Neurobiology of Autism Spectrum Disorders

Preface
Contents
Chapter 1: Dysfunctional Circuit Mechanisms of Sensory Processing in FXS and ASD: Insights from Mouse Models
	1.1 Sensory Processing and Decision Making
	1.2 Fragile X Syndrome
	1.3 Mouse Models of Fragile X Syndrome and ASD
	1.4 Sensory Processing Deficits in the Context of Impaired Inhibition
	1.5 Inhibition in the Neurotypical Sensory Cortex
	1.6 Sensory Deficits in the Visual Domain
		1.6.1 Humans
		1.6.2 Mice
	1.7 Sensory Deficits in the Auditory Domain
	1.8 Sensory Deficits in Somatosensory Domain
	1.9 Conclusion
	References
Chapter 2: Theory of Mind in Autism
	2.1 Introduction
	2.2 Critical and Landmark Studies of ToM
		2.2.1 Premack and Woodruff (1978)
		2.2.2 Perner and Wimmer (1983)
		2.2.3 Baron-Cohen, Leslie, and Frith (1985)
		2.2.4 Mirror-Neuron Research
		2.2.5 Studies to Investigate Precursors or Prerequisites of ToM
	2.3 A Challenge to Study Theory of Mind: The Problem of Investigating the Unobservable in Science
	2.4 Conclusion
	References
Chapter 3: Prenatal and Early Life Environmental Stressors: Chemical Moieties Responsible for the Development of Autism Spectrum Disorder
	3.1 Introduction
	3.2 Prenatal/Perinatal Exposure to Environmental Stressors
		3.2.1 Valproic Acid
		3.2.2 Hyperserotonemia
		3.2.3 Maternal Infections
		3.2.4 Endocrine Disruptors
			3.2.4.1 Polychlorinated Biphenyls
			3.2.4.2 Bisphenol – A
		3.2.5 Pesticides
		3.2.6 Heavy Metals
		3.2.7 Nutritional Deficiency
			3.2.7.1 Vitamin D
			3.2.7.2 Amino Acids
			3.2.7.3 B-Vitamins
	3.3 Conclusion
	References
Chapter 4: Animal Models of ASD
	4.1 Non-genetic Animal Models
	4.2 Genetic Animal Models
	4.3 Conclusion
	References
Chapter 5: Mitochondrial Dysfunction in Autism Spectrum Disorders
	5.1 Introduction
	5.2 Etiology and Pathophysiology of ASD
	5.3 Mitochondrial Dysfunction in ASD
		5.3.1 Mitochondrial Dysfunction in the Brain of ASD Subjects
		5.3.2 Alterations in Mitochondrial DNA in ASD Subjects
		5.3.3 Brain Oxidative Stress in ASD
	5.4 Conclusion
	References
Chapter 6: The Usability of Mouse Models to Study the Neural Circuity in Autism Spectrum Disorder: Regulatory Mechanisms of Core Behavioral Symptoms
	6.1 Current Trends in ASD Studies Using Animal Models
	6.2 Assessment of Atypical Social Behavior in Animal Models
	6.3 Neural Circuits Responsible for the Regulation of ASD-Like Behavior
	6.4 Peptide Hormones Regulating Complex Social Behavior
	6.5 OXT-Mediated Neural Circuits
	6.6 AVP-Mediated Neural Circuits
	6.7 Concluding Remarks
	References
Chapter 7: Seizures in Mouse Models of Autism
	7.1 Sex Bias of Presentation of ASD and Epilepsy
	7.2 Early Epileptic Activity and ASD
	7.3 Imbalance of Excitation and Inhibition as a Common Etiology for ASD and Epilepsy
	7.4 Seizures in Monogenetic Mouse Models of ASD
		7.4.1 16p11.2
		7.4.2 ARID1B
		7.4.3 CACNA1C
		7.4.4 CNTNAP2
		7.4.5 CUL3
		7.4.6 DYRK1A
		7.4.7 GTF2I
		7.4.8 RAI1
		7.4.9 SHANK3
		7.4.10 SYNGAP1
		7.4.11 UBE3A
	7.5 Conclusions
	References
Chapter 8: Lipid-Related Pathophysiology of ASD
	8.1 Lipids Are Essential to Biomechanisms
		8.1.1 Lipids in the Periphery
			8.1.1.1 Cholesterol Transport and Lipoproteins
			8.1.1.2 Lipoproteins Transport Materials Including Steroids and miRNA
		8.1.2 Lipids in the CNS
			8.1.2.1 Cholesterol Production in the Brain
			8.1.2.2 Cholesterol’s Role in Development
			8.1.2.3 Cholesterol’s Role in Signaling
			8.1.2.4 Cholesterol’s Role in Synaptic Function
			8.1.2.5 Other Lipids in the Brain
	8.2 Lipid-Related Abnormalities Have Been Found in ASD-Related Genetic Disorders
		8.2.1 Smith-Lemli-Opitz Syndrome
		8.2.2 Fragile X Syndrome
		8.2.3 Rett Syndrome
	8.3 Lipid Disorders with Known Genetic Variants Not Associated with ASD
		8.3.1 Post-Squalene Disorders Involved with Cholesterol Biosynthesis
