Associate Editors
List of Boxes
Sections
List of Contributors
Eighth Edition Acknowledgments and History
Preface to the Eighth Edition
Part I: Cellular Neurochemistry and Neural Membranes
Chapter 1. Cell Biology of the Nervous System
Overview
Cellular Neuroscience is the Foundation of Modern Neuroscience
Neurons: Common Elements and Diversity
Macroglia: More than Meets the Eye
Microglia
Blood–Brain Barriers and the Nervous System
The Neurovascular Unit Includes Multiple Components
Acknowledgements
References
Chapter 2. Cell Membrane Structures and Functions
Phospholipid Bilayers
Membrane Proteins
Biological Membranes
References
Chapter 3. Membrane Transport
Introduction
Primary Active Transport (P-Type) Pumps
Na,K-Adenosinetriphosphatase (Na,K-ATPase)
Ca Adenosinetriphosphatases and Na,Ca Antiporters
The Primary Plasma Membrane Ca Transporter (PMCA)
Smooth Endoplasmic Reticulum Calcium Pumps (SERCA)
Other P-Type Transporters
V0V1 Proton Pumps
ATP-Binding Cassettes
Secondary Active Transport
General Physiology of Neurotransmitter Uptake and Storage
The Cation Antiporters
The Anion Antiporters
Facilitated Diffusion: Aquaporins and Diffusion of Water
Facilitated Diffusion of Glucose and Myoinositol
References
Chapter 4. Electrical Excitability and Ion Channels
Membrane Potentials and Electrical Signals in Excitable Cells
Action Potentials in Electrically Excitable Cells
Functional Properties of Voltage-Gated Ion Channels
The Voltage-Gated Ion Channel Superfamily
The Molecular Basis for Ion Channel Function
Ion Channel Diversity
Acknowledgments
References
Chapter 5. Lipids
Introduction
Properties of Brain Lipids
Complex Lipids
Analysis of Brain Lipids
Brain Lipid Biosynthesis
Genes for Enzymes Catalyzing Synthesis and Degradation of Lipids
Lipids in the Cellular Milieu
Summary
Acknowledgments
References
Chapter 6. The Cytoskeleton of Neurons and Glia
Introduction
Molecular Components of the Neuronal Cytoskeleton
Ultrastructure and Molecular Organization of Neurons and Glia
Cytoskeletal Structures in the Neuron Have Complementary Distributions and Functions
Summary
References
Chapter 7. Intracellular Trafficking
Introduction
General Mechanisms of Intracellular Membrane Trafficking in Mammalian Cells Include Both Universal and Highly Specialized Processes
Fundamentals of Membrane Trafficking are Based on a set of Common Principles
The biosynthetic Secretory Pathway Includes Synthetic, Processing, Targeting and Secretory Steps
The Endocytic Pathway Plays Multiple Roles in Cells of the Nervous System
Synaptic Vesicle Trafficking is a Specialized Form of Regulated Secretion and Recycling Optimized for Speed and Efficiency
Acknowledgments
References
Chapter 8. Axonal Transport
Introduction
Neuronal Organelles in Motion
Discovery and Development of the Concept of Fast and Slow Components of Axonal Transport
Fast Axonal Transport
Slow Axonal Transport
Molecular Motors: Kinesin, Dynein and Myosin
AXONAL Transport and Neuropathology
Acknowledgments
References
Chapter 9. Cell Adhesion Molecules
Overview
Immunoglobulin Superfamily
Cadherins
Integrins
Cooperation and Crosstalk between Cell Adhesion Molecules
Summary
References
Chapter 10. Myelin Structure and Biochemistry
The Myelin Sheath
Characteristic Composition of Myelin
Acknowledgments
References
Chapter 11. Energy Metabolism of the Brain
