Excerpt

Basic Neurochemistry had its origin in the Conference on Neurochemistry Curriculum initiated and organized by R. Wayne Albers, Robert Katzman and George J. Siegel under the sponsorship of the National Institute for Neurological Diseases and Stroke, June 19 and 20, 1969, Bronx, New York. At this conference, a group of 30 neuroscientists constructed a syllabus outline delineating the scope of a neurochemistry curriculum appropriate for medical, graduate and postgraduate neuroscience students. Out of this outline grew the first edition, edited by R. Wayne Albers, George J. Siegel, Robert Katzman and Bernard W. Agranoff. It was anticipated that the book would evolve with the emergence of the field and would stimulate continuing reappraisal of the scientific and educational aspects of neurochemistry.

Contents

• Acknowledgments
• Preface
• Part One. Cellular Neurochemistry and Neural Membranes
  • Chapter 1. Neurocellular Anatomy
    Cedric S Raine.
    • Understanding Neuroanatomy is Necessary to Study Neurochemistry
      • Diverse cell types are organized into assemblies and patterns such that specialized components are integrated into a physiology of the whole organ
    • Characteristics of the Neuron
      • General structural features of neurons are the perikarya, dendrites and axons
      • Neurons contain the same intracellular components as do other cells
      • Molecular markers can be used to identify neurons
    • Characteristics of Neuroglia
      • Virtually nothing can enter or leave the central nervous system parenchyma without passing through an astrocytic interphase
      • Oligodendrocytes are myelin-producing cells in the central nervous system
      • The microglial cell plays a role in phagocytosis and inflammatory responses
      • Ependymal cells line the brain ventricles and the spinal cord central canal
      • The Schwann cell is the myelin-producing cell of the peripheral nervous system
      • The extracellular space between peripheral nerve fibers is occupied by bundles of collagen fibrils, blood vessels and endoneurial cells
    • Acknowledgments
    • References
  • Chapter 2. Cell Membrane Structures and Functions
    R Wayne Albers.
    • Phospholipid Bilayers
      • Cells are separated from their environment by lipid bilayers
      • Amphipathic molecules form bilayered lamellar structures spontaneously if they have an appropriate geometry
      • Most bilayer phospholipids are physically constrained by association with integral membrane proteins
      • Diffusional flow of water directly through lipid bilayers largely accounts for the water permeability of most cell membranes
      • The head-group regions of phospholipid monolayers facilitate lateral diffusion of protons and possibly of other ions
    • Membrane Proteins
      • Integral proteins have transmembrane domains that insert directly into the lipid bilayer
      • Transmembrane domains are usually α helices
      • Proteins with one transmembrane domain may have soluble domains at either or both surfaces
      • Transmembrane helices are usually closely packed
      • The fluidity of the lipid bilayer permits dynamic interactions among membrane proteins
      • Mechanical functions of cells require interactions between integral membrane proteins and the cytoskeleton
      • Certain transmembrane glycoproteins can mediate interactions between the cytoskeleton and the extracellular matrix
      • Covalently attached lipids often participate in binding proteins to membranes
      • Membrane associations can occur by selective protein binding to lipid head groups
    • Membrane Dynamics
      • Nascent membrane proteins must be inserted through the bilayer and transported to their destinations
      • “Molecular chaperones” are frequently required to mediate correct protein folding
      • Newly synthesized plasma membrane proteins travel from the endoplasmic reticulum through a succession of Golgi compartments
      • Some membrane proteins can be selectively tagged by ubiquitin for recycling or degradation
    • References
  • Chapter 3. Lipids
    Bernard W Agranoff, Joyce A Benjamins, and Amiya K Hajra.
    • Properties of Brain Lipids
      • Lipids have multiple functions in brain
      • Membrane lipids are amphiphilic molecules
      • The hydrophobic components of many lipids consist of either isoprenoids or fatty acids and their derivatives
      • Isoprenoids have the unit structure of a five-carbon branched chain
      • Brain fatty acids are long-chain carboxylic acids which may contain one or more double bonds
    • Complex Lipids
      • Glycerolipids are derivatives of glycerol and fatty acids
      • In sphingolipids, the long-chain aminodiol sphingosine serves as the lipid backbone
    • Analysis of Brain Lipids
      • Chromatographic methods are employed to analyze and classify brain lipids
    • Brain Lipid Biosynthesis
      • Acetyl coenzyme A is the precursor of both cholesterol and fatty acids
      • Phosphatidic acid is the precursor of all glycerolipids
      • Sphingolipids are biosynthesized by adding head groups to the ceramide moiety
    • Lipids in the Cellular Milieu
      • Lipids are transported between membranes
      • Membrane lipids may be asymmetrically oriented
      • Some proteins are bound to membranes by covalently linked lipids
      • Lipids have multiple roles in cells
    • References
    • General References
  • Chapter 4. Myelin Formation, Structure and Biochemistry
    Pierre Morell and Richard H Quarles.
    • The Myelin Sheath
      • Myelin facilitates conduction
      • Myelin has a characteristic ultrastructure
      • Myelin is an extension of a cell membrane
      • Myelin can be isolated in high yield and purity by conventional methods of subcellular fractionation
    • Characteristic Composition of Myelin
      • Central nervous system myelin is enriched in certain lipids
      • Peripheral and central nervous system myelin lipids are qualitatively similar
      • Central nervous system myelin contains some unique proteins
      • Peripheral myelin contains some unique proteins and some shared with central nervous system myelin
      • Myelin contains enzymes that function in metabolism and possibly ion transport
    • Developmental Biology of Myelin
      • Myelination follows the order of phylogenetic development
      • The composition of myelin changes during development
      • Myelin subfractions may represent transitional forms of myelin
    • Synthesis and Metabolism of Myelin
      • Synthesis of myelin components is rapid during deposition of myelin
      • Sorting and transport of lipids and proteins take place during myelin assembly
      • Myelin components exhibit great heterogeneity of metabolic turnover
    • Molecular Architecture of Myelin
    • Acknowledgments
    • References
  • Chapter 5. Membrane Transport
    R Wayne Albers and George J Siegel.
    • Transport Processes
      • Ion gradients are generated across cell membranes by transport proteins and are required for some of the most basic neural functions
      • Concentration gradients across membranes result from two opposing processes: diffusion and active transport
      • Membrane-transport processes store energy, whereas channel-mediated processes dissipate energy
    • The ATP-Dependent Na⁺,K⁺ Pump
      • Three different α-subunit isoforms are specified by three different genes in mammals
      • A major fraction of cerebral energy production is required for extrusion of intracellular Na⁺ that enters during excitation and secondary transport
      • Coupled active transport of Na⁺ and K⁺ results from a cycle of conformational transitions of the transport protein
      • The Na⁺,K⁺ pump and the cell-membrane potential interact with each other
      • Phosphorylation of the catalytic subunit by cAMP-dependent protein kinase reduces pump activity
      • The isoforms of the α-subunit genes differ with respect to regulatory DNA base sequences in their 5′-flanking regions
    • ATP-Dependent Ca²⁺ Pumps
      • ATP-dependent Ca²⁺ pumps and Na⁺,Ca²⁺ antiporters act in concert to maintain a low concentration of free cytosolic Ca²⁺
    • Other P-Type Cation Transporters
    • Mitochondrial and Vacuolar Atpases
      • F-type ATPases occur as part of the F₁F₀ ATP synthase of mitochondria, chloroplasts and prokaryocyte plasma membranes
      • Vacuolar ATP-dependent proton transporters occur in Golgi-derived membranes
    • ATP-Binding Cassette Proteins
      • The ATP-binding cassette proteins are members of a superfamily with functions that encompass transport, ion conductance and regulation
    • Secondary Transport Systems
      • Secondary active-transport systems mediate diverse neural functions
      • Rapid clearance of K⁺ from the extracellular space is critical because high extracellular K⁺ depolarizes neurons
      • An outwardly directed Cl⁻ pump is necessary for the inhibitory, that is, hyperpolarizing, functions of GABA and glycine-gated ion channels
      • Intracellular pH in brain is regulated by Na⁺,H⁺ antiporters, anion antiporters and Na⁺, HCO⁻₃ symporters
      • Cell-volume regulation involves control of the content of osmotically active impermeant molecules and ions
    • Uncoupled Transporters
    • References
  • Chapter 6. Electrical Excitability and Ion Channels
    Bertil Hille and William A Catterall.
    • Electrical Phenomena in Excitable Cells
      • All excitable cells have a membrane potential
      • Electrical signals recorded from cells are basically of two types: stereotyped action potentials characteristic of each cell type and a variety of slow potentials
    • The Ionic Hypothesis and Rules of Ionic Electricity
      • How do membrane potentials arise?
      • Equilibrium potential is the membrane potential at which there are no net ion movements
      • Real cells are not at equilibrium
      • During excitation, ion channels open or close, ions move and the membrane potential changes
      • Transport systems also may produce membrane potentials
    • Electrically Excitable Cells
      • Permeability changes of the action potential
      • Gating mechanisms for Na⁺ and K⁺ channels in the axolemma are voltage dependent
      • The action potential is propagated by local spread of depolarization
      • Membranes at nodes of Ranvier are characterized by high concentrations of Na⁺ channels
      • A wide repertoire of voltage-sensitive channels is found among cell types
    • Functional Properties of Voltage-Gated Ion Channels
      • Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane
      • Voltage-dependent gating requires voltage-dependent conformational changes in the protein component(s) of ion channels
      • Pharmacological agents acting on ion channels help define their functions
    • Molecular Components of Voltage-Gated Ion Channels
      • Radiolabeled neurotoxins that act on Na⁺ channels are used as molecular probes to tag the channel proteins, allowing their identification
      • Purified Na⁺ channels are functional after reconstitution
      • Primary structures of Na⁺- channel subunits have been determined using cDNA cloning
      • Ca²⁺ channels have a similar structure to Na⁺ channels
      • K⁺ channels have been identified by genetic means
      • How do the primary structures of the ion channel subunits carry out their functions?
    • Other Channels
      • K⁺ channels have many relatives
      • There are many other kinds of ion channels
    • Acknowledgments
    • References
  • Chapter 7. Cell Adhesion Molecules
    David R Colman and Marie T Filbin.
    • Overview
      • Cell adhesion molecules comprise several “families”
    • The Immunoglobulin Gene Superfamily
      • The formation of immunoglobulin-like domains may confer characteristics important for extracellular presentation and interaction with other molecules
      • The siglecs constitute a novel subfamily of immunoglobulin-like molecules that bind to sialosides
      • Immunoglobulin-like cell adhesion molecules signal to the cytoplasm
    • The Integrin Family
      • Heterogeneity of integrin subunits increases the complexity of this family
    • The Cadherin Family
      • The classic cadherins are homophilic adhesion molecules
      • The first cadherin to be expressed in the nervous system is N-cadherin
    • Cell Adhesion Molecules and Axonal Outgrowth
      • Cell adhesion molecules influence axonal outgrowth
      • Cell adhesion molecules are responsible for axonal fasciculation
      • Cell adhesion molecules may also function in regeneration
    • Cell Adhesion Molecules in Myelination
    • Summary
    • References
  • Chapter 8. Cytoskeleton of Neurons and Glia
    Laura L Kirkpatrick and Scott T Brady.
    • Molecular Components of the Neuronal Cytoskeleton
      • The cytoskeleton is one of several biological elements that define eukaryotic cells
      • Microtubules act as both dynamic structural elements and tracks for organelle traffic
      • Neuronal and glial intermediate filaments provide support for neuronal and glial morphology
      • Actin microfilaments and the membrane cytoskeleton play critical roles in neuronal growth and secretion
    • Ultrastructure and Molecular Organization of Neurons and Glia
      • A dynamic neuronal cytoskeleton provides specialized functions in different regions of the neuron
      • Both the composition and organization of cytoskeletal elements in axons and dendrites become specialized early in differentiation
    • Cytoskeletal Structures in the Neuron Have Complementary Distributions and Functions
      • Microfilament and microtubule dynamics underlie growth cone motility and function
      • The axonal cytoskeleton may be influenced by glia
      • Levels of cytoskeletal protein expression change after injury and during regeneration
      • Alterations in the cytoskeleton are frequent hallmarks in neuropathology
      • Phosphorylation of cytoskeletal proteins is involved in both normal function and neuropathology
    • Conclusions
    • References
  • Chapter 9. Intracellular Trafficking
    Thomas C Südhof.