		8.3.2 Hypoapolipoprotein Disorders: Hypoalphalipoproteinemia, Hypobetalipoproteinemia, Abetalipoproteinemia, and Familial Combined Hypolipidemia
		8.3.3 Hyperlipidemic Disorders Caused by Variants in Genes That Also Cause Hypolipidemic Disorders
	8.4 Lipid Abnormalities Associated with ASD that Are Not Observed with Known Genetic Disorders
	References
Chapter 9: Perinatal Insulin-Like Growth Factor as a Risk Factor for Autism
	9.1 Introduction
	9.2 Methods
	9.3 Results/Discussion
		9.3.1 Conclusions
	References
Chapter 10: Prophylactic Treatment of ASD Based on Sleep-Wake Circadian Rhythm Formation in Infancy to Early Childhood
	10.1 Introduction
	10.2 Circadian Rhythm Formation
	10.3 Age-related Changes in Sleep Development
		10.3.1 Sleep Duration
		10.3.2 Sleep Characteristics of Children with ASD
		10.3.3 Night Awakening (Sleep Fragmentation)
		10.3.4 Difference in Sleep Duration Between Weekdays and Weekends
		10.3.5 Social Jet Lag Tendency of Infants and Young Children
	10.4 Appropriate Period of Nocturnal Sleep
	10.5 Direction of ASD Treatment
	10.6 Appropriate Age for Treatment
	10.7 Therapy for Sleep Disorders in Infancy to Early Childhood
		10.7.1 Sleep Hygiene
			10.7.1.1 Sleep-Wake Rhythm Adjustment
			10.7.1.2 Awakening During Night
				Discontinuing (Breast) Feeding at Night (Fig. 10.5)
		10.7.2 Pharmacotherapy (Figs. 10.6, 10.7 and 10.8)
			10.7.2.1 Delayed Sleep Onset (Sleep Onset Insomnia)
				Melatonin
				Clonidine
				Benzodiazepine
				Triclofos Sodium(TFS)
			10.7.2.2 Awakening (Sleep Fragmentation)
				Antihistamine
				Risperidone
		10.7.3 Hospitalization
	10.8 Summary
	References
Chapter 11: Imbalances of Inhibitory and Excitatory Systems in Autism Spectrum Disorders
	11.1 The Excitation/Inhibition Imbalance Model and Autism
	11.2 Clinical Evidence for E/I Imbalance in ASD
	11.3 Links Between E/I Imbalance and Autism-Like Behavior in Model Systems
	11.4 Implications for Therapeutic Treatments Targeting E/I Imbalance
	References
Chapter 12: Shared Developmental Neuropathological Traits Between Autism and Environmental Lead Exposures: Insights into Convergent Sulfur-Dependent Neurobiological Mechanisms
	12.1 Brief Literature Review of the Last Decade
	12.2 Glutathione as a Shared Neurobiological Target for Understanding Late-to-Early Neurodevelopmental Disorders and Its Implications on the GABA-Shift
	12.3 Lead Poisoning and Autism Alter Brain Glutathione Levels
	12.4 Understanding the Physical Chemistry Between Lead and Sulfur Compounds
	12.5 Sulfur-Dependent Approaches for Ameliorating Lead Poisoning and Autism: Taurine Neuroprotection Through Glutathione
	12.6 Discussion and Conclusions
	References
Chapter 13: Epidemiological Surveys of ASD: Current Findings and New Directions
	13.1 Introduction
	13.2 Review of Prevalence Surveys
	13.3 Special Issues
		13.3.1 Case Definition and Case Status Determination
		13.3.2 The Problems of Parental Reports
		13.3.3 Novel Approaches to Case Finding/Ascertainment
		13.3.4 Worldwide Studies and Cultural Issues
		13.3.5 Surveillance
	13.4 Conclusions
	References
Chapter 14: Metabolic Approaches to the Treatment of Autism Spectrum Disorders
	14.1 Vitamins
		14.1.1 Vitamin B1
		14.1.2 Vitamin B2
		14.1.3 Vitamin B3
		14.1.4 Vitamin B5
		14.1.5 Vitamin B6
		14.1.6 Vitamin B7
		14.1.7 Vitamin B9
		14.1.8 Vitamin B12
		14.1.9 Vitamin C
		14.1.10 Vitamin A
		14.1.11 Vitamin D
		14.1.12 Vitamin E
	14.2 Minerals
		14.2.1 Zinc
		14.2.2 Magnesium
		14.2.3 Lithium
		14.2.4 Molybdenum
	14.3 Other Nutrients
		14.3.1 Omega-3 Fatty Acids
		14.3.2 N-acetyl Cysteine
		14.3.3 Coenzyme Q10
		14.3.4 Alpha-Lipoic Acid
		14.3.5 Creatine Monohydrate
		14.3.6 Sulforaphane
		14.3.7 Melatonin
		14.3.8 Carnitine
		14.3.9 Tetrahydrobiopterin
	14.4 Dietary Interventions with a Metabolic Approach
