Translational Anatomy and Cell Biology of Autism Spectrum Disorder (Advances in Anatomy, Embryology and Cell Biology (224))

Autism spectrum disorder (ASD) affects approximately 1 % of the human population and is characterized by a core symptomatology including deficits in social interaction and repetitive patterns of behaviour plus various co-morbidities. Although a lot of progress has been made to uncover underlying causes and mechanisms throughout the last decade, we are still at the very beginning to understand this enormously complex neurodevelopmental condition. This special volume is focused on translational anatomy and cell biology of ASD. International experts from the field including several members of the EU-AIMS initiative launched by the European Union to develop novel treatments for ASD have contributed chapters on several topics covering all crucial aspects of translational ASD research with a special emphasis on ASD model systems including stem cells and animals. Primary objective is to clarify how anatomical and cell biological phenotypes of ASD will help to translate basic mechanisms to clinical practice and to efficiently treat affected individuals in the near future. Preface 6 Contents 8 Chapter 1: Anatomy and Cell Biology of Autism Spectrum Disorder: Lessons from Human Genetics 10 1.1 Introduction 10 1.2 From Chromosomal Rearrangements to Copy Number Variants in ASD 11 1.3 From Candidate Genes to Whole Exome and Genome Sequencing Studies in ASD 12 1.4 Rare and Common Variants in ASD 15 1.5 Anatomy of ASD Genes 18 1.6 From Genetics to Pathways Associated with ASD 19 1.7 Protein Synthesis and Synaptic Plasticity 24 1.8 Conclusions 26 References 28 Chapter 2: Neuroanatomy and Neuropathology of Autism Spectrum Disorder in Humans 35 2.1 Introduction 35 2.2 Early Brain Overgrowth in ASD During Early Childhood 36 2.3 Neurobiological Mechanisms Mediating Brain Growth During Early Childhood (2 Years) 38 2.3.1 Cellular Mechanisms Underlying Typical Brain Maturation During Gestation and Early Childhood 38 2.3.2 Cellular Mechanisms Underlying Atypical Early Brain Maturation in ASD 41 2.4 Brain Development Across Late Childhood and Adolescence in ASD 43 2.5 The Core Neural Systems Underlying ASD 44 2.6 Microstructural Findings in the ASD Brain 46 2.6.1 Cortical Neuropathology of ASD 47 2.6.2 Limbic Neuropathology in ASD 48 2.6.3 Cerebellar Neuropathology in ASD 48 2.7 Conclusions 49 References 50 Chapter 3: Modelling Autistic Neurons with Induced Pluripotent Stem Cells 57 3.1 Introduction 57 3.2 The Need for Human Cellular Models 58 3.3 Neural Differentiation of iPSCs 60 3.4 Modelling ASD in a Dish Using iPSCs 61 3.4.1 Fragile X Syndrome 61 3.4.2 Rett Syndrome and MECP2 Duplication Syndrome 62 3.4.3 Timothy Syndrome 63 3.4.4 Phelan-McDermid Syndrome and SHANK3-Associated ASD 64 3.4.5 Non-syndromic ASD 65 3.5 Limitations of iPSCs 67 3.6 Conclusions 67 References 68 Chapter 4: Modelling Autistic Features in Mice Using Quantitative Genetic Approaches 73 4.1 Introduction 73 4.1.1 Clinical Definition of ASD 73 4.1.2 Prevalence 74 4.1.3 Treatment 74 4.1.4 Risk Factors 74 4.1.5 Genetics 75 4.2 Animal Models Based on Environmental and Genetic Findings 75 4.2.1 Lesion Studies 76 4.2.2 Foetal Valproate Syndrome 76 4.2.3 Genetic Disorders 76 4.3 Strengths and Limitations of Animal Models 77 4.3.1 Construct Validity 77 4.3.2 Predictive Validity 78 4.3.3 Face Validity 78 4.4 Evolutionary Perspective of Inherited Behaviours 79 4.4.1 Communication and Social Behaviour 80 4.4.2 Stereotyped and Restricted Behaviours 80 4.4.3 Behavioural Development 81 4.4.4 Genetic Background and Genotype-Phenotype Relationships 82 4.5 Forward Genetic Approaches in Mice 82 4.6 Continuous Variation in ASD-Related Behavioural Traits 83 4.6.1 Modelling Genetic Diversity 84 4.7 Conclusions 85 4.7.1 Behavioural Responses and Evolutionary Conserved Processes 85 4.7.2 Quantitative Biological Parameters 86 4.7.3 Behavioural Trajectories and Therapeutic Intervention 86 References 87 Chapter 5: Behavioural Phenotypes and Neural Circuit Dysfunctions in Mouse Models of Autism Spectrum Disorder 93 5.1 Introduction 93 5.2 Social Behaviours 94 5.3 Stereotyped Behaviours 96 5.4 Meta-Analysis of ASD Mouse Models 97 5.4.1 Cluster I 99 5.4.2 Cluster II 100 5.5 Relating Behavioural Phenotypes with Structural and Functional Characteristics 101 5.6 Mouse Models Carrying Mutations in the Shank Genes 102 5.7 Refining the Analysis to Describe Behavioural Impairments 