    • Intracellular Membrane Traffic
      • Two types of intracellular membrane traffic can be distinguished in the nervous system
      • All intracellular membrane traffic is based on the same fundamental operations
      • Synaptic membrane traffic leading to neurotransmitter release is of central importance for brain function
    • The Synaptic Vesicle Cycle in the Nerve Terminal
      • The synaptic vesicle cycle forms the basis for neurotransmitter release by the terminal
      • Active transport of neurotransmitters into synaptic vesicles is an energy-driven process that requires ATP
      • The synaptic vesicle cycle includes basic processes characteristic of all intracellular trafficking
    • Composition of Synaptic Vesicles
      • The only known function of synaptic vesicles is neurotransmitter release
      • The proteins of synaptic vesicles are divided into two classes based on function
      • Most trafficking proteins are members of gene families containing multiple isoforms
    • Characteristics of Synaptic Vesicle Exocytosis
      • The most important step in the synaptic vesicle cycle is the Ca²⁺ triggered synaptic vesicle fusion reaction
      • The Ca²⁺ triggered step that leads to neurotransmitter release occurs in less than one millisecond
      • Fusion is a complex process involving both the inner and outer leaflets of both the plasmalemma and the vesicle membrane
    • Proteins that Function in Synaptic Vesicle Exocytosis
      • Synapsins may function in the docking of synaptic vesicles
      • After docking, synaptic vesicles undergo a priming reaction that prepares them for Ca²⁺-triggered release
      • Ca²⁺-triggered release may result from binding of multiple calcium ions to synaptotagmin, a relatively low-affinity sensor
    • Characteristics and Proteins of Synaptic Vesicle Endocytosis
      • After exocytosis, synaptic vesicles undergo rapid endocytosis, which likely is mediated by clathrin-coated pits and coated vesicles
      • Dynamin may be responsible for the rapid endocytosis of synaptic vesicles
      • Synaptojanin is another protein that has been implicated in synaptic vesicle endocytosis
    • Implications for Intracellular Trafficking
    • References
• Part Two. Intercellular Signaling
  • Chapter 10. Synaptic Transmission and Cellular Signaling: An Overview
    Ronald W Holz and Stephen K Fisher.
    • Synaptic Transmission
      • Chemical transmission between nerve cells involves multiple steps
      • Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells
      • A variety of methods have been developed to study exocytosis
      • The neuromuscular junction is a well-defined structure that mediates the release and postsynaptic effects of acetylcholine
      • Quantal analysis defines the mechanism of release as exocytosis
      • Ca²⁺ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis
      • Presynaptic events during synaptic transmission are rapid, dynamic and interconnected
      • There are important differences between fast synaptic transmission at nerve terminals and the release of proteins and peptides from nerve terminals and neuroendocrine cells
      • Discrete steps in the regulated secretory pathway can be defined in neuroendocrine cells
    • Cellular Signaling Mechanisms
      • Three phases of receptor-mediated signaling can be identified
      • Four distinct molecular mechanisms that link agonist occupancy of cell-surface receptors to functional responses have been identified
      • Cross-talk can occur between intracellular signaling pathways
      • Signaling molecules can activate gene transcription
      • Nitric oxide acts as an intercellular signaling molecule in the central nervous system
    • Acknowledgments
    • References
  • Chapter 11. Acetylcholine
    Palmer Taylor and Joan Heller Brown.
    • Chemistry of Acetylcholine
    • Organization of the Cholinergic Nervous System
      • Acetylcholine receptors have been classified into subtypes based on the pharmacology of the receptors
      • The intrinsic complexity and the multiplicity of cholinergic receptors became evident upon elucidation of their primary structures
    • Functional Aspects of Cholinergic Neurotransmission
      • Both muscarinic and nicotinic responses are found in brain and spinal cord
      • Neurotransmission in autonomic ganglia is more complex than depolarization mediated by a single transmitter
      • Muscarinic receptors are widely distributed at postsynaptic parasympathetic effector sites
      • Stimulation of the motoneuron for skeletal muscle results in the release of acetylcholine and contraction of the skeletal muscle fibers
      • Competitive blocking agents cause muscle paralysis by preventing access of acetylcholine to its binding site on the receptor
    • Synthesis, Storage and Release of Acetylcholine
      • Acetylcholine is synthesized from its two immediate precursors, choline and acetyl coenzyme A
      • Acetylcholine formation is limited by the intracellular concentration of choline, which is determined by uptake of choline into the nerve ending
      • A second transport system concentrates acetylcholine in the synaptic vesicle
      • Choline is supplied to the neuron either from plasma or by metabolism of choline-containing compounds
      • A slow release of acetylcholine from neurons at rest probably occurs at all cholinergic synapses
      • The relationship between the amount of acetylcholine in a vesicle and the quanta of acetylcholine released can only be estimated
      • Depolarization of the nerve terminal by an action potential increases the number of quanta released per unit time
      • All of the acetylcholine contained within the cholinergic neuron does not behave as if in a single compartment
    • Acetylcholinesterase and the Termination of Acetylcholine Action
      • Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues
      • Acetylcholinesterases exist in several molecular forms
      • The primary and tertiary structures of the cholinesterases are known
      • The catalytic mechanism for acetylcholine hydrolysis involves formation of an acyl enzyme, followed by deacylation
      • Inhibition of acetylcholinesterase occurs by several distinct mechanisms
      • Consequences of acetylcholinesterase inhibition differ between synapses
    • Nicotinic Receptors
      • The nicotinic acetylcholine receptor is the best characterized neurotransmitter receptor
      • Purification of the nicotinic acetylcholine receptor facilitated examination of its overall structure
      • The nicotinic acetylcholine receptor consists of five subunits arranged around a pseudoaxis of symmetry
      • Analysis of the opening and closing events of individual channels has provided information about ligand binding and activation of the receptor
      • Continued exposure of nicotinic receptors to agonist leads to desensitization of the receptors
      • Nicotinic receptor subunits are part of a large superfamily of ligand-gated channels
      • Both nicotinic receptors and acetylcholinesterase are regulated tightly during differentiation and synapse formation
    • Muscarinic Receptors
      • Muscarinic receptor stimulation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels
      • Radioligand-binding studies have been used to characterize muscarinic receptors
      • The binding properties of the antagonist pirenzepine led to the initial classification of muscarinic receptors
      • Transgenic mice are being generated to assess the functions of receptor subtypes in vivo
    • References
  • Chapter 12. Catecholamines
    Michael J Kuhar, Pastor R Couceyro, and Philip D Lambert.
    • Biosynthesis of Catecholamines
      • Tyrosine hydroxylase is the rate-limiting enzyme for the biosynthesis of catecholamines
      • DOPA decarboxylase catalyzes the removal of the carboxyl group from DOPA to form dopamine
      • For neurons that synthesize epinephrine or norepinephrine, dopamine β-hydroxylase is the next step in the biosynthetic pathway
      • In cells that synthesize epinephrine, the final step in the pathway is catalyzed by the enzyme phenylethanolamine N-methyltransferase
    • Storage and Release of Catecholamines
      • Catecholamines are concentrated in storage vesicles that are present at high density within nerve terminals
      • The concentration of catecholamines within nerve terminals remains relatively constant
      • Monoamine oxidase and catechol-O-methyltransferase are primarily responsible for the inactivation of catecholamines
      • The action of catecholamines released at the synapse is terminated by diffusion and reuptake into presynaptic nerve terminals
    • Anatomy of Catecholaminergic Systems
      • Our understanding of the function of catecholamine-containing neurons has been aided by neuroanatomical methods of visualizing these neurons
      • Cell bodies of noradrenergic neurons are clustered in the medulla oblongata, pons and midbrain and are considered to be anatomically part of the reticular formation
      • Large numbers of cell bodies of dopamine-containing neurons are located in the midbrain
    • Catecholamine Receptors
      • The brain contains multiple classes of receptors for catecholamines
    • Dopamine Receptors
      • Multiple dopamine receptor subtypes exist
      • The number of D1 and D2 receptors can be modulated by antagonists or neurotoxins
      • Direct and indirect agonists at dopamine receptors, including amphetamine, bromocriptine and lisuride, have been shown to induce psychotic episodes
    • α- and β-Adrenergic Receptors
      • The pharmacological responses to catecholamines were ascribed to effects of α- and β-adrenergic receptors in the late 1940s
      • The amino acid sequences of β-adrenergic receptors in brain and various tissues have been determined
      • Two families of α-adrenergic receptors exist
    • Dynamics of Catecholamine Receptors
      • Changes in the number of receptors appear to be associated with altered synaptic activity
      • Changes in the number of dopamine receptors may also be involved in pharmacological actions of neuroleptic drugs
      • Exposure of cells to agonists results in diminished responsiveness, referred to as desensitization
    • Acknowledgments
    • References
  • Chapter 13. Serotonin
    Alan Frazer and Julie G Hensler.
    • Serotonin
      • The indolealkylamine 5-hydroxytryptamine, serotonin, was identified initially because of interest in its cardiovascular effects
      • Understanding the neuroanatomical organization of serotonergic cells in brain provides insight into the functions of this neurotransmitter
      • The amino acid l-tryptophan serves as the precursor for the synthesis of 5-hydroxytryptamine
      • The synthesis of 5-hydroxytryptamine can increase markedly under conditions requiring a continuous supply of the neurotransmitter
      • As with other biogenic amine transmitters, 5-hydroxytryptamine is stored primarily in vesicles and released by an exocytotic mechanism
      • The activity of 5-hydroxytryptamine in the synapse is terminated primarily by its re-uptake into serotonergic terminals
      • The primary catabolic pathway for 5-hydroxytryptamine is oxidative deamination by the enzyme monoamine oxidase
    • Serotonin Receptors
      • Pharmacological and physiological studies have contributed to the definition of the many receptor subtypes for serotonin
      • Molecular biological techniques have led to the rapid discovery of additional serotonin-receptor subtypes and their properties
      • The many serotonin-receptor subtypes are differentiated by their localization in the central nervous system
      • Many serotonin-receptor subtypes do not appear to undergo compensatory regulatory changes
    • Serotonin Involvement in Physiological Function and Behavior
      • Serotonin may set the tone of brain activity in relationship to the state of behavioral arousal/activity
      • Serotonin appears to be involved in a wide variety of physiological functions and behaviors, such as eating, sleep, circadian rhythmicity and neuroendocrine function
      • 5-Hydroxytryptamine not only has important physiological effects of its own but also is the precursor of the hormone melatonin
    • Serotonin Neurons and Receptors as Drug Targets
    • References
  • Chapter 14. Histamine
    Lindsay B Hough.
