Rho GTPases, dendritic structure, and mental retardation. , 2005, Journal of neurobiology.

[217]  Mark J. Harris,et al.  Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication , 2010, Molecular autism.

[218]  Thomas C. Südhof,et al.  A Splice Code for trans-Synaptic Cell Adhesion Mediated by Binding of Neuroligin 1 to α- and β-Neurexins , 2005, Neuron.

[219]  A. Beaudet,et al.  Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. , 2011, Human molecular genetics.

[220]  Kenji F. Tanaka,et al.  Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism , 2012, Science.

[221]  Jian Jin,et al.  Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons , 2011, Nature.

[222]  V. Budnik,et al.  Crucial Role of Drosophila Neurexin in Proper Active Zone Apposition to Postsynaptic Densities, Synaptic Growth, and Synaptic Transmission , 2007, Neuron.

[223]  H. Zoghbi,et al.  Genetic Modifiers of MeCP2 Function in Drosophila , 2008, PLoS genetics.

[224]  J. Guénet,et al.  Genetics of the Mouse , 2014, Springer Berlin Heidelberg.

[225]  C. Köhler,et al.  Evolution, function, and regulation of genomic imprinting in plant seed development. , 2012, Journal of experimental botany.

[226]  J. Frahm,et al.  Neuroligin‐3‐deficient mice: model of a monogenic heritable form of autism with an olfactory deficit , 2009, Genes, brain, and behavior.

[227]  R. Gibbs,et al.  Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders , 2011, Human molecular genetics.

[228]  Larry J. Young,et al.  The prairie vole: an emerging model organism for understanding the social brain , 2010, Trends in Neurosciences.

[229]  Xiao-Rong Liu,et al.  Autism in Dravet syndrome: Prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation , 2011, Epilepsy & Behavior.

[230]  Joseph P. McCleery,et al.  EEG evidence for mirror neuron dysfunction in autism spectrum disorders. , 2005, Brain research. Cognitive brain research.

[231]  H. Taniguchi,et al.  Silencing of Neuroligin Function by Postsynaptic Neurexins , 2007, The Journal of Neuroscience.

[232]  H. Markram,et al.  General developmental health in the VPA-rat model of autism , 2013, Front. Behav. Neurosci..

[233]  Michael Davis,et al.  The amygdala , 2000, Current Biology.

[234]  D. Geschwind,et al.  Language‐related Cntnap2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds , 2010, The Journal of comparative neurology.

[235]  B. Leventhal,et al.  Autism and tuberous sclerosis , 1991, Journal of autism and developmental disorders.

[236]  Jane Qiu,et al.  Epigenetics: Unfinished symphony , 2006, Nature.

[237]  V. Tropepe,et al.  Can zebrafish be used as a model to study the neurodevelopmental causes of autism? , 2003, Genes, brain, and behavior.

[238]  T. Bourgeron,et al.  Progress toward treatments for synaptic defects in autism , 2013, Nature Medicine.

[239]  J. Crabbe,et al.  Genetics of mouse behavior: interactions with laboratory environment. , 1999, Science.

[240]  P. Worley,et al.  Shank, a Novel Family of Postsynaptic Density Proteins that Binds to the NMDA Receptor/PSD-95/GKAP Complex and Cortactin , 1999, Neuron.

[241]  Xavier Estivill,et al.  Copy Number Variants and Common Disorders: Filling the Gaps and Exploring Complexity in Genome-Wide Association Studies , 2007, PLoS genetics.

[242]  D. Clair,et al.  Deregulation of EIF4E: a novel mechanism for autism , 2009, Journal of Medical Genetics.

[243]  Xiankun Zeng,et al.  Neurexin‐1 is required for synapse formation and larvae associative learning in Drosophila , 2007, FEBS letters.

[244]  F. Gage,et al.  Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline , 2007, The Journal of Neuroscience.

[245]  J. Sutcliffe,et al.  Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. , 2005, American journal of human genetics.

[246]  Stephen J. Guter,et al.  Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. , 1998, American journal of human genetics.

[247]  Hansen Wang,et al.  Reversing autism by targeting downstream mTOR signaling , 2013, Front. Cell. Neurosci..

[248]  A. Muotri,et al.  Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients , 2011, Human molecular genetics.

[249]  M. V. Van Allen,et al.  15q Duplication associated with autism in a multiplex family with a familial cryptic translocation t(14;15)(q11.2;q13.3) detected using array‐CGH , 2006, Clinical genetics.

[250]  C Eng,et al.  Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations , 2005, Journal of Medical Genetics.

[251]  Follow-up study of eleven autistic children originally reported in 1943 , 1971, Journal of autism and childhood schizophrenia.

[252]  P. Worley,et al.  Coupling of mGluR/Homer and PSD-95 Complexes by the Shank Family of Postsynaptic Density Proteins , 1999, Neuron.

[253]  T. Curran,et al.  Role of the reelin signaling pathway in central nervous system development. , 2001, Annual review of neuroscience.

[254]  T. Wassink,et al.  Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder , 2001, Molecular Psychiatry.

[255]  F. Rathjen,et al.  Neurofascin induces neurites by heterophilic interactions with axonal NrCAM while NrCAM requires F11 on the axonal surface to extend neurites , 1996, The Journal of cell biology.

[256]  Boris Yamrom,et al.  Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders , 2011, Neuron.

[257]  D. Pinto,et al.  SHANK1 Deletions in Males with Autism Spectrum Disorder. , 2012, American journal of human genetics.

[258]  K. Davis,et al.  Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. , 2004, The American journal of psychiatry.

[259]  Axel Benner,et al.  Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. , 2001, Human molecular genetics.

[260]  J. Sanes,et al.  Gamma protocadherins are required for synaptic development in the spinal cord. , 2005, Proceedings of the National Academy of Sciences of the United States of America.