4 Chapter One with one another by means of specialized contacts that Sherrington called synapses. The work that framed this debate was recognized by the award of the Nobel Prize for Physiology or Medicine in 1906 to both Golgi and Cajal( the joint award suggests some ongoing concern about just who was correct, despite Cajals overwhelming evidence). The subsequent work of Sherrington and others demonstrating the transfer of electrical signals at ynaptic junctions between nerve cells provided strong support of the"neu- ron doctrine, but challenges to the autonomy of individual neurons remained. It was not until the advent of electron microscopy in the 1950s that any lingering doubts about the discreteness of neurons were resolved The high-magnification, high-resolution pictures that could be obtained with the electron microscope clearly established that nerve cells are functionally independent units; such pictures also identified the specialized cellular junc tions that Sherrington had named synapses(see Figures 1.3 and 1.4) The histological studies of Cajal, Golgi, and a host of successors led to the further consensus that the cells of the nervous system can be divided into two broad categories: nerve cells(or neurons), and supporting cells called neuroglia(or simply glia; see Figure 1.5). Nerve cells are specialized for elec trical signaling over long distances, and understanding this process repre- sents one of the more dramatic success stories in modern biology(and the subject of Unit I of this book). Supporting cells, in contrast, are not capable of electrical signaling; nevertheless, they have several essential functions in the developing and adult brain Neurons Neurons and glia share the complement of organelles found in all cells, including the endoplasmic reticulum and Golgi apparatus, mitochondria, and a variety of vesicular structures. In neurons, however, these organelles re often more prominent in distinct regions of the cell. In addition to the distribution of organelles and subcellular components, neurons and glia are in some measure different from other cells in the specialized fibrillar or tubular proteins that constitute the cytoskeleton(Figures 1.3 and 1.4 Although many of these proteins-isoforms of actin, tubulin, and myosin, as well as several others-are found in other cells, their distinctive organization in neurons is critical for the stability and function of neuronal processes and synaptic junctions. The filaments, tubules, vesicular motors, and scaffolding proteins of neurons orchestrate the growth of axons and dendrites; the traf- ficking and appropiate positioning of membrane components, organelles, and vesicles; and the active processes of exocytosis and endocytosis that underlie synaptic communication. Understanding the ways in which these molecular components are used to insure the proper development and func- tion of neurons and glia remains a primary focus of modern neurobiology The basic cellular organization of neurons resembles that of other owever, they are clearly distinguished by specialization for intercellular communication. This attribute is apparent in their overall morphology, in the specific organization of their membrane components for electrical signaling, and in the structural and functional intricacies of the synaptic contacts between neurons(see Figures 1.3 and 1.4). The most obvious sign of neu- ronal specialization for communication via electrical signaling is the exten- sive branching of neurons. The most salient aspect of this branching for typ- ical nerve cells is the elaborate arborization of dendrites that arise from the neuronal cell body(also called dendritic branches or dendritic processes). Den drites are the primary target for synaptic input from other neurons and are
4 Chapter One with one another by means of specialized contacts that Sherrington called “synapses.” The work that framed this debate was recognized by the award of the Nobel Prize for Physiology or Medicine in 1906 to both Golgi and Cajal ( the joint award suggests some ongoing concern about just who was correct, despite Cajal’s overwhelming evidence). The subsequent work of Sherrington and others demonstrating the transfer of electrical signals at synaptic junctions between nerve cells provided strong support of the “neuron doctrine,” but challenges to the autonomy of individual neurons remained. It was not until the advent of electron microscopy in the 1950s that any lingering doubts about the discreteness of neurons were resolved. The high-magnification, high-resolution pictures that could be obtained with the electron microscope clearly established that nerve cells are functionally independent units; such pictures also identified the specialized cellular junctions that Sherrington had named synapses (see Figures 1.3 and 1.4). The histological studies of Cajal, Golgi, and a host of successors led to the further consensus that the cells of the nervous system can be divided into two broad categories: nerve cells (or neurons), and supporting cells called neuroglia (or simply glia; see Figure 1.5). Nerve cells are specialized for electrical signaling over long distances, and understanding this process represents one of the more dramatic success stories in modern biology (and the subject of Unit I of this book). Supporting cells, in contrast, are not capable of electrical signaling; nevertheless, they have several essential functions in the developing and adult brain. Neurons Neurons and glia share the complement of organelles found in all cells, including the endoplasmic reticulum and Golgi apparatus, mitochondria, and a variety of vesicular structures. In neurons, however, these organelles are often more prominent in distinct regions of the cell. In addition to the distribution