    • Histamine: A Messenger Molecule Within and Outside of the Nervous System
      • The chemical structure of histamine has similarities to the structure of other biogenic amines, but important differences also exist
      • Outside of the central nervous system, histamine is a mediator of several physiological and pathological processes
    • Histaminergic Cells of the Central Nervous System: Anatomy and Morphology
      • The brain stores and releases histamine from more than one type of cell
      • Histaminergic fibers originate from the tuberomammillary region of the posterior hypothalamus
      • Histaminergic neurons have morphological and membrane properties that are similar to those of neurons storing other biogenic amines
      • Histaminergic fibers project widely to most regions of the central nervous system
      • Histaminergic neurons are present in many species
    • Dynamics of Histamine in the Brain
      • Specific enzymes control histamine synthesis and breakdown
      • Several forms of histidine decarboxylase may derive from a single gene
      • Histamine synthesis in the brain is controlled by the availability of l-histidine and the activity of histidine decarboxylase
      • Histamine is stored within and released from neurons, but no evidence for active neuronal re-uptake has been discovered
      • In the vertebrate brain, histamine metabolism occurs predominantly by methylation
      • Neuronal histamine is probably methylated outside of histaminergic nerve terminals
      • The activity of histaminergic neurons is regulated by H₃ autoreceptors
    • Molecular Sites of Histamine Action
      • Binding and molecular biological techniques have been used to characterize brain H₁ receptors
      • H₂ receptors have been studied with biochemical and molecular biological techniques
      • Both positive and negative interactions may occur between H₁ and H₂ receptors
      • There may be more than one type of H₃ receptor
      • It is likely that histamine acts at sites that are distinct from H₁, H₂ and H₃ receptors, but selective antagonists for these responses are lacking
    • Histamine Actions in the Central Nervous System
      • Histamine in the brain may act as both a neuromodulator and classical transmitter
      • Histaminergic neurons can regulate and be regulated by other neurotransmitter systems
      • Histamine in the central nervous system may participate in a variety of brain functions
      • Histamine may contribute to brain diseases or disorders
    • Significance of Brain Histamine for Drug Action
      • The sedative properties of some drugs on the central nervous system are attributable to their H₁-blocking effects
      • Morphine-like analgesics activate histaminergic mechanisms in the brain
      • Brain-penetrating drugs that act on the H₃ receptor are being developed to treat obesity, sleep disturbances, epilepsy, pain and cognitive disorders
    • Acknowledgments
    • References
  • Chapter 15. Glutamate and Aspartate
    Raymond Dingledine and Chris J McBain.
    • Three Classes of Ionotropic Glutamate Receptor
      • Five functional families can be defined by structural homologies
      • AMPA and kainate receptors both are blocked by quinoxalinediones but have different desensitization pharmacology
      • N-Methyl-d-aspartate receptors have multiple regulatory sites
      • The transmembrane topology of glutamate receptors differs from that of nicotinic receptors
      • Genetic regulation via splice variants and RNA editing further increases receptor heterogeneity
      • The permeation pathway of all glutamate receptors is similar
    • Metabotropic Receptors Modulate Synaptic Transmission
      • Eight metabotropic glutamate receptors that embody three functional classes have been identified
      • Metabotropic glutamate receptors are linked to diverse effector mechanisms
      • Postsynaptic metabotropic glutamate receptors modulate ion channel activity
      • Metabotropic receptors can mediate presynaptic inhibition
      • Genetic knockouts provide clues to metabotropic glutamate receptor functions
    • Glutamate and Aspartate Are the Major Excitatory Transmitters in the Brain
      • The transmitter pool of glutamate is stored in synaptic vesicles
      • Glutamate-receptor activation underlies most fast excitatory synaptic transmission in the brain
      • Ca²⁺ influx through N-methyl-d-aspartate and AMPA receptors mediates synaptic plasticity
      • Receptor knockouts reveal clues to ionotropic receptor functions
    • Glutamate Transporters
    • Excessive Glutamate Receptor Activation and Neurological Disorders
      • Glutamate and aspartate can be excitotoxins, especially when energy metabolism is compromised
      • Glutamate receptors are involved in ischemic cell damage and neuroprotection
      • Epileptiform activity involves glutamate receptor activation
      • Some neurodegenerative disorders may involve chronic glutamate receptor activation
    • Future Prospects
    • References
  • Chapter 16. GABA and Glycine
    Richard W Olsen and Timothy M DeLorey.
    • GABA Synthesis, Uptake and Release
      • GABA is formed in vivo by a metabolic pathway referred to as the GABA shunt
    • GABA Receptor Physiology and Pharmacology
      • GABA receptors have been identified electrophysiologically and pharmacologically in all regions of the brain
      • GABA_B receptors, which are always inhibitory, are coupled to G proteins
      • The GABA_A receptor is part of a larger GABA/drug receptor—Cl⁻ ion channel macromolecular complex
      • The GABA_A receptor is the major molecular target for the action of many drugs in the brain
      • Neurosteroids, which may be physiological modulators of brain activity, enhance GABA_A receptor function
    • Cloning GABA Receptors
      • A family of pentameric GABA_A-receptor protein subtypes exists
      • Sequencing revealed that the GABA_A receptor is a member of a superfamily of ligand-gated ion channel receptors
    • Glycine Receptors
      • Glycine is synthesized from glucose and other substrates in the brain
    • Glycine Receptor Physiology and Pharmacology
      • A number of amino acids can activate, to varying degrees, the inhibitory glycine receptor
      • Glycine is inhibitory on ligand-gated, strychnine-sensitive Cl⁻ channel receptors but excitatory on N-methyl-d-aspartate receptors
    • Cloning Glycine Receptors
      • Glycine receptors belong to the same gene superfamily as the GABA_A receptor
    • GABA and Glycine are the Major Rapidly Acting Inhibitory Neurotransmitters in Brain
    • References
  • Chapter 17. Purinergic Systems
    Joel M Linden.
    • Purine Release and Metabolism
      • Many cells in the nervous system release adenosine and adenine nucleotides
      • Nucleotides can be metabolized in the extracellular space
      • Adenosine is considered to be a neuromodulator
    • Purinergic Receptors
      • Adenosine also binds to an intracellular site on adenylyl cyclase
      • There are four subtypes of adenosine receptor that have been cloned
      • Xanthines block P1, but not P2, receptors
      • Subtypes of P2 receptors can be classified pharmacologically
      • Receptors exist for diadenosine polyphosphates, distinct from P1 or P2 receptors
    • Effects of Purines in the Nervous System
      • Adenosine receptors
      • ATP receptors
    • References
  • Chapter 18. Peptides
    Richard E Mains and Betty A Eipper.
    • The Neuropeptides
      • Many neuropeptides were originally identified as pituitary or gastrointestinal hormones
      • Peptides can be grouped by structural and functional similarity
      • The function of peptides as first messengers is evolutionarily very old
      • Various techniques are used to identify additional neuropeptides
      • The neuropeptides exhibit a few key differences from the classical neurotransmitters
      • Neuropeptides are often found in neurons with conventional neurotransmitters
      • The biosynthesis of neuropeptides is fundamentally different from that of conventional neurotransmitters
      • Many of the enzymes involved in peptide biogenesis have been identified
      • Neuropeptides are packaged into large dense core vesicles
      • Diversity is generated by families of propeptides, alternative splicing, proteolytic processing and post-translational modifications
    • Neuropeptide Receptors
      • Most neuropeptide receptors are seven-transmembrane-domain, G protein-coupled receptors
      • Neuropeptide receptors are not confined to synaptic regions
      • Expression of peptide receptors and the corresponding peptides is not well matched
      • The amiloride-sensitive FMRF-amide-gated sodium channel was the first peptide-gated ion channel identified
    • Neuropeptide Functions and Regulation
      • The study of peptidergic neurons requires a number of special tools
      • Peptides play a role in the plurichemical coding of neuronal signals
      • Neuropeptides make a unique contribution to signaling
      • Regulation of neuropeptide expression is exerted at several levels
    • Peptidergic Systems in Disease
      • Diabetes insipidus occurs with loss of vasopressin production in the Brattleboro rat model
      • A mutation in the carboxypeptidase E gene causes late-onset diabetes with hyperproinsulinemia
      • Obesity has several central nervous system components
      • Cholecystokinin agonists and antagonists yield insights into panic attacks and satiety
      • Enkephalin knockout mice reach adulthood and are healthy
    • References
  • Chapter 19. Growth Factors
    Gary E Landreth.
    • Growth Factors Are Essential for Nervous System Development and Function
      • Peptide growth factors are proteins that stimulate cellular proliferation and promote cellular survival
      • Cells respond to growth factors as a consequence of their binding to specific cell-surface receptors
    • Classes of Growth Factors Acting in the Nervous System
      • The neurotrophins comprise a family of related molecules which support the survival and phenotypic specificity of subsets of neurons
      • Nerve growth factor and other neurotrophins influence neurotransmission and synaptic plasticity
      • Neurokines, or neuropoietins, are a small group of molecules which are highly related to cytokines
      • The fibroblast growth factors comprise a gene family of nine members which share substantial sequence homology
      • Transforming growth factors β are the prototypical members of a superfamily of related factors which have diverse roles both in development and in the mature animal
      • Epidermal growth factor and related factors have a diverse range of actions in the nervous system
      • Other growth factors, such as platelet-derived growth factor and insulin-like growth factor, play a role in the nervous system
    • Growth Factors Act Combinatorially and Sequentially to Regulate Nervous System Development
    • References
• Part Three. Intracellular Signaling
  • Chapter 20. G Proteins
    Eric J Nestler and Ronald S Duman.
    • Heterotrimeric G Proteins
      • Multiple forms of heterotrimeric G proteins exist in the nervous system
      • Each G protein is a heterotrimer composed of single α, β and γ subunits
      • The functional activity of G proteins involves their dissociation and reassociation in response to extracellular signals
      • G proteins couple some neurotransmitter receptors directly to ion channels
      • G proteins regulate intracellular concentrations of second messengers
      • G proteins have been implicated in membrane trafficking
      • G protein βγ subunits subserve numerous functions in the cell
      • The functioning of heterotrimeric G proteins is modulated by several other proteins
      • G proteins are modified covalently by the addition of long-chain fatty acids
      • The functioning of G proteins may be influenced by phosphorylation
    • Small G Proteins
      • The best characterized small G protein is the Ras family, a series of related proteins of ~21 kDa
      • Rab is a family of small G proteins involved in membrane vesicle trafficking
    • Other Features of G Proteins
      • Some G proteins can be modified by ADP-ribosylation
      • G proteins may be involved in disease pathophysiology
      • G proteins may be regulated by psychotropic drugs
    • References
  • Chapter 21. Phosphoinositides
    Stephen K Fisher and Bernard W Agranoff.
    • Background
      • Stimulation of secretion is accompanied by incorporation of inorganic phosphate into phospholipids, revealing a cycle of glycerolipid breakdown and reutilization
    • Chemistry of the Inositol Lipids and Phosphates
      • The three quantitatively major phosphoinositides are structurally and metabolically related
      • Phosphoinositides are cleaved by a family of phosphoinositide-specific phospholipase C isozymes
      • Cleavage of phosphatidylinositol 4,5-bisphosphate initiates two interlinked cycles: one in which the diacylglycerol backbone is conserved and recycled and another in which inositol is reutilized
    • The Inositol Phosphates
      • d-myo-Inositol 1,4,5-trisphosphate is a second messenger that liberates Ca²⁺ from the endoplasmic reticulum via intracellular receptors
      • The metabolism of inositol phosphates leads to regeneration of free inositol
    • Diacylglycerol
      • Protein kinase C is activated by diacylglycerol
      • Diacylglycerols can be derived from phosphoinositides and other lipids
    • Functional Correlates of Phosphoinositide-Linked Receptors in the Nervous System
      • The complexity of the brain is reflected by a diverse array of receptors coupled to stimulation of phosphoinositide turnover
      • What is the physiological significance of stimulated phosphoinositide turnover in the nervous system?
      • Does the sharing of a single system by multiple cell-surface receptors lead to degeneracy of the signal?
      • Does the action of Li⁺ on the phosphoinositide-labeling cycle explain the therapeutic action of Li⁺ in manic-depressive psychosis?
    • Acknowledgments
    • References
  • Chapter 22. Cyclic Nucleotides
    Ronald S Duman and Eric J Nestler.