		14.4.1 Ketogenic Dietary Therapies
	14.5 Summary and Conclusions
	References
Chapter 15: Autism and Neurodiversity
	15.1 Heterogeneity in Autism
	15.2 What Is Neurodiversity
	15.3 Medical Model
		15.3.1 Historical Medical Model
		15.3.2 Modern Medical Model
	15.4 Social Model of Disability
	15.5 Ecological Model of Neurodiversity
	15.6 Indigenous Models of Neurodiversity
	15.7 Major Autism Movements
	15.8 Unifying View of Autism with Combined Models
	15.9 Recommendations for Biological Studies of Autism
	15.10 Conclusion
	References
Chapter 16: Principal Findings of Auditory Evoked Potentials in Autism Spectrum Disorder
	16.1 Introduction
	16.2 Evidence of Neurophysiological Abnormalities with ABR in ASD
	16.3 Evidence of Neurophysiological Abnormalities with LLAEP in ASD
	16.4 Conclusion
	References
Chapter 17: Developmental Origins of the Structural Defects Implicated in ASD: Insights from iPSC and Post-Mortem Studies
	17.1 Introduction
		17.1.1 2D and 3D iPSC Models
		17.1.2 The Need for an Integrated Approach
	17.2 Complementary Findings in iPSC and Postmortem Studies of ASD
		17.2.1 Brain Size and Neuronal Numbers
		17.2.2 Proliferation and Neurogenesis
		17.2.3 Differentiation and Cell-Type Comittment
		17.2.4 Apoptosis
		17.2.5 Cortical Cytoarchitecture
		17.2.6 Neuropathological Alterations in Morphology and Synapses
		17.2.7 Excitatory/Inhibitory (E/I) Imbalance
		17.2.8 Reelin (RELN) Dysfunction
		17.2.9 Gliogenesis
		17.2.10 Transcriptional Landscape of ASD from iPSC and Post-Mortem Studies
	17.3 Conclusions and Future Directions
	References
Chapter 18: Genes and their Involvement in the Pathogenesis of Autism Spectrum Disorder: Insights from Earlier Genetic Studies
	18.1 Introduction
	18.2 Genetic Studies of ASD
		18.2.1 Twin Studies
		18.2.2 Family Studies
		18.2.3 Linkage Studies
		18.2.4 Genome-Wide Association Studies
		18.2.5 Cytogenetic Studies
		18.2.6 Copy Number Variation (CNV) Analysis
	18.3 Genes Involved in ASD Pathogenesis
		18.3.1 RELN (Reelin) Gene
		18.3.2 SHANK (SH3 and Multiple Ankyrin Repeat Domains Protein) Gene
		18.3.3 NLGN (Neuroligin) Gene
		18.3.4 OXTR (Oxytocin Receptor) Gene
		18.3.5 GABR (Gamma-Aminobutyric Acid Receptor) Gene
		18.3.6 MET (Mesenchymal Epithelial Transition) Gene
		18.3.7 SLC6A4 (Solute Carrier Family 6 Member 4) Gene
		18.3.8 SLC25A12 (Solute Carrier Family 25 Member 12) Gene
		18.3.9 MAO (Monoamine Oxidase) Gene
		18.3.10 ITGB3 (Integrin-β 3) Gene
	18.4 Concluding Remarks
	References
Chapter 19: Electrophysiology of Semantic Processing in ASD
	19.1 Electrophysiology of Semantic Processing in Healthy Population
	19.2 Classic ERPs Components Associated with Semantic Processing
		19.2.1 N400
		19.2.2 Later Positivities
		19.2.3 Later Sustained Negativity
	19.3 Electrophysiology of Semantic Processing in ASD
		19.3.1 Semantic Processing of Verbal Information
		19.3.2 Semantic Processing of Visual Information
		19.3.3 Semantic Processing of Cross-Modal Information
	19.4 Oscillatory Activation
		19.4.1 Future Directions
			19.4.1.1 The Visual Ease Assumption
	References
Chapter 20: Gestational Exposure to Di-n-Butyl Phthalate Induces Autism-Like Behavior Through Inhibition of Neuro-Steroidogenesis
	20.1 Introduction
	20.2 Materials and Methods
		20.2.1 Animals
		20.2.2 High-Performance Liquid Chromatography (HPLC)
		20.2.3 Western Blotting
		20.2.4 Immunohistochemical Analysis
		20.2.5 cDNA Preparation and Quantitative Real-Time PCR Analysis
		20.2.6 Scanning Electron Microscopy
		20.2.7 Statistical Analysis
		20.2.8 Results
			20.2.8.1 DBP Levels in the Brain of Offspring
			20.2.8.2 Gestational Exposure to DBP Disrupts Key Proteins in Steroidogenesis
			20.2.8.3 Gestational Exposure to DBP Reduces the Expression of Steroidogenic and GABAergic Proteins
		20.2.9 Discussion
	References
Index