Introduction
Substrates for Cerebral Energy Metabolism
Age and Development Influence Cerebral Energy Metabolism
Fueling Brain: Supply–Demand Relationships and Cerebral Metabolic Rate
Metabolism in the Brain is Highly Compartmentalized
Glycolysis: Conversion of Glucose to Pyruvate
Glycogen is Actively Synthesized and Degraded in Astrocytes
The Pentose Phosphate Shunt has Essential Roles in Brain
The Malate–Aspartate Shuttle has a key Role in Brain Metabolism
There is Active Metabolism of Lactate in Brain
Major Functions of the Tricarboxylic Acid (TCA) Cycle: Pyruvate Oxidation to CO2, NADH/FADH2 Formation for ATP Generation and Synthesis of Glutamate and Aspartate
Mitochondrial Heterogeneity: Differential Distribution of Many TCA Cycle Enzymes and Components of Oxidative Phosphorylation in Neuronal and Glial Mitochondria
Glutamate–Glutamine Metabolism is Linked to Energy Metabolism
Metabolic Studies in Brain: Imaging and Spectroscopy
Relation of Energy Metabolism to Pathological Conditions in the Brain
Acknowledgments
References
Part II: Intercellular Signaling
Chapter 12. Synaptic Transmission and Cellular Signaling: An Overview
Synaptic Transmission
Cellular Signaling Mechanisms
Acknowledgments
References
Chapter 13. Acetylcholine
Introduction
Synthesis, Storage and Release of Acetylcholine: Distribution of Cholinergic Pathways
Enzymatic Breakdown of Acetylcholine
Nicotinic Cholinergic Receptors
Muscarinic Cholinergic Receptors
References
Chapter 14. Catecholamines
Overview of Catecholamines
Neuroanatomy
Adrenergic Receptors
Agonist-Induced Downregulation
Repeated Antagonist Treatment
References
Chapter 15. Serotonin
Serotonin, The Neurotransmitter
Serotonin Receptors
References
Chapter 16. Histamine
Introduction
Histamine: The Molecule and the Messenger
Histaminergic Cells of the Central Nervous System: Anatomy and Morphology
Dynamics of Histamine in the Brain
Molecular Sites of Histamine Action
Histamine Actions on the Nervous System
Significance of Brain Histamine for Drug Action
References
Chapter 17. Glutamate and Glutamate Receptors
The Amino Acid Glutamate is the Major Excitatory Neurotransmitter in the Brain
Brain Glutamate is Derived from Blood-Borne Glucose and Amino Acids that Cross the Blood–Brain Barrier
Glutamine is an Important Immediate Precursor for Glutamate: The Glutamine Cycle
Synaptic Vesicles Accumulate Transmitter Glutamate by Vesicular Glutamate Transporters
Is Aspartate a Neurotransmitter?
Long-Term Potentiation or Depression of Glutamatergic Synapses May Underlie Learning
The Neuronal Pathways of the Hippocampus are Essential Structures for Memory Formation
Ionotropic and Metabotropic Glutamate Receptors are Principal Proteins at the Postsynaptic Density
Three Classes of Ionotropic Glutamate Receptors are Identified
Glutamate Produces Excitatory Postsynaptic Potentials
Metabotropic Glutamate Receptors Modulate Synaptic Transmission
Glutamate Receptors Differ in their Postsynaptic Distribution
Proteins of the Postsynaptic Density Mediate Intracellular Effects of Glutamate Receptor Activation
Dendritic Spines are Motile, Changing their Shape and Size in Response to Synaptic Activity within Minutes
Sodium-Dependent Symporters in the Plasma Membranes Clear Glutamate from the Extracellular Space