    • The Second-Messenger Hypothesis
    • Adenylyl Cyclases
      • Multiple forms of adenylyl cyclase exist in the nervous system
      • The different forms of adenylyl cyclase are similar in structure
      • Adenylyl cyclases are regulated by G_αs and G_αi
      • Adenylyl cyclase subtypes also are regulated by βγ subunits
      • Adenylyl cyclases show differential regulation by Ca²⁺
      • Adenylyl cyclases are regulated upon phosphorylation
      • Three general categories of adenylyl cyclase can be delineated based on their regulatory properties
      • Adenylyl cyclase is subject to long-term regulation in the nervous system
    • Guanylyl Cyclase
      • Membrane-bound forms of guanylyl cyclase are plasma membrane receptors
      • Soluble forms of guanylyl cyclase are activated by nitric oxide
      • Nitric oxide functions as a second messenger
    • Cyclic Nucleotide Phosphodiesterases
      • There are multiple forms of phosphodiesterase in brain
      • Phosphodiesterases show a distinctive molecular structure
      • Phosphorylation is a primary mechanism for regulation of phosphodiesterase activity
      • Phosphodiesterase inhibitors show promise as pharmacotherapeutic agents
    • Functional Roles for cAMP and cGMP
      • cAMP can be viewed as subserving two major functions in the nervous system
      • Most of the effects of cAMP on cell function are mediated via protein phosphorylation
      • The mechanisms by which cGMP produces its physiological effects are more varied
    • Future Perspectives
    • References
  • Chapter 23. Calcium
    James W Putney, Jr.
    • The Concept of Ca²⁺ as a Cellular Signal
    • Measurement of Cellular Ca²⁺ Concentrations and Movements
    • Ca²⁺ Regulation at the Plasma Membrane
      • Two distinct mechanisms for controlling [Ca²⁺]_i at the plasma membrane are a Ca²⁺-ATPase pump and a Na⁺-Ca²⁺ exchanger
    • Ca²⁺ Stores and Ca²⁺ Pools
      • The only known mechanism for accumulation of Ca²⁺ by the endoplasmic reticulum is through the actions of SERCA pumps
      • Mitochondria may accumulate Ca²⁺ by an energy-dependent process
      • Calcium is stored at other significant sites in the cell
    • Ca²⁺ Signaling
      • Release of intracellular Ca²⁺ is mediated primarily via inositol 1,4,5-trisphosphate receptors and ryanodine receptors
      • Ca²⁺ enters cells either via voltage- or ligand-dependent channels or by means of capacitative entry
      • Periodic temporal and spatial patterns of Ca²⁺ signaling give rise to calcium oscillations and waves
      • Release of intracellular Ca²⁺ may occur from “calciosomes,” a subfraction of the endoplasmic reticulum
      • Although distinct, Ca²⁺-signaling events in excitable and nonexcitable cells share some common characteristics
    • Ca²⁺-Regulated Processes
      • Ca²⁺ is required for acute cellular responses, such as contraction or secretion
      • Ca²⁺ also plays a role in more prolonged cellular events, such as mitogenesis and apoptosis
    • References
  • Chapter 24. Serine and Threonine Phosphorylation
    Eric J Nestler and Paul Greengard.
    • Protein Phosphorylation is of Fundamental Importance in Biological Regulation
      • Regulation of protein phosphorylation involves a protein kinase, a protein phosphatase and a substrate protein
    • Protein Serine-Threonine Kinases
      • Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation
      • The mitogen-activated protein kinase cascade is second messenger-independent
      • The brain contains many other types of second messenger-independent protein kinases
      • Most protein serine-threonine kinases undergo autophosphorylation
    • Protein Serine-Threonine Phosphatases
      • The brain contains multiple forms of protein serine-threonine phosphatases
      • Protein serine-threonine phosphatases play a critical role in the control of cell function
      • Protein phosphatase 1 and protein phosphatase 2A are regulated by protein phosphatase inhibitor proteins
      • Mitogen-activated protein kinase phosphatases are dual-function protein phosphatases
    • Neuronal Phosphoproteins
      • Virtually all types of neuronal proteins are regulated by phosphorylation
      • Protein phosphorylation is an important mechanism of memory
      • Neuronal phosphoproteins differ considerably in the number and types of amino acid residues phosphorylated
      • The phosphorylation of a protein can influence its functional activity in several ways
    • Cellular Signals Converge at the Level of Protein Phosphorylation Pathways
    • Protein Phosphorylation Mechanisms in Disease
      • Abnormal phosphorylation of specific neural proteins may contribute to the development of Alzheimer's disease
      • Upregulation of the cAMP pathway is one mechanism underlying opiate addiction
    • References
  • Chapter 25. Tyrosine Phosphorylation
    Lit-fui Lau and Richard L Huganir.
    • Tyrosine Phosphorylation in the Nervous System
    • Protein Tyrosine Kinases
      • Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper functioning of the enzyme
      • Receptor protein tyrosine kinases consist of an extracellular domain, a single transmembrane domain and a cytoplasmic domain
    • Protein Tyrosine Phosphatases
      • Nonreceptor protein tyrosine phosphatases are structurally different from serine/threonine phosphatases and contain a cysteine residue in their active sites
      • Receptor protein tyrosine phosphatases consist of an extracellular domain, a transmembrane domain and one or two intracellular catalytic domains
    • Role of Tyrosine Phosphorylation in the Nervous System
      • Tyrosine phosphorylation is involved in every stage of neuronal development
      • Tyrosine phosphorylation plays an important role in synaptic transmission
    • Acknowledgments
    • References
  • Chapter 26. Transcription Factors in the Central Nervous System
    James Eberwine.
    • The Transcriptional Process
    • Regulation of Transcription by Transcription Factors
    • Glucocorticoid and Mineralocorticoid Receptors as Transcription Factors
      • Corticosteroid receptors regulate transcription in the nervous system
      • The mechanisms of corticosteroid receptor regulation of transcription have been elucidated
    • cAMP Regulation of Transcription
      • cAMP controls phosphorylation of the cAMP response element—binding protein
      • The cAMP response element—binding protein is a member of a family containing interacting proteins
      • The function of the cAMP response element—binding protein has been modeled in transgenic organisms
    • Transcription as a Target for Drug Development
    • References
• Part Four. Growth, Development and Differentiation
  • Chapter 27. Development
    Jean de Vellis and Ellen Carpenter.
    • Fundamental Concepts Unifying Developmental Diversity
    • General Development of the Nervous System
    • Developmental Processes: Environmental Forces Molding Genetic Potential
      • Selective cell survival and proliferation determine the number of each type of nerve cell
      • Specific paths of cell migration to final target environments are controlled by gradients of diffusible and substrate-bound neurochemical signals
      • Cell process outgrowth determines the cytoarchitecture and circuitry of the nervous system
    • Molecular Mechanisms of Development
      • Environmental factors control developmental decisions made by cells of each lineage
      • Genetic networks function in neural development
      • There are multiple levels of integration within the transcriptional regulator network
      • Early response genes function as development-control signals
      • Transcriptional regulator networks function in invertebrate development
      • Transcriptional regulator networks determine vertebrate development
    • Cell Lineages of the Nervous System
      • The neural crest lineage is progressively restricted to specific sublineages
      • Environmental factors control lineage decisions of neural crest cells
      • Neural crest lineage is transcriptionally regulated
      • Glial cell development is critical to nervous system development
      • The oligodendrocyte lineage has been studied in vitro
      • Oligodendrocyte lineage in vivo resembles that seen in vitro
      • Growth factors regulate oligodendrocyte development
      • The Schwann cell lineage is also characterized by sequential and overlapping expression of many stage-specific markers
    • Conclusions
    • Acknowledgments
    • References
  • Chapter 28. Axonal Transport
    David L Stenoien and Scott T Brady.
    • Neuronal Organelles in Motion
    • Discovery and Conceptual Development of Fast and Slow Axonal Transport
      • The size and extent of many neurons presents a special set of challenges
      • Fast and slow components of axonal transport differ in both their constituents and their rates
      • Features of fast axonal transport, demonstrated by biochemical and pharmacological approaches, are apparent from video images
    • Fast Axonal Transport
      • Newly synthesized membrane and secretory proteins destined for the axon travel by fast anterograde transport
      • Passage through the Golgi apparatus is obligatory for most proteins destined for fast transport
      • Anterograde transport moves synaptic vesicles, axolemmal precursors and mitochondria down the axon
      • Retrograde transport returns trophic factors, exogenous material and old membrane constituents to the cell body
      • Molecular sorting mechanisms ensure delivery of proteins to discrete membrane compartments
    • Slow Axonal Transport
      • Cytoplasmic and cytoskeletal elements move coherently at slow transport rates
      • Axonal growth and regeneration are limited by rates of slow axonal transport
      • Properties of slow transport suggest molecular mechanisms
    • Molecular Motors: Kinesin, Dynein and Myosin
      • The characteristic properties of different molecular motors aid in their identification
      • Kinesins mediate anterograde transport in a variety of organisms and tissues
      • Multiple members of the kinesin superfamily are expressed in the nervous system
      • Cytoplasmic dyneins may have multiple roles in the neuron
      • Different classes of myosin are important for neuronal function
      • Matching motors to physiological functions may be difficult
    • Axonal Transport and Neuropathology
    • Conclusions
    • Acknowledgments
    • References
  • Chapter 29. Axon Sprouting and Regeneration
    Carl W Cotman.
    • Introduction
    • Axon Sprouting and Reactive Synaptogenesis
      • The response of the hippocampus to the unilateral removal of the entorhinal cortex provides an illustration of the general principles of reactive synaptogenesis
      • Sprouting in the adult brain results in an increase in the inputs already present without new pathway formation
      • Collateral sprouting and reactive synaptogenesis occur in discrete stages
      • Glial cells set the pace for reactive synaptogenesis
      • Cytokines and neurotrophic factors are induced after lesions of the entorhinal cortex
      • Cell adhesion molecules influence neuronal growth
      • Cytoskeletal protein concentrations increase after lesions
      • Synaptic proteins are produced in response to lesions
      • Molecular cascades involving cytokines appear to regulate the growth response
      • The hippocampus in Alzheimer's disease shows plasticity similar to that observed in the rodent brain after entorhinal lesions
      • In Alzheimer's disease, plasticity may become pathological and result in plaque biogenesis
    • Regeneration
      • Peripheral nerve and Schwann cells promote regeneration
      • Peripheral nerve and Schwann cells will induce brain and spinal cord neurons to regenerate
      • Axons can be induced to regenerate after spinal cord injury and can mediate functional recovery if myelin-associated inhibitory molecules are blocked
    • Brain and Spinal Cord Transplants
      • Regeneration of adult axons can occur in white matter tracts if the astrocytic reaction is absent
      • Transplants of olfactory ensheathing cells can mediate repair of the adult corticospinal tract
      • Transplants integrate into central nervous system circuitry and may restore some function in Parkinson's disease
      • Central nervous system stem cells provide an opportunity to improve the prospects for successful transplantation
    • Summary and Conclusions
    • References
  • Chapter 30. Biochemistry of Aging
    Caleb E Finch and George S Roth.