103 5.8 Conclusions 104 References 104 Chapter 6: Cerebellar and Striatal Pathologies in Mouse Models of Autism Spectrum Disorder 110 6.1 Introduction 110 6.2 Human Cerebellum in ASD 111 6.3 Cerebellum in ASD Mouse Models 112 6.3.1 Mouse Models for Syndromic ASD 112 6.3.2 Mouse Models for Non-syndromic ASD 114 6.3.3 Converging Cerebellar Phenotypes Among Several Mouse Models 115 6.4 Human Striatum in ASD 116 6.5 Striatum in ASD Mouse Models 116 6.6 Conclusions 118 References 121 Chapter 7: Neurotrophic Factors in Mouse Models of Autism Spectrum Disorder: Focus on BDNF and IGF-1 127 7.1 Introduction 127 7.2 Neurotrophic Factors in Individuals with ASD 128 7.3 BDNF in Mouse Models of ASD 130 7.3.1 BDNF in Mouse Models of Fragile X Syndrome 130 7.3.2 BDNF in Mouse Models of Rett Syndrome 131 7.3.3 BDNF in Other Mouse Models of ASD 132 7.4 IGF-1 in Mouse Models of ASD 132 7.4.1 IGF-1 in Mouse Models of Rett Syndrome 132 7.4.2 IGF-1 in Other Mouse Models of ASD 134 7.5 Conclusions 134 References 135 Chapter 8: The Role of the Oxytocin/Arginine Vasopressin System in Animal Models of Autism Spectrum Disorder 141 8.1 Introduction 142 8.2 OXT/AVP Systems and ASD 142 8.3 Oxt and Avp System-Related Animal Models of ASD 144 8.3.1 Genotype-Based Models: Oxt System 144 8.3.2 Genotype-Based Models: Avp System 148 8.3.3 The Oxt/Avp System in Monogenic Mouse Models of ASD 148 8.3.4 Phenotype-Based Models 149 8.4 Therapeutic Strategies for Targeting the OXT/AVP System 150 8.4.1 Acute Administration 150 8.4.2 Chronic Administration 150 8.4.3 Stimuli Enhancing Synthesis or Release of Oxt and Avp in Animals 151 8.5 Translational Medicine of OXT and AVP 152 8.5.1 Effects of Single-Dose Administration of OXT on Social Cognition in Humans 153 8.5.2 Effects of Acute OXT Administration in Adult Patients with ASD 153 8.5.3 Multiple-Dose Studies of Intranasal OXT in Patients with ASD 153 8.5.4 Endogenous Release of OXT/AVP in Humans 154 8.6 Conclusions 154 References 155 Chapter 9: Extracerebral Dysfunction in Animal Models of Autism Spectrum Disorder 165 9.1 Introduction 165 9.1.1 Enteric and Immune System Abnormalities in ASD 166 9.1.2 Abnormal Amino Acid Metabolism in ASD 167 9.1.3 Trace Metals in ASD 168 9.2 Overview of the Enteric Nervous System in ASD 168 9.3 Animal Models of Enteric Dysfunction in ASD 169 9.4 Overview of Maternal Infection and Inflammatory Processes in ASD 170 9.5 Animal Models of Maternal Infection and Inflammation 172 9.6 Overview of Amino Acid Metabolism in ASD 173 9.7 Animal Models for Amino Acid Metabolism in ASD 174 9.8 Overview of Zinc Biology in the Brain and GI Tract 175 9.8.1 Prenatal Zinc Deficiency and Synaptic Function 176 9.8.2 Prenatal Zinc Deficiency, Gastrointestinal Function and Inflammation 177 9.9 Animal Models for Prenatal Zinc Deficiency in ASD 178 9.10 Role of the Microbiome 179 9.11 Role of Other ASD Risk Factors 181 9.12 Conclusions 182 References 184 Chapter 10: Genetic and Pharmacological Reversibility of Phenotypes in Mouse Models of Autism Spectrum Disorder 194 10.1 Introduction 194 10.2 Genetic Reversibility 195 10.2.1 Fmr1 195 10.2.2 Mecp2 196 10.2.3 Ube3a 197 10.2.4 Nrxn-Nlgn-Shank 198 10.2.5 Syngap1 199 10.3 Pharmacological Reversibility 201 10.3.1 Negative and Positive Allosteric Modulators of Group I mGluRs 201 10.3.2 Agonists and Antagonists of the NMDAR 205 10.3.3 Inhibitors of mTOR 206 10.3.4 Insulin-Like Growth Factor I 207 10.3.5 Oxytocin 208 10.4 Conclusions 208 References 210 Front Matter....Pages i-viii Anatomy and Cell Biology of Autism Spectrum Disorder: Lessons from Human Genetics....Pages 1-25 Neuroanatomy and Neuropathology of Autism Spectrum Disorder in Humans....Pages 27-48 Modelling Autistic Neurons with Induced Pluripotent Stem Cells....Pages 49-64 Modelling Autistic Features in Mice Using Quantitative Genetic Approaches....Pages 65-84 Behavioural Phenotypes and Neural Circuit Dysfunctions in Mouse Models of Autism Spectrum Disorder....Pages 85-101 Cerebellar and Striatal Pathologies in Mouse Models of Autism Spectrum Disorder....Pages 103-119 Neurotrophic Factors in Mouse Models of Autism Spectrum Disorder: Focus on BDNF and IGF-1....Pages 121-134 The Role of the Oxytocin/Arginine Vasopressin System in Animal Models of Autism Spectrum Disorder....Pages 135-158 Extracerebral Dysfunction in Animal Models of Autism Spectrum Disorder....Pages 159-187 Genetic and Pharmacological Reversibility of Phenotypes in Mouse Models of Autism Spectrum Disorder....Pages 189-211