Sodium-Dependent Glutamine Transporters in Plasma Membranes Mediate the Transfer of Glutamine from Astrocytes to Neurons
Excessive Glutamate Receptor Activation may Mediate Certain Neurological Disorders
References
Chapter 18. GABA
Introduction
GABA Synthesis, Release and Uptake
GABA Receptor Physiology and Pharmacology
Structure and Function of GABA Receptors
GABA is the Major Rapidly Acting Inhibitory Neurotransmitter in Brain
References
Chapter 19. Purinergic Signaling
Nomenclature of Purines and Pyrimidines
Purine Release
Purinergic Receptors
Effects of Purines in the Nervous System
Disorders of the Nervous System—Purines and Pain: A1R, P2X and P2Y Receptors
Disorders of the Nervous System: Adenosine Kinase and the Adenosine Hypothesis of Epilepsy
Disorders of the Nervous System: Parkinson’s Disease and A2A Antagonists
Concluding Comments
References
Chapter 20. Peptides
Neuropeptides
Neuropeptide Receptors
Neuropeptide Functions and Regulation
Peptidergic Systems in Disease
References
Part III: Intracellular Signaling
Chapter 21. G Proteins
Heterotrimeric G Proteins
Small G Proteins
Other Features of G Proteins
References
Chapter 22. Cyclic Nucleotides in the Nervous System
Introduction: Second Messengers
Adenylyl Cylcases
Guanylyl Cyclases
Phosphodiesterases
Spatiotemporal Integration and Regulation of Cyclic Nucleotide Signaling in Neurons
Conclusion and Future Perspective
References
Chapter 23. Phosphoinositides
Introduction
The Inositol Lipids
The Inositol Phosphates
Diacylglycerol
Phosphoinositides and Cell Regulation
References
Chapter 24. Calcium
The Calcium Signal in Context
Calcium Measurement
Calcium Homeostasis at the Plasma Membrane
Cellular Organelles and Calcium Pools
Ca2+ Signaling Begins in Microdomains
Local and Global Ca2+ Signaling: Integrative Roles for Astrocytes?
Conclusions
References
Chapter 25. Serine and Threonine Phosphorylation
Protein Phosphorylation is a Fundamental Mechanism Regulating Cellular Functions
Protein Ser/Thr Kinases
Protein Ser/Thr Phosphatases
Common strategies used for the evaluation of neuronal functions of protein kinases and phosphatases
Neuronal Phosphoproteins
Protein Phosphorylation is a Fundamental Mechanism Underlying Synaptic Plasticity and Memory Functions
Protein Phosphorylation in Human Neuronal Disorders
Acknowledgments
References
Chapter 26. Tyrosine Phosphorylation
Tyrosine Phosphorylation in the Nervous System
Protein Tyrosine Kinases
Protein Tyrosine Phosphatases
Role of Tyrosine Phosphorylation in the Nervous System
References
Chapter 27. Transcription Factors in the Central Nervous System
The Transcriptional Process
Regulation of Transcription by Transcription Factors
Glucocorticoid and Mineralocorticoid Receptors as Transcription Factors
cAMP Regulation of Transcription
The Role of Transcription Factors in Cellular Phenotype
The Transcriptome Dictates Cellular Phenotype
Transcription as a Target for Drug Development
References
Part IV: Growth, Development and Differentiation
Chapter 28. Development of the Nervous System
Introduction
Early Embryology of the Nervous System
Spatial Regionalization
Neurogenesis and Gliogenesis
PNS Development and Target Interactions
Axon Guidance Contributes to Correct Connections
Synapse Formation
Activity and Experience Shape Long-Lasting Connections
Summary
References
Chapter 29. Growth Factors
Introduction: What is a Growth Factor?