    • Overview on Aging
      • Despite taxonomic diversity, general aging changes can be shown in short- and long-lived mammals
      • Aging changes involve gene—environment interactions
    • Cell Numbers
      • The distinction between neuronal loss and neuronal atrophy during aging is a major issue
      • Very long-term responses to 6-hydroxydopamine are a model for neuronal atrophy during aging and in Parkinson's disease
      • Glial hyperactivity generally is observed during aging but not always with irreversible neurodegeneration
      • Transgenic mice provide models of age-related neurodegeneration
    • Plasticity and Aging
      • How aging impairs neuronal plasticity is one of the major themes in neurogerontology
      • Many adaptive hormonal and cellular responses are slowed during aging
      • The supersensitization, or upregulation, of receptors in response to chronic treatment with antagonists is partially impaired
    • Neurotransmitters and Receptors
      • The loss of cholinergic markers during Alzheimer's disease and aging has led to the cholinergic hypothesis of memory deficits
    • Aging Pigments and Membranes
      • Intracellular pigments, such as lipofuscins and neuromelanins, show cell-type specificity and little relation to neuronal death
      • Brain membrane compositional changes may influence membrane fluidity
      • Vascular membrane changes may alter microperfusion and may contribute to brain age changes
    • Energy Metabolism
    • Instability in the Nuclear and Mitochondrial Genomes
      • Age-related changes show cell-type specificity
    • Gene Expression
      • mRNA levels also show cell-type selectivity during aging
      • Age-related changes in gene expression may be mediated by steroid receptors
    • Proteins
      • Altered proteins may increase through oxidative damage
      • Slowing of protein synthesis could be a factor in slowed axoplasmic flow
    • Experimental Manipulations of Brain Aging
      • Diet restriction and hypophysectomy delay aging in many organs of rodents
      • Some hypothalamic and hippocampal aging changes are linked to steroid exposure
    • Neuroendocrinology and Sleep During Aging
    • Mammals Are Not the Only Animal Models for Aging
    • Prospects
    • Acknowledgments
    • References
• Part Five. Metabolism
  • Chapter 31. Circulation and Energy Metabolism of the Brain
    Donald D Clarke and Louis Sokoloff.
    • Intermediary Metabolism
      • ATP production in brain is highly regulated
      • Glycogen is a dynamic but limited energy store in brain
      • Brain glycolysis is regulated mainly by hexokinase and phosphofructokinase
      • The pyruvate dehydrogenase complex plays a key role in regulating oxidation
      • Energy output and oxygen consumption are associated with high rates of enzyme activity in the Krebs cycle
      • The pentose shunt, also termed the hexose monophosphate pathway, is active in brain
      • Glutamate in brain is compartmented into separate pools
    • Differences Between In Vitro and In Vivo Brain Metabolism
      • In contrast to cells of other tissues, individual nerve cells do not function autonomously
      • The blood—brain barrier selectively limits the rates of transfer of soluble substances between blood and brain
    • Cerebral Energy Metabolism In Vivo
      • Behavioral and central nervous system physiology are correlated with blood and cerebrospinal fluid chemical changes
      • Brain samples are removed for biochemical analyses
      • Radioisotope incorporation can identify and measure routes of metabolism
      • Oxygen utilization in the cortex is measured by polarographic techniques
      • Arteriovenous differences identify substances consumed or produced by brain
      • Combining cerebral blood flow and arteriovenous differences permits measurement of rates of consumption or production of substances by brain
    • Regulation of Cerebral Metabolic Rate
      • The brain consumes about one-fifth of total body oxygen utilization
      • The main energy-demanding functions of the brain are those of ion flux related to excitation and conduction
      • Continuous cerebral circulation is absolutely required to provide sufficient oxygen
      • Local rates of cerebral blood flow and metabolism can be measured by autoradiography and are coupled to local brain function
    • Substrates of Cerebral Metabolism
      • Normally, the substrates are glucose and oxygen and the products are carbon dioxide and water
      • In brain, glucose utilization is obligatory
      • The brain utilizes ketones in states of ketosis
    • Age and Development Influence Cerebral Energy Metabolism
      • Metabolic rate increases during early development
      • Metabolic rate declines and plateaus after maturation
      • Tissue pathology, but not aging, produces secondary changes in metabolic rate
    • Cerebral Metabolic Rate in Various Physiological States
      • Cerebral metabolic rate is determined locally by functional activity in discrete regions
      • Metabolic rate and nerve conduction are related directly
      • It is difficult to define metabolic equivalents of consciousness, mental work and sleep
    • Cerebral Energy Metabolism in Pathological States
      • Psychiatric disorders may produce effects related to anxiety
      • Coma and systemic metabolic diseases depress brain metabolism
      • Measurement of local cerebral energy metabolism in humans
    • References
  • Chapter 32. Blood—Brain—Cerebrospinal Fluid Barriers
    John Laterra, Richard Keep, Lorris A Betz, and Gary W Goldstein.
    • Constancy of the Internal Environment of the Brain
    • Membrane Transport Processes
      • Physical and biological processes determine molecular movement across membranes of the blood—brain— cerebrospinal fluid barriers
      • Transport processes combine to provide stability for constituents of cerebrospinal fluid and brain extracellular fluid
    • Blood—Brain Barrier
      • Endothelial cells in brain capillaries are the site of the blood—brain barrier
      • Substances with a high lipid solubility may move across the blood—brain barrier by simple diffusion
      • Carrier-mediated transport enables molecules with low lipid solubility to traverse the blood—brain barrier
      • Metal ions are exchanged between plasma and brain very slowly compared with other tissues
      • Some proteins cross the blood—brain barrier by binding to receptors or by absorption on the endothelial cell membrane
      • Metabolic processes within the brain capillary endothelial cells are important to blood—brain barrier function
      • Carrier-mediated blood—brain barrier transport protects the brain from blood-borne neurotoxins and drugs
      • The blood—brain barrier undergoes development
    • Blood—Cerebrospinal Fluid Barrier
      • The choroid plexus epithelial cells and the arachnoid membrane form the blood—cerebrospinal fluid barrier
      • Cerebrospinal fluid is secreted primarily by the choroid plexus
      • Cerebrospinal fluid circulates through the ventricles, over the surface of the brain, and is absorbed at the arachnoid villi and at the cranial and spinal nerve root sheaths
      • The choroid plexus is the major route of blood—brain barrier exchange for some compounds
      • Cerebrospinal fluid has a number of functions
    • Cerebrospinal Fluid—Brain interface
    • Bypassing the Barriers with Drugs
    • Acknowledgments
    • References
  • Chapter 33. Nutrition and Brain Function
    Gary E Gibson and John P Blass.
    • Nutrition and Functional Neurochemistry
      • Nutrition can influence neurotransmitter concentrations and associated behaviors
      • Nutrition can influence brain energy reserve
      • Vitamins can regulate normal neuronal activity
      • The brain depends on select vitamins and closely related compounds as antioxidants to control potentially damaging free radicals
      • Trace nutrients in the diet have a vital role in maintaining normal brain function
    • Nutrition and Structural Aspects of the Brain
      • The essential polyunsaturated fatty acids belong to two families, ω6 and ω3, that are characterized by the indicated number of carbons of the first double bond from the methyl terminal
      • Feeding isoenergetic diets rich in saturated fatty acids alters the response of neurotransmitter receptors
    • Nutrition and Brain Development
    • Nutrition and Aging of the Nervous System
      • Antioxidants may provide an important way to delay aging of the brain
      • Restricting intake of a balanced diet is an effective means of extending life span and of reducing several measures of oxidative stress in the brain under laboratory conditions in rodents and primates
      • Other treatments can also diminish age-related increases in oxidative stress
    • Nutrition and the Treatment of Neurodegenerative Disease
    • Nutrition and Genetics
      • Genetic factors may determine susceptibility to chronic disease as well as the response to diet
      • Nutrients are involved in gene transcription, mRNA processing, mRNA stability and mRNA translation
    • Neuronal Control of Food Intake
    • Summary
    • References
  • Chapter 34. Hypoxic-Ischemic Brain Injury and Oxidative Stress
    Laura L Dugan and Dennis W Choi.
    • Hypoxia-Ischemia and Brain infarction
      • Energy failure, an early consequence of hypoxia-ischemia, causes disruption of ionic homeostasis and accumulation of extracellular neurotransmitters
      • Focal and global ischemia produce different distributions of injury
      • “Selective vulnerability” of certain neurons is not explained by vascular distribution
    • Microvascular injury in Hypoxia-Ischemia
      • Hypoxia-ischemia disrupts the blood—brain barrier and damages endothelial cells
      • Edema may lead to secondary ischemia, which can produce further brain damage
    • Excitotoxic injury in Hypoxia-Ischemia
      • NMDA and AMPA/kainate receptors contribute to excitotoxic neuronal degeneration
      • Excitotoxicity leads to increased Ca²⁺ influx, which can activate cytotoxic intracellular pathways
      • Excitatory amino acid-receptor antagonists can provide neuroprotection in experimental models of hypoxia-ischemia
    • Zn²⁺ and Hypoxia-Ischemia
    • Ischemic Apoptosis
      • Hypoxia-ischemia may initiate apoptosis in parallel with necrosis
      • Triggers of ischemic apoptosis may include decreased supply of or reduced sensitivity to neurotrophins, development of oxidative stress and exposure to inflammatory cytokines
    • Free Radicals in Hypoxia-Ischemia
      • Oxygen free radicals are required intermediates in many biological reactions but may damage macromolecules during oxidative stress
      • Reactive oxygen species generated during ischemia-reperfusion contribute to the injury
      • Mitochondria, nitric oxide synthase and arachidonic acid metabolism are sources of reactive oxygen species during ischemia-reperfusion injury
      • Nitric oxide and peroxynitrite contribute to oxidative damage
      • Production of eicosanoids from polyunsaturated fatty acids such as arachidonic acid may generate reactive oxygen species
      • The role of xanthine oxidase in human stroke is unclear
      • Brain antioxidant defenses modify ischemia-reperfusion injury
      • Reactive oxygen species may modify both the excitotoxic and the apoptotic components of ischemic brain damage
    • References
  • Chapter 35. Eicosanoids, Platelet-Activating Factor and Inflammation
    Nicolas G Bazan.
    • Sources of Bioactive Lipids
    • Phospholipases a₂
      • Calcium ion-dependent phospholipases A₂ with a preference for arachidonoyl chains are involved in bioactive lipid formation
      • Synaptic stimulation, ischemia or seizures activate phospholipases A₂ and release arachidonic acid
      • Secretory phospholipases A₂ require millimolar Ca²⁺ concentrations, as found in the extracellular milieu, for catalytic activity
    • Eicosanoids
      • Prostaglandins are very rapidly released from neurons and glial cells
    • Platelet-Activating Factor
    • Cyclooxygenases
    • Lipid Signaling Pathways and Neuroinflammation
      • A platelet-activating factor—stimulated signal-transduction pathway is a major component of the kainic acid—induced cyclooxygenase-2 expression in hippocampus
      • In cerebrovascular diseases, the phospholipase A₂-related signaling triggered by ischemia-reperfusion may be part of a delicate balance between neuroprotection and neuronal cell death
    • References
  • Chapter 36. Neuropathy
    David E Pleasure.
    • Regeneration in the Central and Peripheral Nervous Systems
      • The peripheral and central nervous systems have many anatomical and molecular features in common
      • Cellular and molecular properties of the peripheral nervous system are important in disease susceptibility and regenerative capacity
      • Clinical features of polyneuropathies reflect vulnerability of the longest axons to degeneration and segmental demyelination
    • Examples of Peripheral Nervous System-Specific Diseases
      • The lepromatous form of leprosy is characterized by loss of cutaneous sensibility
      • Diphtheria causes a demyelinative neuropathy
      • Excess vitamin B₆ causes a progressive, purely sensory axonal polyneuropathy
      • Botulinus exotoxin impedes release of neurotransmitter vesicles from cholinergic terminals at neuromuscular junctions
      • Immune-mediated neuropathies may be related to various sources of antigens
      • Demyelinative polyneuropathies may be genetic in origin
      • Diabetes mellitus is the most common cause of peripheral neuropathy in the United States
    • Diseases Affecting Both the Peripheral and Central Nervous Systems
      • Neurofibromatosis type 1, von Recklinghausen's disease, is the most frequent dominantly inherited disorder affecting the nervous system
      • Neurofibromatosis type 2 is a much rarer dominantly inherited disease
      • Acute intermittent porphyria is a dominantly inherited partial deficiency of porphobilinogen deaminase
      • Adrenoleukodystrophy is an X-linked disorder caused by mutations of a gene encoding a peroxisomal protein
      • Friedreich's ataxia is an autosomal recessive disorder
      • Inherited motor neuron diseases may entail death of motor neurons in the spinal cord and brainstem, resulting in motor axonal degeneration in the peripheral nervous system
    • Diseases of the Enteric Nervous System
    • References
  • Chapter 37. Epileptic Seizures and Epilepsy
    Brian Meldrum and Astrid Chapman.
