Modeling the Psychopathological Dimensions of Schizophrenia

From Molecules to Behavior

1st Edition, Volume 23 - November 5, 2015
Editors: Mikhail Pletnikov, John Waddington
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 9 8 1 - 9
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 0 1 1 8 4 - 3

Modeling the Psychopathological Dimensions of Schizophrenia: From Molecules to Behavior is the first book to offer a comprehensive review of the new theoretical, clinical,… Read more

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Modeling the Psychopathological Dimensions of Schizophrenia: From Molecules to Behavior is the first book to offer a comprehensive review of the new theoretical, clinical, and basic research framework that considers psychotic illness as a group of dimensional representations of psychopathology rather than as traditional distinct categorical diagnoses. Psychotic illness, typified by schizophrenia, is a devastating condition increasingly recognized as a disorder of abnormal brain development and dysconnectivity. Its complex etiology involves both genetic and environmental factors, as well as the interplay among them.

This book describes the current understanding of the clinical and pathological features of schizophrenia, with a particular focus on the evolving conceptualization of schizophrenia and related diagnostic categories of psychotic illness as combinations of dimensional abnormalities. It provides an overview of modern strategies for generating cellular and whole animal models of schizophrenia as well as detailed reviews of the specific experimental preparations and paradigms aimed at molecular, developmental, and brain-network mechanisms that are the underlying aspects of abnormal behavior and various aspects of schizophrenia.

This groundbreaking book is an authoritative overview of the translational impact of emerging clinical insights on basic research approaches in schizophrenia that will advance the reader’s understanding of the five major dimensions of psychopathology in schizophrenia and related psychoses and resolve the genetic and neurobiological underpinnings of these dimensions.