Neurotrophins
Regulation of Neurotrophin Expression
Proneurotrophins
Neurotrophin Receptors
Glial Cell line–Derived Neurotrophic Factor (GDNF)
GFL Receptors
Neuregulins
Neurotrophic Cytokines
Summary and Conclusions
References
Chapter 30. Stem Cells in the Nervous System
Introduction/Overview
Stem Cells are Multipotent and Self-Renewing
Neural Stem Cells Contribute to Neurons and Glia During Normal Development
Stem Cells can be Identified Antigenically and Functionally
Stem Cells Offer Potential for Repair in the Adult Nervous System
References
Chapter 31. Formation and Maintenance of Myelin
Introduction
Schwann Cell Development
Oligodendrocyte Development
Regulation of Myelination
Developmental and Metabolic Aspects of Myelin
Genetic Disorders of Myelination
Myelin Maintenance
Remyelination
Acknowledgments
References
Chapter 32. Axonal Growth in the Adult Mammalian Nervous System: Regeneration and Compensatory Plasticity
Introduction
Regeneration in the Peripheral Nervous System
Regeneration in the Central Nervous System
Central Nervous System Injury and Compensatory Plasticity
Summary
Acknowledgments
References
Part V: Cell Injury and Inflammation
Chapter 33. Molecular Mechanisms and Consequences of Immune and Nervous System Interactions
Introduction
Distinguishing Friend from FOE
The Nervous System Regulates Both Innate and Adaptive Immunity
Immune Privilege Is Not Immune Isolation: The CNS as an Immune-Active Organ
Immune-Regulated Changes in Neuronal Function and Mammalian Behavior
Summary: Manipulating Neuroimmune Interactions
References
Chapter 34. Neuroinflammation
Neuroinflammation: Introduction
The Highly Regulated Activation of Microglia and Phagocytosis
Microglial Dysfunction During Aging
Protein Aggregation
Cytokines/Chemokines
Lipid Mediator Pathways in Neuroinflammation
Ischemia-Reperfusion Damage
The Interface Between Inflammation and the Immune System in the CNS
Mitochondria: A Connection Between Inflammation and Neurodegeneration
Neuroprotective Signaling Circuits
References
Chapter 35. Brain Ischemia and Reperfusion: Cellular and Molecular Mechanisms in Stroke Injury
Brain Responses to Ischemia
Injury in the Ischemic Phase
Brain Injury During the Reperfusion Phase: Free Radicals in Ischemia–Reperfusion Injury
Breakdown of the Neurovascular Unit and Brain Edema
Neuroprotection Signaling and Resolution of Inflammation: Mechanisms
Potential Therapeutic Strategies for Acute Ischemic Stroke
Acknowledgments
References
Chapter 36. Lipid Mediators: Eicosanoids, Docosanoids and Platelet-Activating Factor
Storage of Lipid Messengers in Neural Membrane Phospholipids
Phospholipases A2
Eicosanoids
Platelet-Activating Factor
Cyclooxygenases
Lipoxygenases
Diacylglycerol Kinases
Lipid Signaling in Neuroinflammation
Docosahexaenoic Acid
Lipid Peroxidation and Oxidative Stress
Docosanoids
Neuroprotectin D1: A Docosahexaenoic-Acid–Derived Mediator
The Future of Neurolipidomic Signaling
References
Chapter 37. Apoptosis and Necrosis
Distinguishing Features of Apoptosis and Necrosis
Apoptosis
Necrosis
Targeting Apoptosis and Necrosis in Neurological Disorders
References
Part VI: Inherited and Neurodegenerative Diseases
Chapter 38. Peripheral Neuropathy: Neurochemical and Molecular Mechanisms
Introduction
Peripheral Nerve Organization
Genetically Determined Neuropathies
Diabetic Neuropathy
Autoimmune Neuropathies
Other Causes of Peripheral Nerve Disorders
Axon Degeneration and Protection
References
Chapter 39. Diseases Involving Myelin