    • Epilepsies Are Disorders Characterized by Spontaneous, Recurrent Seizures
    • Epileptogenesis
      • Epilepsy sometimes has a genetic basis
      • Some developmental disorders are associated with epilepsy
      • Traumatic injury and focal lesions can be epileptogenic
      • Metabolic disorders may trigger seizures
    • Epilepsy Models
      • Maximal electroshock triggers seizures
      • Convulsions can be induced by drugs
      • Seizure-susceptible inbred strains of rodents exhibit spontaneous or evoked seizures
      • Absence seizures in rodents resemble absence epilepsy in humans
      • After an initial episode of severe status epilepticus, rats develop recurrent, spontaneous seizures
      • Kindling, which is recurrent, subconvulsant stimulation, provides an experimental model of epileptogenesis
      • Spontaneous seizures are observed in transgenic mice with a wide range of gene deletions or overexpressions
    • Basic Electrophysiology
      • Macroelectrodes show spikes, while intracellular microelectrodes show paroxysmal depolarizing shifts
      • Ionic movements occur in brain during seizures
      • Inhibition and excitation have roles in the synaptic synchronization that spreads through anatomical networks
    • Changes in Neurotransmitter Systems Underlying Epilepsy
      • GABA and benzodiazepine receptors decrease in some conditions
      • Glutamate sensitivity at N-methyl-d-aspartate receptors may increase
      • Noradrenergic innervation may increase or decrease in rodent models
      • Opioid peptides have both convulsant and anticonvulsant actions
    • Anticonvulsant Drug Mechanisms
    • Metabolic Consequences of Seizures
      • Energy metabolism in the discharge pathway is massively increased during seizures
      • Energy metabolites decrease rapidly
      • Concentrations of lactate and certain amino acids change rapidly
      • Second messengers change rapidly
      • Free fatty acids and prostaglandins increase
      • Release of neurotransmitter amino acids is rapidly increased at the beginning of a seizure
      • Seizures produce changes in gene expression and protein synthesis
      • Positron emission tomography studies show ictal hypermetabolism and interictal hypometabolism
    • Pathological Changes Secondary to Seizures or Related to Epileptogenesis
      • Status epilepticus causes damage in vulnerable neurons
      • Epileptogenesis is associated with regenerative sprouting in the hippocampus
    • References
  • Chapter 38. Metabolic Encephalopathies
    Roger F Butterworth.
    • Brain Energy Metabolism
    • Hypoglycemic Encephalopathy
      • Hypoglycemia usually results from insulin overdose, hepatic disease resulting in decreased hepatic gluconeogenesis or renal disease
      • Reduced synthesis of neurotransmitters rather than a global cerebral energy deficit explains the neurological symptoms and EEG changes in moderate hypoglycemia
    • Hypoxic Encephalopathy
      • An uninterrupted supply of oxygen is vital for cerebral function
      • Glycolysis is stimulated to maintain brain ATP levels in moderate hypoxia
      • All forms of hypoxia result in alterations of neurotransmitter synthesis and release
    • Hepatic Encephalopathy
      • Hepatic encephalopathy is a neuropsychiatric disorder occurring in both acute and chronic liver diseases
      • Liver failure, whether acute or chronic, leads to the accumulation in brain of neurotoxic substances
      • Ammonia has deleterious effects on cerebral function by both direct and indirect mechanisms
      • If sufficiently elevated, ammonia may depress metabolic energy reserves
      • Hepatic encephalopathy is a disorder of multiple neurotransmitter systems
    • Hypercapnic Encephalopathy
      • Respiratory acidosis leads to decreased brain pH
    • Uremic and Dialysis Encephalopathies
      • Uremia leads to alterations in the characteristics of the blood—brain barrier
      • Parathyroid hormone may be implicated in the pathogenesis of uremic encephalopathy
      • Aluminum toxicity may play a role in the pathogenesis of dialysis encephalopathy
    • References
  • Chapter 39. Diseases Involving Myelin
    Richard H Quarles, Pierre Morell, and Henry F McFarland.
    • General Classification
      • A deficiency of myelin can result either from failure to produce the normal amount of myelin during development or from myelin breakdown after it is formed
      • Many of the biochemical changes associated with central nervous system demyelination are similar regardless of etiology
    • Acquired Disorders of Myelin
      • Damage in many acquired allergic and infectious demyelinating diseases is directed specifically against myelin or myelin-forming cells
      • Experimental allergic encephalomyelitis is an animal model of autoimmune demyelination
      • A number of animal diseases caused by viruses involve primary demyelination and often are associated with inflammation
      • Multiple sclerosis is the most common demyelinating disease of the central nervous system in humans
      • Some human peripheral neuropathies involving demyelination are thought to be immune-mediated
      • Other acquired disorders affecting myelin in humans may be secondary to viral infections, neoplasias or immunosuppressive therapy
    • Genetic Disorders of Myelin
      • Spontaneous mutations in experimental animals provide insights about the structure and assembly of myelin
      • The human leukodystrophies are inherited disorders affecting central nervous system white matter
      • Deficiencies of peripheral nerve myelin in several inherited neuropathies are caused by genetic mutations in sheath proteins
    • Toxic and Nutritional Disorders of Myelin
      • Biological toxins can produce myelin loss
      • Many chemical toxins can impair myelin formation or cause its breakdown
      • General undernourishment or dietary deficiencies of specific substances can lead to a preferential reduction in myelin formation
    • Disorders Primarily Affecting Neurons with Secondary Involvement of Myelin
      • The archetypical model for secondary demyelination is Wallerian degeneration
      • Secondary demyelination occurs in subacute sclerosing panencephalitis and other diseases of the central nervous system
    • Remyelination
      • The capacity for remyelination is generally greater in the peripheral than in the central nervous system
      • Remyelination in the central nervous system can be promoted by various treatments
    • References
• Part Six. Inherited and Neurodegenerative Diseases
  • Chapter 40. Genetics of Inherited Diseases
    Kunihiko Suzuki.
    • Genetic Neurological Disorders
      • Reverse genetics involves linkage analysis, positional cloning and diagnosis using linked markers
    • Nature of Mutations in Genetic Disorders
      • Point mutations, or single-base substitutions, are the most common form of mutations
      • Deletion, insertion and duplication also are frequent causes of many genetic disorders
      • Trinucleotide expansion is one of the most important categories of mutation underlying neurodegenerative disorders
    • Gene Transfer and Expression
      • Cloned genes can be expressed in many different ways on different levels
      • Endogenous genes can be specifically targeted for inactivation or introduction of a mutation, allowing creation of murine models of genetic diseases
      • Gene therapy provides ultimate hope and is steadily developing
    • Unique Nature of Genetic Disorders Affecting the Brain
      • Successful therapy of disorders involving the nervous system must overcome some unique features of the brain
    • References
  • Chapter 41. Lysosomal and Peroxisomal Diseases
    Kunihiko Suzuki and Marie T Vanier.
    • The Lysosome
    • The Peroxisome
    • Molecular Genetics
    • Diagnosis and Treatment
    • Animal Models
    • Lysosomal Disease
      • Sphingolipidoses are caused by genetic defects in a series of lysosomal enzymes and other proteins essential for the catabolism of sphingolipids
      • Mucopolysaccharidoses are caused by genetic enzymatic defects in the degradation of carbohydrate chains of glycosaminoglycans
      • Glycoprotein disorders result from defects in lysosomal hydrolases
      • There are other genetic disorders due to abnormalities in lysosomal function
    • Peroxisomal Disease
      • Disorders of function can result from genetic defects in factors that are critical for peroxisomal formation
      • Disorders of the peroxisomal β-oxidation pathway result in a loss of peroxisomal function
    • Update Added in Proof
    • References
  • Chapter 42. Diseases of Carbohydrate, Fatty Acid and Mitochondrial Metabolism
    Salvatore diMauro and Darryl C De Vivo.
    • Diseases of Carbohydrate and Fatty Acid Metabolism in Muscle
      • One class of glycogen or lipid metabolic disorders in muscle is manifest as acute, recurrent, reversible dysfunction
      • A second class of disorders of glucose and fatty acid metabolism causes progressive weakness
      • The impairment of energy production from carbohydrate, which is the common consequence of these defects, should result in similar, exercise-related signs and symptoms
    • Diseases of Carbohydrate and Fatty Acid Metabolism in Brain
      • Defective transport of glucose across the blood—brain barrier is caused by deficiency in the glucose transporter protein
      • One class of carbohydrate and fatty acid metabolism disorders is caused by defects in enzymes that function in the brain
      • Another class of carbohydrate and fatty acid metabolism disorders is caused by systemic metabolic defects that affect the brain
    • Diseases of Mitochondrial Metabolism
      • Mitochondrial dysfunction produces syndromes involving muscle and the central nervous system
      • Mitochondrial DNA is inherited maternally
      • The genetic classification of mitochondrial diseases divides them into three groups
      • The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism
    • Acknowledgments
    • References
  • Chapter 43. Disorders of Muscle Excitability
    Robert L Barchi.
    • Muscle Fibers Are Organized in Repeating Units
      • Muscle contraction is due to relative sliding of two sets of filaments identified by light and electron microscopy
      • Actin and myosin form the chief components of the thin and thick filaments, respectively
      • Tropomyosin and troponin regulate the interaction of actin and myosin
    • Membrane Systems Couple Nerve Excitation to Muscle Contraction
      • The neuromuscular junction connects nerve to muscle
      • The muscle sarcolemma spreads the message
      • The transverse tubular system and sarcoplasmic reticulum combine to link electrical signals to Ca²⁺ release
    • Defects in Neuromuscular Transmission Can Interrupt Normal Muscle Function
      • Botulinum toxin blocks the release of synaptic vesicles from the presynaptic nerve terminal
      • Black widow spider venom stimulates abnormal release of acetylcholine
      • Some snake venoms contain β-toxins that interrupt presynaptic events
      • Autoimmune diseases can interfere with neurotransmitter release
    • Toxins and Diseases Can Also Block Transmission at the Postsynaptic Level
      • α-Neurotoxins block the activation of nicotinic acetylcholine receptors
      • In myasthenia gravis, an autoimmune response against the acetylcholine receptor leads to neuromuscular failure
      • Genetic defects in receptor structure can produce clinical disease
      • Abnormalities in acetylcholinesterase activity can interfere with neuromuscular transmission
    • Abnormal Excitability of the Sarcolemma Can Affect Muscle Function
      • Normal excitability in the sarcolemma requires the integrated function of numerous ion channels
      • Abnormalities of membrane Cl⁻ conductance can induce repetitive firing in the sarcolemma
      • Mutations in the ClC1 muscle Cl⁻ channel produce human disease
      • When the sarcolemma is not sufficiently excitable, weakness or paralysis can result
      • Na⁺ channel mutations cause periodic paralysis
      • Na⁺ channel mutations also occur in heart and brain
      • Ca²⁺ channel mutations produce hypokalemic periodic paralysis
    • Defects at the Triad Can Also Affect Muscle Function
      • A congenital absence of the L-type Ca²⁺ channel is fatal
      • Malignant hyperthermia is linked to mutations in the ryanodine receptor protein
    • References
  • Chapter 44. Diseases of Amino Acid Metabolism
    Marc Yudkoff.