Contributors
Preface
Part I. From Clinical Dimensions to Animal Models
- Clinical and Pathological Aspects
  - Chapter 1. Overview of Schizophrenia: Dimensions of Psychopathology
    - The Inadequacy of Diagnostic Categories
    - Psychopathological Dimensions—A Challenge to Categorical Approach to Diagnosis
    - The Need for a Precise Dimensional Model
    - Specificity to Disorder
    - Chronological Stability of Dimensions
    - Differential Associations of Dimensions with Biological and Clinical Parameters
    - Categories or Dimensions, or Both?
    - Conclusion
  - Chapter 2. A Review of the Epidemiology of Schizophrenia
    - Introduction
    - Evidence for Environmental Factors in Schizophrenia
    - Infections after Birth
    - Gene–Environment Interaction
    - Future Directions
    - Conclusion
- Animal Models of Psychotic Disorders: Dimensional Approach
  - Chapter 3. Modeling Dimensions of Psychopathology: Integration with the Epidemiology and Pathobiology of Psychotic Illness
    - Introduction
    - Modeling Dimensions of Psychopathology
    - Modeling Dimensions of Psychopathology in the Context of the Epidemiology of Psychotic Illness
    - Modeling Dimensions of Psychopathology in the Context of the Pathobiology of Psychotic Illness
    - Conclusions
  - Chapter 4. Modeling the Positive Symptoms of Schizophrenia
    - Introduction
    - Delusions and Hallucinations
    - Neuroimaging Studies on Positive Symptoms
    - Delusional and Hallucinogenic Signaling
    - Methods to Investigate Positive Symptom-Related Behaviors in Animal Models
    - Conclusion
  - Chapter 5. Animal Models of Psychotic Disorders: Dimensional Approach Modeling Negative Symptoms
    - Introduction
    - Modeling Symptomatology
    - Model Validity
    - Modeling Techniques
    - Modeling the Negative Symptoms
    - Conclusions
  - Chapter 6. Modeling Cognitive Impairment
    - Cognitive Dysfunctions in Schizophrenia and Mouse Models
    - Executive Control
    - Working Memory
    - Attention
    - Social Cognition
    - Conclusions and Future Directions
  - Chapter 7. Modeling Affective Symptoms of Schizophrenia
    - Introduction
    - Anhedonia
    - Social Interaction
    - Avolition
    - Animal Models of Schizophrenia
    - Pharmacological Models
    - Lesion Models
    - Developmental Models
    - Genetic Models
    - Affective Assays in Models of Schizophrenia
    - Conclusion
Part II. Neurobiology of Psychotic Disorders
- Non-Genetic Models
  - Chapter 8. Dysregulation of Dopamine Systems in a Developmental Disruption Model of Schizophrenia: Implications for Pathophysiology, Treatment, and Prevention
    - Schizophrenia as a Neurodevelopmental Disorder
    - Cellular Mechanisms of Prenatal MAM Exposure
    - Effects of Prenatal MAM Exposure on Cortical Development
    - Subcortical Hyperdopaminergia in MAM: Behavioral Correlates, Direct Measures, and Hippocampal Involvement
    - Prodromal Hypersensitivity to Stress in MAM-17
    - Sensorimotor Gating Deficits in MAM-17
    - Deficits in Prefrontal-Dependent Behaviors and Aberrant Prefrontal Activity
    - Functional Disconnection within Limbic Circuits
    - Oscillatory Activities in MAM
    - Social Withdrawal in MAM
    - Antipsychotic Drug Actions in MAM
    - Testing Novel Treatment in the MAM Model
    - MAM-E17 as a Model to Study Developmental Trajectory
  - Chapter 9. Social Isolation Rearing and Sensorimotor Gating in Rat Models of Relevance to Schizophrenia: What We Know, and What We Do Not Know
    - Social Isolation Rearing in Rats
    - Reduced Prepulse Inhibition after SIR
    - Relevance to Deficient Sensorimotor Gating in Schizophrenia?
    - Conclusions
  - Chapter 10. Glutamate Pharmacological Models Relevant to Schizophrenia and Psychosis: Can a Receptor Occupancy Normalization Approach Reduce the Gap between Animal and Human Experiments?
    - Behavioral Effects in Humans
    - Relating to Negative Symptoms of Schizophrenia
    - Relating to Cognitive Symptoms of Schizophrenia
    - Other Effects
    - Neurobiology of NMDA-R Antagonism
    - Linking NMDA-R Hypofunction and Schizophrenia
    - Rodent Modeling of Human NMDA-R Antagonism
    - Diversity of NMDA-R Antagonists
    - NMDA-R Antagonist Behavioral Effects in Rodents
    - Representing Positive Symptoms
    - Representing Negative Symptoms
    - Conclusion and Synthesis
  - Chapter 11. Modeling the Maternal Immune Activation Risk Factor for Schizophrenia
    - Introduction
    - Maternal Infection Risk Factors for Schizophrenia
    - Modeling MIA Using Prenatal Polyinosine-Polycytidylic Injections
    - Gene–Environment Interactions
    - Environment–Environment Interactions
    - Neonatal Poly (I:C) Model
    - Modeling MIA in Primates
    - MIA as a Risk Factor for Autism Spectrum Disorder and Schizophrenia
    - Potential Mechanisms Underlying the Effects of MIA
    - Immune Abnormalities in Schizophrenia
    - Immune-Related Genetic Risk Factors for Schizophrenia
    - Conclusion
  - Chapter 12. Etiological Environmental Models: Virus Infection Models
    - Background
    - Experimental Models Employing Viruses
    - Specific Experimental Infections
    - Concluding Remarks
  - Chapter 13. Toward a Diathesis-Stress Model of Schizophrenia in a Neurodevelopmental Perspective
    - Introduction
    - Stress as a Risk Factor for Psychopathology
    - An Integrative Neurodevelopmental Approach to the Etiopathogenesis of Schizophrenia
    - Animal Models of Schizophrenia
    - Modeling Schizophrenia with Prenatal Stress
    - Common Mechanisms Underlying Prenatal Adversities Associated with Schizophrenia
    - Environmental Impact on the Epigenetic Shaping and Implications for Schizophrenia
  - Chapter 14. The Toxoplasma gondii Model of Schizophrenia
    - Introduction
    - Toxoplasma gondii as a Culpable Parasite
    - Relationship between Toxoplasma gondii and Schizophrenia
    - Schizophrenia, Toxoplasma gondii, and Potential Shared Mechanism(s) of Action
    - Schizophrenia Risk Genes and Potential Interactions in Toxoplasma gondii Infection
    - Gene–Environment Interactions—“A > Two-hit Toxoplasma gondii Model of Schizophrenia”
    - Future Potential Toxoplasma gondii Models of Schizophrenia
    - General Discussion
    - Conclusions