General Classification
Acquired Immune-Mediated and/or Infectious Diseases of Myelin
Genetically Determined Disorders of Myelin
Other Diseases Primarily Involving Myelin
Disorders Primarily Affecting Neurons with Secondary Involvement of Myelin
Repair in Demyelinating Diseases
Acknowledgments
References
Chapter 40. The Epilepsies: Phenotypes and Mechanisms
Epilepsy is a Common Neurological Disorder
Terminology and Classification
Mechanisms of Antiseizure Drugs
Genetics of Epilepsy
References
Chapter 41. Genetics of Neurodegenerative Diseases
Genetic Aspects of Common Neurodegenerative Diseases
Alzheimer’s Disease
Parkinson’s Disease
Dementia with Lewy Bodies
Frontotemporal Dementia
Amyotrophic Lateral Sclerosis
Neurodegenerative Triplet Repeat Disorders
Creutzfeld-JaKob Disease and other Prion Diseases
Concluding Remarks
References
Chapter 42. Disorders of Amino Acid Metabolism
Introduction
Disorders of Branched-Chain Amino Acids: Maple Syrup Urine Disease
Disorders of Phenylalanine Metabolism: Phenylketonuria
Disorders of Glycine Metabolism: Nonketotic Hyperglycinemia
Disorders of Sulfur Amino Acid Metabolism: Homocystinuria
The Urea Cycle Defects
Disorders of Glutathione Metabolism
Disorders of -Aminobutyric Acid Metabolism
Disorders of N-Acetyl Aspartate Metabolism
References
Chapter 43. Inborn Metabolic Defects of Lysosomes, Peroxisomes, Carbohydrates, Fatty Acids and Mitochondria
Lysosomal Storage Diseases
Peroxisomal Diseases
Classification of Peroxisomal Diseases
Therapy of Peroxisomal Diseases
Diseases of Carbohydrate and Fatty Acid Metabolism
Diseases of Mitochondrial Metabolism
Acknowledgments and Dedication
References
Chapter 44. Disorders of Muscle Excitability
Organization of the Neuromuscular Junction
Excitation and Contraction of the Muscle Fiber
Genetic Disorders of the Neuromuscular Junction
Hereditary Diseases of Muscle Membranes
Immune Diseases of Muscle Excitability
Toxins and Metabolites that Alter Muscular Excitation
References
Chapter 45. Motor Neuron Diseases
Amyotrophic Lateral Sclerosis Is the Most Common Adult-Onset Motor Neuron Disease
Models of Motor Neuron Disease Induced by Experimental Nerve Injury Have been Instructive
Selected Genetic Models of Relevance to ALS and Other Motor Neuron Diseases Have been Identified or Generated
Available Genetic Mouse Models Will Aid in Discovering Disease Mechanisms and Novel Means of Therapy
Acknowledgments
References
Chapter 46. Neurobiology of Alzheimer’s Disease
Alzheimer’s Disease is the Most Prevalent Neurodegenerative Disease of the Elderly
Conclusions
Acknowledgments
References
Chapter 47. Synucleinopathies and Tauopathies
Introduction
Synucleins
Parkinson’s Disease and Other Lewy Body Diseases
Multiple System Atrophy
Synthetic α-Synuclein Filaments
Animal Models of Synucleinopathies
Synucleinopathies—Outlook
Microtubule-Associated Protein Tau
Tau and Alzheimer’s Disease
Other Tauopathies
MAPT Mutations Causing Tauopathy
Relevance for Other Tauopathies
Synthetic Tau Filaments
Animal Models of Human Tauopathies
Tauopathies—Outlook
References
Chapter 48. Cellular and Molecular Basis of Neurodegeneration in the CAG–Polyglutamine Repeat Diseases
Introduction to the CAG–Polyglutamine Repeat Diseases
Expanded Polyglutamine Tracts Promote Protein Misfolding to Drive Neurotoxicity
The Role of Protein turnover Pathways in Polyglutamine Disease Pathogenesis
The Importance of Normal Function in the Polyglutamine Repeat Diseases
RNA Toxicity in the Polyglutamine Repeat Diseases?