    • Biochemistry of Amino Acid Disorders
    • Pathogenesis of Clinical Features
    • Branched-Chain Amino Acid Metabolism
      • Maple syrup urine disease was the first congenital defect of branched-chain amino acid catabolism to be described
    • Disorders of Organic Acid Metabolism
      • The cause of isovaleric acidemia is a congenital deficiency of isovaleryl-CoA dehydrogenase, which mediates formation of 3-methylcrotonate
      • 3-Methylcrotonic aciduria is caused by defects in a biotin-dependent reaction that forms 3-methylglutaconic acid
      • 3-Methylglutaconic aciduria is caused by deficiencies of 3-methylglutaconyl-CoA hydratase, which mediates formation of 3-hydroxy-3-methylglutaryl-CoA
      • 3-Hydroxy-3-methylglutaric aciduria is caused by a lack of 3-hydroxy-3-methylglutaryl-CoA lyase, which catalyzes conversion of 3-hydroxy-3-methylglutarate to acetoacetate and acetyl-CoA
      • β-Ketothiolase deficiency syndrome is caused by defects in 2-methylacetoacetyl-CoA thiolase, which mediates the conversion of 2-methylacetoacetyl-CoA to acetyl-CoA and propionyl-CoA
      • 3-Hydroxyisobutyryl-CoA deacylase deficiency causes a block in valine catabolism by preventing the conversion of 3-hydroxybutyryl-CoA to 3-hydroxyisobutyric acid
    • Organic Acid Metabolism
      • Propionyl-CoA carboxylase deficiency blocks the biotin- and ATP-dependent conversion of propionyl-CoA to methylmalonyl-CoA
      • Methylmalonyl-CoA mutase deficiency prevents the isomerization of methylmalonyl-CoA to succinyl-CoA
      • Methylmalonic aciduria may be secondary to defects of cobalamin metabolism
      • Glutaryl-CoA dehydrogenase deficiency blocks oxidation of glutaryl-CoA and produces degeneration in basal ganglia and white matter
      • Type II glutaric aciduria results from a deficiency in electron transfer proteins involved in mitochondrial respiration
    • Phenylalanine Metabolism: Phenylketonuria
      • Phenylketonuria is most commonly caused by a deficiency of phenylalanine hydroxylase, which converts phenylalanine into tyrosine
      • Phenylketonuria may also be caused by defects of biopterin metabolism
    • Glycine Metabolism: Nonketotic Hyperglycinemia
      • Nonketotic hyperglycinemia is caused by deficiencies in the glycine-cleavage system
    • Sulfur Amino Acid Metabolism: Homocystinuria
      • The most common cause of homocystinuria is a deficiency of cystathionine β-synthetase
      • Remethylation deficiency homocystinuria is usually caused by aberrations in the metabolism of methylfolate or methylcobalamin
      • Methylenetetrahydrofolate reductase deficiency interferes with pteridine reduction and produces severe brain disease
      • Methionine synthetase deficiency, also termed cobalamin-E disease, results in the inability to transfer a methyl group from methyltetrahydrofolate to homocysteine to yield methionine
      • Cobalamin-C disease results from a defect in the activation of vitamin B ₁₂
      • Cobalamin-D disease is an extremely rare variant
      • Hereditary folate malabsorption causes megaloblastic anemia, seizures and a syndrome of progressive neurological deterioration
    • Urea Cycle
      • Urea cycle defects cause hyperammonemia and may result in coma, convulsions and vomiting during the first few days of life
      • Carbamyl phosphate synthetase deficiency prevents the formation of carbamyl phosphate from ammonia
      • N-Acetylglutamate synthetase deficiency leads secondarily to carbamyl phosphate synthetase deficiency
      • Ornithine transcarbamylase deficiency prevents the conversion of carbamyl phosphate to citrulline and is the most common of the urea cycle defects
      • Deficiencies in arginosuccinate synthetase cause citrullinemia
      • Argininosuccinic aciduria results from a deficiency in arginosuccinic lyase, preventing the formation of arginine
      • Arginase deficiency blocks the conversion of arginine to urea and ornithine and causes a progressive, spastic tetraplegia, especially in the lower extremities
      • Hyperornithinemia, hyperammonemia and hypercitrullinemia may also be caused by a failure of mitochondrial ornithine uptake
      • Lysinuric protein intolerance is caused by defects in the transport of lysine, ornithine and arginine
      • Protein restriction is the mainstay of therapy for the management of urea cycle defects
    • Biotin Metabolism
      • Holocarboxylase synthetase deficiency prevents biotinylation of holocarboxylase and results in metabolic acidosis, marked tachypnea, hypotonia, vomiting and seizures
      • Biotinidase deficiency prevents recycling of biotin and often causes developmental retardation, hypotonia, seizures, cerebellar signs, alopecia, dermatitis and conjunctivitis
    • Glutathione Metabolism
      • Glutathione synthetase deficiency leads to excessive formation of 5-oxoproline and may result in severe metabolic acidosis
      • γ-Glutamylcysteine synthetase deficiency is rare
      • γ-Glutamyltranspeptidase deficiency blocks the major pathway for glutathione utilization and causes glutathionuria
    • GABA Metabolism
      • Pyridoxine dependency is characterized by severe seizure activity of early onset, perhaps even in utero
      • GABA-transaminase deficiency causes increased concentrations of GABA and β-alanine in the blood and cerebrospinal fluid
      • Succinic semialdehyde dehydrogenase deficiency causes increased excretion of succinic semialdehyde and 4-hydroxybutyric acid
    • N-Acetylaspartate Metabolism: Canavan's Disease
    • References
  • Chapter 45. Neurotransmitters and Disorders of the Basal Ganglia
    J Sian, MBH Youdim, P Riederer, and M Gerlach.
    • Biochemical Anatomy of the Basal Ganglia and Associated Neural Systems
      • Neurotransmitter systems involving catecholamines, serotonin and GABA have been identified in the basal ganglia
      • The basal ganglia are heterogeneous structures
      • Excitatory amino acids provide afferent input to the basal ganglia
      • Ionotropic and metabotropic excitatory amino acid receptors are localized on striatal neurons
      • GABA is the neurotransmitter of most striatal efferent neurons
      • Acetylcholine is the neurotransmitter of striatal interneurons
      • Dopamine is the neurotransmitter of the nigrostriatal pathway
      • Dopamine is primarily metabolized by O-methylation and oxidative deamination
      • The circuits of the basal ganglia are regulated by feedback systems and modulatory peptide cotransmitters
    • Parkinson's Disease
      • The chemical pathology of Parkinson's disease includes degeneration of the dopaminergic nigrostriatal tract and reduction in striatal dopamine
      • l-DOPA is used to treat Parkinson's disease
      • l-DOPA treatment is potentiated by inhibition of peripheral decarboxylation
      • l-DOPA treatment is potentiated by monoamine oxidase or catechol-O-methyltransferase inhibition
      • There are other alternatives and adjuncts to l-DOPA treatment of Parkinson's disease
      • Parkinson's disease can also be treated surgically
    • MPTP-Induced Parkinsonian Syndrome
      • MPTP toxicity was discovered after inadvertent self-administration by drug abusers
      • MPTP provides clues to the pathogenesis of Parkinson's disease
      • Neuroprotective strategies have some benefits in Parkinson's disease
    • Drug- Or Toxin-Induced Movement Disorders
      • Pharmacological dopamine depletion induces parkinsonism
      • Neuroleptics may induce parkinsonism or dyskinesias
      • Chronic heavy metal and industrial toxin exposure can cause movement disorders
    • Hepatolenticular Degeneration: Wilson's Disease
    • Amyotrophic Lateral Sclerosis—Parkinsonism—Dementia of Guam
    • Huntington's Disease
      • Excitotoxin-induced lesions in animals mimic Huntington's disease
    • Kernicterus
    • Acknowledgments
    • References
  • Chapter 46. Biochemistry of Alzheimer's and Prion Diseases
    Dennis J Selkoe and Peter J Lansbury, Jr.
    • Alzheimer's Disease Is the Most Common Neurodegenerative Disorder
      • Amyloid-bearing plaques, neurofibrillary tangles and neuronal dystrophy and loss characterize the pathology of Alzheimer's disease
      • Neurons in the limbic and association cortices and the subcortical nuclei that project to them are particularly vulnerable to neurofibrillary tangle formation
      • Multiple neurotransmitter systems are affected in a pattern that correlates with the cellular pathology
      • The search for etiologies has resulted in a focus on genetic factors
      • Clues to the mechanisms of familial Alzheimer's disease have arisen from biochemical analyses of the neuropathological phenotype
      • Neurofibrillary tangles and dystrophic cortical neurites contain post-translationally modified forms of tau proteins
      • Amyloid in Alzheimer's disease plaques is composed of a 40- to 42-amino-acid portion of an integral membrane glycoprotein, the β-amyloid precursor protein
      • Deposition of amyloid β protein precedes the lesions of Alzheimer's disease and arises from alternative proteolytic processing of β-amyloid precursor protein
      • A rare form of autosomal dominant Alzheimer's disease is caused by point mutations in the gene that encodes β-amyloid precursor protein
      • Mutations in the presenilin 1 and 2 genes represent the most common cause of early-onset, autosomal dominant Alzheimer's disease
      • The ϵ4 allele of apolipoprotein E is a major genetic risk factor for late-onset Alzheimer's disease
      • Genotype-to-phenotype relationships implicate β-amyloidosis as an early and necessary factor in all known forms of familial Alzheimer's disease
      • Therapeutic strategies arise from understanding the molecular basis of Alzheimer's disease
    • Prion Diseases
      • The brain pathology of prion diseases, like Alzheimer's disease, involves neurodegeneration and abnormal protein aggregates
      • Prion diseases were originally described in sheep
      • The infectious agent may contain only the prion protein
      • The prion protein is a normal host protein that is required for scrapie infection
      • Mutations in the prion protein cause human prion diseases
      • Elucidation of the infectious mechanism and of normal prion protein conversion to scrapie prion protein is necessary to design compounds for therapeutic intervention
      • The mechanism of prion neurotoxicity is unknown
    • References
• Part Seven. Neural Processing and Behavior
  • Chapter 47. Molecular Biology of Vision
    Hitoshi Shichi.
    • Physiological Background
      • Light-absorbing pigments differentiate rod cells for black—white vision and three types of cone cells for color vision
      • Absorption of light causes inhibition of vertebrate photoreceptor cells, which then initiate programs of responses among retinal neurons
      • Retinal responses to different light frequencies are encoded in the retina and conveyed to the thalamus and visual cortex
    • Photoreceptor Membranes and Visual Pigments
      • Rod outer segment membranes are arranged in stacks of disks containing rhodopsin
      • Rhodopsin is a transmembrane protein linked to 11-cis-retinal, which, on photoabsorption, decomposes to opsin and all-trans-retinal
      • Bleached rhodopsin must be regenerated to maintain normal vision
      • Cone-cell pigments contain different opsins that have high sequence homology
    • Phototransduction
      • Light absorption by rhodopsin leads to closure of Na⁺-conductance channels via a chemical messenger system
      • A G-protein/cGMP system in outer segments is responsive to photoactivated rhodopsin
    • Color Blindness
      • Red—green color blindness is explained by unequal intragenic recombination between a pair of X chromosomes
    • Retinitis Pigmentosa
      • Mutations in rhodopsin and other photoreceptor proteins are linked to retinitis pigmentosa
    • Age-Related Macular Degeneration
      • A genetic defect leads to macular degeneration among the elderly
    • References
  • Chapter 48. Molecular Biology of Olfaction and Taste
    Stuart J Firestein, Robert F Margolskee, and Sue Kinnamon.