  - Chapter 15. Maternal Nutritional Deficiencies and Schizophrenia: Lessons from Animal Models with a Focus on Developmental Vitamin D Deficiency
    - Maternal Nutrition and Schizophrenia: Ecological Data
    - Which Micronutrient Deficiencies Are Most Relevant to Schizophrenia?
    - Epidemiology of Maternal Nutritional Risk Factors for Schizophrenia
    - Controlled Trials of Nutritional Supplements for Treatment of Schizophrenia
    - Maternal Nutritional Deficiencies and Schizophrenia-Relevant Phenotypes in Animal Models
    - The DVD-Deficiency Animal Model of Schizophrenia
    - Maternal Nutritional Deficiencies Produce a Convergent Phenotype in Adult Offspring
    - Are Alterations in the Ontogeny of Developing DA Systems a Convergent Early Mechanism in Models of Maternal Nutritional Deficiency?
    - Conclusions
- Genetic Models
  - Chapter 16. Mouse Models of Schizophrenia: Risk Genes
    - Introduction
    - Endophenotypes
    - Constitutive, Conditional Knockouts, and Transgenic Models
    - Neuregulin 1
    - Disrupted in Schizophrenia 1
    - Dysbindin 1
    - 22q11.2 Chromosome Microdeletion
    - Genetic Mutant Models Related to Putative Pathophysiology
    - Glutamate Hypothesis of Schizophrenia
    - Methodological Challenges and Limitations of Genetic Mouse Models
    - Conclusions
  - Chapter 17. Dimensional Deconstruction and Reconstruction of CNV-Associated Neuropsychiatric Disorders
    - Common and Rare Genetic Variants
    - Need for Dimensional Scales of Neuropsychiatric Disorders
    - Dimensional Behavioral Measures in Mice
    - Validity of Mouse Models
    - Genetic Mouse Models of CNVs
    - Technical Issues in the Use of Genetic Mouse Models
    - Deconstructing CNV Mouse Models of Neuropsychiatric Disorders
    - Bridging Behavioral Dimensions to Neurobiological Phenotypes
    - Reconstructing Dimensional Phenotypes of CNVs
  - Chapter 18. Genetic Rat Models for Schizophrenia
    - Introduction
    - Animal Models for Schizophrenia
    - Genetic Modeling in Rats
    - Forward Genetic Rat Models
    - Reverse Genetic Rat Models
    - Genetic Rat Models for Schizophrenia: Some Examples
    - Conclusions and the Road Ahead
- Gene–Gene and Gene–Environment Models
  - Chapter 19. Modeling Gene–Gene Interactions in Schizophrenia
    - Introduction
    - Genetics of Schizophrenia
    - Gene–Gene Interactions: Closing the “Missing Heritability” Gap
    - Gene–Gene Interactions and Schizophrenia: Evidence from Clinical and Neuroimaging Studies
    - Translational Genetic Approaches for Studying Schizophrenia
    - Measuring Schizophrenia in Mice
    - Gene–Gene Interactions and Schizophrenia: Evidence from Mutant Mouse Models
    - Conclusions
  - Chapter 20. Modeling Gene–Environment Interaction in Schizophrenia
    - Introduction
    - Genes and Environment in Schizophrenia
    - Gene–Environment Interplay in Schizophrenia
    - Animal Models of GEI Relevant to Schizophrenia
    - Summary
    - Future Prospects
  - Chapter 21. Rodent Models of Multiple Environmental Exposures with Relevance to Schizophrenia
    - Introduction
    - Prenatal Infection × Postnatal Stress
    - Prenatal Infection × Adolescent Cannabis Intake
    - Prenatal Infection × Prenatal Iron Deficiency
    - Cesarean Section × Perinatal Anoxia
    - Neonatal × Adolescent Stress
    - Concluding Remarks
- Cell Models
  - Chapter 22. Synaptic Abnormalities and Neuroplasticity: Molecular Mechanisms of Cognitive Dysfunction in Genetic Mouse Models of Schizophrenia
    - Introduction
    - Dendritic Spines Influence Cognitive Function
    - Dendritic Spines and Schizophrenia
    - Genetic Mouse Models of Schizophrenia
    - NRXN1
    - 22q11
    - MIR137
    - NR1
    - RELN
    - DISC1
    - NRG1/ERRB
    - KALRN
    - DTNBP1
    - PAK
    - Conclusion
  - Chapter 23. hiPSC Models Relevant to Schizophrenia
    - Introduction
    - Existing Cell-Based Models
    - Reprogramming Overview
    - Overview of Neuronal Differentiation
    - Human-Induced Pluripotent Stem Cell Models of SCZ
    - Adaptation to High-Throughput Technologies
  - Chapter 24. Alternative Human Cell Models for Neuropsychiatric Research: Induced Neuronal Cells, Olfactory Epithelium, and Related Resources
    - Introduction
    - Cell Models Based on Cell Fate Conversion: Induced Neuronal Cells and Their Relatives
    - OE and Derived Cells: Cell Models Free from Genetic Manipulation
    - Future Perspectives
    - Conclusions
  - Chapter 25. Astrocytes as Pharmacological Targets in the Treatment of Schizophrenia: Focus on Kynurenic Acid
    - Introduction
    - Kynurenic Acid in the Brain: Multiple Receptor Targets
    - The Kynurenine Pathway of Tryptophan Metabolism
    - Brain Kynurenic Acid Synthesis: Focus on Astrocytes and KAT II
    - Causes and Effects of KYNA Fluctuations in the Brain
    - Behavioral Effects of Moderate KYNA Fluctuations in the Brain
    - Kynurenic Acid and Cognitive Deficits in Schizophrenia
    - Pharmacological Approaches to Reduce Excessive KYNA Function in the Brain
    - Future Perspectives
- Molecular Studies
  - Chapter 26. Dimensions of GSK3 Monoamine-Related Intracellular Signaling in Schizophrenia
    - Introduction
    - GSK3 Regulating Pathways
    - GSK3 in Schizophrenia
    - Regulation of GSK3 by Antipsychotics
    - How GSK3 Affects Behavior
    - Biomarkers
    - Conclusions
  - Chapter 27. Hormones and Schizophrenia
    - Introduction
    - History
    - The HPG Axis and Schizophrenia
    - Prolactin and Schizophrenia
    - Thyroid Hormones and Schizophrenia
    - The Hypothalamic-Pituitary-Thyroid Axis
    - Conclusion
  - Chapter 28. Role of Redox Dysregulation in White Matter Anomalies Associated with Schizophrenia
    - Introduction
    - Imbalance of Redox Homeostasis in Schizophrenia
    - White Matter Impairments in Schizophrenia
    - Role of Redox Imbalance in Myelin Impairments Associated with Schizophrenia
    - Conclusions and Perspectives
  - Chapter 29. Role of Immune and Autoimmune Dysfunction in Schizophrenia
    - Introduction
    - Primer on Basic Immunology
    - Historical Perspective of the Immune–Schizophrenia Association
    - Where are We Today with the Adaptive Immune Hypotheses?
    - Moving toward Innate Immunity and “The Process of Immune Activation”
    - Concluding Remarks
  - Chapter 30. Future Directions
    - Overview
    - Confronting the Challenges
Index