Gene Silencing is a Promising Therapy for Polyglutamine Repeat Disease
References
Chapter 49. Neurotransmitters and Disorders of the Basal Ganglia
Anatomy and Physiology of the Basal Ganglia
Disorders that Involve Basal Ganglia Dysfunction
Conclusion
References
Chapter 50. Molecular Basis of Prion Diseases
Introduction
Prion Diseases are Biologically Unique
Animal Prion Diseases
Human Prion Diseases
Prion Disease Pathology and Pathogenesis
The Protein-Only Hypothesis of Prion Propagation
Characterization of PrPC
Characterization of PrPSc
The Molecular Basis of Prion Strain Diversity
Prion Transmission Barriers
Future Perspectives
References
Part VII: Sensory Transduction
Chapter 51. Molecular Biology of Vision
Structure and Development of the Visual System
Photoreceptors and Phototransduction
Signaling Downstream of Photoreceptors
Recycling of Phototransduction Molecules
Retinal Neurodegeneration
References
Chapter 52. Molecular Basis of Olfaction and Taste
Olfaction
Taste
Acknowledgments
References
Chapter 53. Molecular Biology of Hearing and Balance
General Features of Mechanotransduction
Non-Vertebrate Model Systems
Hair Cells
Hair Cells in the Inner Ear
Balance: Vestibular Organs
Hearing: Cochlea
Conclusions
References
Chapter 54. Pain
Nociceptive Versus Clinical Pain
Nociceptors are First Responders
Pain Transmission in the Spinal Cord
Brainstem, Thalamus and Cortex
Opioid Analgesia
Cannabinoids
Inflammatory Pain
Neuropathic Pain
Genetic Factors
Conclusion
Acknowledgments
References
Part VIII: Neural Processing and Behavior
Chapter 55. Endocrine Effects on the Brain and Their Relationship to Behavior
Introduction
Behavioral Control of Hormonal Secretion
Classification of Hormonal Effects
Biochemistry of Steroid and Thyroid Hormone Actions
Intracellular Steroid Receptors: Properties and Topography
Membrane Steroid Receptors and Signaling Pathways
Biochemistry of Thyroid Hormone Actions on Brain
Diversity of Steroid-Hormone Actions on the Brain
Summary
References
Chapter 56. Learning and Memory
Brief History of Memory Research in Humans
Divisions of Memory
Molecular Mechanisms of Learning
Molecular Mechanisms of Memory Consolidation and Storage
Neural Population-Level Memory Traces and Their Organizing Principles
References
Chapter 57. The Neurochemistry of Sleep and Wakefulness
Sleep Phenomenology and Function: The Search for Neurochemical Substrates
Development of Sleep Disorders Medicine and Sleep Neurobiology
Monoamines
Acetylcholine
Dopamine
Hypocretins/Orexins
Amino Acids
Adenosine
Conclusions and Future Directions
References
Chapter 58. The Neurochemistry of Schizophrenia
Clinical Aspects of Schizophrenia
Brain Imaging
Cellular and Molecular Studies
Summary
References
Chapter 59. The Neurochemistry of Autism
Clinical Aspects of Autism Spectrum Disorders (ASDs)
Genetic Studies
Neurochemical Studies
Conclusion
References
Chapter 60. Neurobiology of Severe Mood and Anxiety Disorders
Mood Disorders
Neurotransmitter and Neuropeptide Systems and the Pathophysiology of Mood Disorders
Neuroanatomical and Neuropathological Correlates of Mood Disorders
Intracellular Signaling Pathways
Anxiety Disorders
The Neurochemistry of Fear and Anxiety
Intracellular Targets for Anxiety Disorders
Future Directions and the Development of Novel Therapeutics
References
Chapter 61. Addiction
General Principles
Neuronal Circuitry of Addiction
Opiates
Psychomotor Stimulants
Cannabinoids (Marijuana)
Nicotine
Ethanol, Sedatives and Anxiolytics
Hallucinogens and Dissociative Drugs
Addiction and Neuronal Plasticity Share Common Cellular Mechanisms
Acknowledgments
References
Glossary
Index