    • Olfaction
      • The mammalian olfactory system possesses enormous discriminatory power
      • The initial events in olfaction occur in a specialized olfactory neurepithelium
      • Odor discrimination is likely to depend upon the ability of different olfactory sensory neurons to recognize different odorants
      • Odor discrimination could involve a very large number of different odorant receptors, each highly specific for one or a small set of odorants
      • The information generated by hundreds of different receptor types must be organized to achieve a high level of olfactory discrimination
      • The reputed sensitivity of the olfactory system is likely to derive from the capacity of the olfactory transduction apparatus to effectively amplify and rapidly terminate signals
      • Odorant recognition initiates a second-messenger system leading to the depolarization of the neuron and the generation of action potentials
      • Negative feedback processes mediate adaptation in the odor-induced response
      • Alternative second-messenger pathways may be at work in olfactory transduction
      • The vomeronasal organ is an accessory chemosensing system devoted to detecting conspecific chemical cues, also known as pheromones
    • Taste
      • Taste perception can be reduced to primary stimuli
      • Taste receptor cells are organized into taste buds
      • Sensory afferents within three cranial nerves innervate the taste buds
      • Information coding of taste is not strictly according to a labeled line
      • Taste cells have multiple types of ion channels
      • Salts and acids are transduced by direct interaction with ion channels
      • Taste cells contain receptors, G proteins and second-messenger-effector enzymes
      • Sweet, bitter and umami involve receptor-coupled second-messenger pathways
      • Expression of some G proteins is elevated in taste cells
      • Gustducin is a taste cell-specific G protein closely related to the transducins
    • Acknowledgments
    • References
  • Chapter 49. Endocrine Effects on the Brain and Their Relationship to Behavior
    Bruce S McEwen.
    • Behavioral Control of Hormonal Secretion
      • The hypothalamic releasing factors regulate release of the anterior pituitary trophic hormones
      • Secretion of pituitary hormones is responsive to behavior and effects of experience
      • Hormones secreted in response to behavioral signals act in turn on the brain and on other tissues
    • Classification of Hormonal Effects
      • Hormonal actions on target neurons are classified in terms of cellular mechanisms of action
    • Biochemistry of Steroid and Thyroid Hormone Actions
      • Steroid hormones are divided into six classes, based on physiological effects: estrogens, androgens, progestins, glucocorticoids, mineralocorticoids and vitamin D
      • Some steroid hormones are converted in the brain to more or less active products that interact with receptors
      • Genomic receptors for steroid hormones have been clearly identified in the nervous system
    • Intracellular Steroid Receptors: Properties and Topography
      • Steroid hormone receptors are phosphoproteins that have a DNA-binding domain and a steroid-binding domain
    • Identification of Membrane Steroid Receptors
    • Biochemistry of Thyroid Hormone Actions on Brain
    • Diversity of Steroid Hormone Actions on the Brain
      • During development, steroid hormone receptors become evident in target neurons of the brain
      • The response of neural tissue to damage involves some degree of structural plasticity, as in development
      • Activation and adaptation behaviors may be mediated by hormones
      • Enhancement of neuronal atrophy and cell loss during aging by severe and prolonged psychosocial stress are examples of allostatic load
    • References
  • Chapter 50. Learning and Memory
    Bernard W Agranoff, Carl W Cotman, and Michael D Uhler.
    • Introduction
      • How do biochemists study behavior?
      • Learning can be defined as an adaptive change in response to an environmental input
      • Studying neurochemical correlates of learning and memory is a compromise between meeting behavioral criteria and the accessibility of the system employed to molecular and cellular biological approaches
      • Investigation of learning and memory in intact behaving animals generally involves one of two strategies: interventive or correlative
    • Basic Assumptions
      • The generally accepted basic behavioral paradigm for studying learning and memory is the conditioned response
      • Protein synthesis is required to form long-term, but not short-term, memory
      • Behavioral information is ultimately stored in synaptic connections
    • Synaptic Plasticity as a Model for Learning and Memory Research
      • Changes in environment can evoke plastic neuronal responses
      • Motor learning can modify synaptic connectivity
      • Endogenous hormones cause structural changes in the nervous system
      • Nerve regeneration serves as a model of neuroplasticity in learning and memory formation
    • Invertebrate Learning and Memory
      • Aplysia provides a cellular model of learning and memory
      • Drosophila are useful as a genetic system for studying learning and memory
      • Other invertebrates are being developed as model systems for experimental studies of memory
    • Studies of Learning and Memory in Vertebrates
      • Long-term potentiation leads to structural changes at the synapse
      • Behavioral measures of learning and memory define types of memory
    • Studies of Learning and Memory in Humans
      • Metabolic correlates of behavior can be localized noninvasively in brain
    • Remaining Questions and Future Directions
      • There are many kinds of learning and memory
      • Can human memory formation or storage be enhanced?
    • References
    • General References
  • Chapter 51. Neurochemistry of Schizophrenia
    Herbert Y Meltzer and Ariel Y Deutch.
    • Clinical Aspects of Schizophrenia
      • Schizophrenia, manic-depressive illness, psychotic depression and organic psychoses of known etiology, such as the alcoholic and senile psychoses, are the major forms of psychotic disorders
      • The psychopathology of schizophrenia is usually described in terms of three somewhat independent syndromes, or symptom clusters
      • The cornerstone of the treatment of schizophrenia is a group of antipsychotic drugs which are of value for most forms of psychosis
    • Etiology
      • It is generally accepted, despite the absence of evidence, that schizophrenia is a group of disorders with a common overlapping phenotype rather than a single disease entity
      • The neurodevelopmental hypothesis suggests that the etiology of schizophrenia may involve pathological processes during brain development
      • Despite extensive efforts to discover a neuropathological basis for schizophrenia, no consistent characteristic lesions, at either the micro- or the macroscopic level, have yet been identified
    • Cellular and Pharmacological Studies
      • The dopamine hypothesis has dominated schizophrenia research since the mid-1960s
      • Serotonin has been implicated in a variety of behaviors and somatic functions which are disturbed in schizophrenia
      • Derangements in central nervous system GABA systems have long been suspected in schizophrenia
      • Excitatory amino acids may play a role in the pathophysiology of schizophrenia
      • Neuropeptides that function as neurotransmitters may play a role in schizophrenia
      • Acetylcholine has also been suggested to play a role in schizophrenia
    • References
  • Chapter 52. Biochemical Hypotheses of Mood and Anxiety Disorders
    Jack D Barchas and Margaret Altemus.
    • Depression and Manic-Depressive Illness: Two Major Categories of Mood Disorders
    • Biological Concomitants of Mood Disorders
      • A number of physiological changes occur in mood disorders
      • Anatomical and metabolic changes in the brain are associated with depression
      • Genetic factors are likely to play a role in mood disorders
      • Pharmacological treatments are effective for mood disorders
    • Monoamine Hypotheses of Mood Disorders
      • Biogenic amines have been important in hypotheses of mood disorders
      • A number of strategies are used to investigate neuroregulators in mood disorders
      • Catecholamine hypotheses remain important for depression and mania
      • Dopamine mechanisms may be important in some forms of depression and mania
      • Serotonin has a role in some forms of depression
    • Acetylcholine Mechanisms Have Been Implicated in Mood Disorders
    • Receptor Hypotheses of Mood Disorders
      • β-Adrenergic and serotonergic receptors may mediate the clinical effects of antidepressant drugs
      • Other receptor mechanisms have been implicated in mood disorders
      • Postreceptor intracellular transduction systems may play a role in mood disorders
    • Li⁺ and Anticonvulsants are Important in the Treatment of Mood Disorders
      • Li⁺ is effective in treating mania and depression
      • Li⁺ has a number of effects on neuroregulatory systems
      • Li⁺ has important effects on the phosphatidylinositol system
      • Anticonvulsants and electroconvulsive shock therapy are effective in the treatment of mood disorders
    • Endocrine, Circadian and Behavioral Processes in Mood Disorders
      • Several endocrine systems are implicated in the pathophysiology of mood disorders
      • The study of sleep and circadian mechanisms and of seasonal affective disorder provides insights into mood disorders
      • Behavioral neurochemistry provides ways to study depression in animal models
    • Anxiety Disorders
      • There are distinct forms of anxiety disorders
    • Biochemical Aspects of Anxiety
      • Benzodiazepines have revolutionized the treatment of anxiety disorders
      • Receptors for the benzodiazepines relate to their behavioral effects
      • Central nervous system benzodiazepine-binding sites are associated with the GABA_A receptor
      • GABA agonists have anxiolytic effects
      • Several classes of compounds act as benzodiazepine antagonists
      • Multiple benzodiazepine receptors are involved in differential pharmacological actions
      • Neurosteroids may modulate anxiety symptoms
      • Mechanisms involving catecholamine function may be important in anxiety
      • Serotonin has been linked to anxiety processes
      • Neuropeptides function in anxiety processes
      • Obsessive-compulsive disorder has neurobiological concomitants
      • Panic disorder has specific biochemical characteristics
      • Brain mapping and imaging are being applied to the study of anxiety disorders
    • References
  • Chapter 53. Neurochemical Bases of Drug Abuse
    George R Uhl.
    • General Principles
    • Molecular Targets for Drug Reward
      • The μ opiate receptor is one of the primary sites for opiate reward in the brain
      • The dopamine transporter is a candidate site for cocaine reward in the brain and is a major contributor to amphetamine reward
      • Cannabinoids appear to exert their rewarding effects at the G protein-linked CB1 receptor
      • Nicotine acts at ligand-gated ion channels that comprise nicotinic acetylcholine receptors
      • Barbiturates and benzodiazepines work at allosteric sites on GABA-gated chloride ion channels
      • The receptors at which a number of hallucinogens bind have been elucidated
      • Inhalants and ethanol are likely to work at multiple chemical sites
    • Brain Circuits Activated by Rewarding Drugs
      • Brain circuits that mediate the rewarding actions of abused drugs include a path with cell bodies in the ventral tegmental area of the midbrain
      • Dopamine efflux from ventral tegmental area neuronal terminals increases during treatment with abused drugs
      • Brain circuits activated during chronic effects of rewarding drugs are unlikely to be only those that mediate acute drug reward
      • Circuits implicated in generalized memory processes may play significant roles in long-term consequences of substance abuse
    • Cellular Changes Exerted by Abused Substances
      • By acting at their primary receptor targets, abused substances effect neurochemical changes in cells that express drug “receptor” target molecules
      • Rapid responses to abused drugs can be induced via ion channel activities
      • Several abused substances alter levels of cellular second messengers
      • Short-term effects of cellular effectors must also be accompanied by longer-term drug effects
    • Individual Differences
      • Drug abuse vulnerability, like many behavioral disorders, is likely influenced by genetic and environmental factors
    • Conclusions
    • Acknowledgments
    • References
  • Chapter 54. Positron Emission Tomography
    Kirk A Frey.
    • Methods in Positron Emission Tomography
      • Positron-emitting tracers are used to produce maps of radioactivity distribution in brain
      • Positron emission tomography can generate a pictorial representation of a physiological or biochemical process as the process occurs regionally within the brain
    • Physiological and Biochemical Measurements Using Positron Emission Tomography
      • The simplest brain parameter to be measured with positron emission tomography is blood volume
      • Measurement of blood—brain barrier permeability to a test substance is based on a two-compartment model representing the intravascular and extravascular spaces
      • Determination of regional cerebral blood flow by positron emission tomography is frequently employed to localize “functional” neural activation
      • Regional cerebral glucose metabolism is imaged for the study of brain activity in vivo
      • Inhalation of [¹⁵O]oxygen allows measurement of regional cerebral oxygen metabolic rate
      • The metabolism of specific neurotransmitters may be evaluated with the use of labeled precursors
      • The in vivo quantification of regional ligand-binding sites has been a long anticipated development
    • Clinical Applications of Cerebral Positron Emission Tomography
      • Studies of Alzheimer's disease assist in diagnosis and test pathophysiological hypotheses
      • Studies of epilepsy assist in characterizing seizure foci
      • Studies of cerebrovascular disease show the evolution of metabolic and blood flow changes in ischemic brain
      • Studies of Parkinson's disease reveal distinct subgroups of patients and permit assessment of medication effects
    • Acknowledgments
    • References
• Glossary
• Amino Acids in Proteins

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