Mikhail Pletnikov

Mikhail V. Pletnikov, M.D., Ph.D. is Professor in Department of Psychiatry at Johns Hopkins University School of Medicine. He received his M.D. in 1986 from I.M. Sechenov Moscow Medical Academy, Moscow, Russia and his Ph.D. in Normal Physiology in 1990 from P.K. Anokhin Institute of Normal Physiology, Moscow, Russia. He did his post-doctoral training under Dr Timothy H. Moran (1996-1999) at the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and under Dr Kathryn M. Carbone (1996-1999) at the laboratory of pediatric and respiratory viral infections, the Center for Biologics Evaluation and Research (CBER), the U.S. Food and Drug Administration. He joined faculty in Department of Psychiatry at Johns Hopkins University in 1999. His current research interests focus on understanding pathogenesis of human psychiatric disease with neurodevelopmental origin, e.g., schizophrenia and autism with particular emphasis on a role of gene-environment interactions and the neuro-immune interplay in the complex pathogenesis of psychiatric conditions. Dr Pletnikov is also Director of the Behavioral Core at the School of Medicine.

Affiliations and expertise

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

John Waddington

John Waddington is currently Professor of Neuroscience in Molecular and Cellular Therapeutics at the Royal College of Surgeons in Ireland (RCSI), Dublin. He received a BA in Natural Sciences from the University of Cambridge, and a PhD in Neuropharmacology followed by a DSc in Neuroscience from the University of London. After working with the UK Medical Research Council in the Division of Psychiatry at their Clinical Research Centre, he joined RCSI and became Chairman of Clinical Pharmacology in 2004. In 2003, he became the first person from RCSI to be elected to membership of the Royal Irish Academy; he has received the Lilly Neuroscience Award from the International College of Neuropsychopharmacology and the Award for Outstanding Achievement in Basic Science from the Schizophrenia International Research Society. His research is focused on the pathobiology and psychopharmacology of psychotic illness, mutant models of schizophrenia and other psychoses, and the pathobiology, psychopharmacology and mutant modelling of movement disorder.

Affiliations and expertise

Molecular & Cellular Therapeutics, Royal College of Surgeons, Dublin, Ireland