of organelles and subcellular components, neurons and glia are in some measure different from other cells in the specialized fibrillar or tubular proteins that constitute the cytoskeleton (Figures 1.3 and 1.4). Although many of these proteins—isoforms of actin, tubulin, and myosin, as well as several others—are found in other cells, their distinctive organization in neurons is critical for the stability and function of neuronal processes and synaptic junctions. The filaments, tubules, vesicular motors, and scaffolding proteins of neurons orchestrate the growth of axons and dendrites; the trafficking and appropiate positioning of membrane components, organelles, and vesicles; and the active processes of exocytosis and endocytosis that underlie synaptic communication. Understanding the ways in which these molecular components are used to insure the proper development and function of neurons and glia remains a primary focus of modern neurobiology. The basic cellular organization of neurons resembles that of other cells; however, they are clearly distinguished by specialization for intercellular communication. This attribute is apparent in their overall morphology, in the specific organization of their membrane components for electrical signaling, and in the structural and functional intricacies of the synaptic contacts between neurons (see Figures 1.3 and 1.4). The most obvious sign of neuronal specialization for communication via electrical signaling is the extensive branching of neurons. The most salient aspect of this branching for typical nerve cells is the elaborate arborization of dendrites that arise from the neuronal cell body (also called dendritic branches or dendritic processes). Dendrites are the primary target for synaptic input from other neurons and are Purves01 5/13/04 1:02 PM Page 4
Studying the Nervous Systems of Humans and Other Animals 5 (A) (B)Axon o Synaptic endings(terminal boutons) Mitochondrion F E D) Myelinated axons bosomed Axons E) Dendrites (F)Neuronal cell body(soma) ( G)Myelinated axon and node of Ranvier Figure 1.3 The major light and electron microscopical features of neurons. (A)D gram of nerve cells and their component parts.( B)Axon initial segment(blue) entering a myelin sheath(gold). (C) Terminal boutons(blue)loaded with synaptic vesicles(arrowheads) forming synapses(arrows)with a dendrite(purple) D) Transverse section of axons(blue)ensheathed by the processes of oligodendro- cytes(gold).(E)Apical dendrites(purple)of cortical pyramidal cells. (F)Nerve cell bodies(purple)occupied by large round nuclei. (G)Portion of a myelinated axon (blue)illustrating the intervals between adjacent segments of myelin(gold)referred to as nodes of Ranvier(arrows).(Micrographs from Peters et al., 1991)
Studying the Nervous Systems of Humans and Other Animals 5 Mitochondrion Endoplasmic reticulum Axons Ribosomes Golgi apparatus Nucleus Dendrite Soma (A) (B) Axon (C) Synaptic endings (terminal boutons) (D) Myelinated axons (E) Dendrites (F) Neuronal cell body (soma) (G) Myelinated axon and node of Ranvier F E B D G C Figure 1.3 The major light and electron microscopical features of neurons. (A) Diagram of nerve cells and their component parts. (B) Axon initial segment (blue) entering a myelin sheath (gold). (C) Terminal boutons (blue) loaded with synaptic vesicles (arrowheads) forming synapses (arrows) with a dendrite (purple). (D) Transverse section of axons (blue) ensheathed by the processes of oligodendrocytes (gold). (E) Apical dendrites (purple) of cortical pyramidal cells. (F) Nerve cell bodies (purple) occupied by large round nuclei. (G) Portion of a myelinated axon (blue) illustrating the intervals between adjacent segments of myelin (gold) referred to as nodes of Ranvier (arrows). (Micrographs from Peters et al., 1991.) Purves01 5/13/04 1:02 PM Page 5
6 Chapter One Figure 1.4 Distinctive arrangement of cytoskeletal elements in neurons. (A) The cell body, axons, and dendrites are istinguished by the distribution of other cytoskeletal elementsin this case, Tau(red), a microtubule-binding protein found only in axons. (B)The strikingly distinct localization of actin (red)to the growing tips of axonal and (D) dendritic processes is shown here in cultured neuron taken from the hip- pocampus. ( C)In contrast, in a cultured epithelial cell, actin(red) is distributed in fibrils that occupy most of the cell body.(D) In astroglial cells in culture, actin(red) is also seen in fibrillar bun- dles.(E)Tubulin(green) is seen throughout the cell body and dendrites of neurons. (F) Although tubulin is a major component of dendrites, extend ing into spines, the head of the spine is enriched in actin(red). (G) The tubulin omponent of the cytoskeleton in non- networks(H-K) Synapses have a dio us neuronal cells is arrayed in filament tinct arrangement of cytoskeletal ele- ments, receptors, and scaffold protein (H) Two axons(green; tubulin) from motor neurons are seen issuing two branches each to four muscle fibers. The red shows the clustering of postsynaptic receptors(in this case for the neuro- transmitter acetylcholine). (I)A higher ower view of a single motor neuron ynapse shows the relationship between the axon(green) and the postsynaptic receptors(red). ()The extracellular space between the axon and its target muscle is shown in green. (K) The clus- tering of scaffolding proteins(in this case, dystrophin) that localize receptors nd link them to other cytoskeletal ele- ments is shown in green. (A courtesy of Y.N. Jan; B courtesy of E. Dent and F. Gertler; C courtesy of D. Arneman and C. Otey: D courtesy of A Gonzales and R. Cheney; E from Sheng, 2003; F from Matus, 2000; G courtesy of T. Salmon et al. H-K courtesy of R Sealock
6 Chapter One Figure 1.4 Distinctive arrangement of cytoskeletal elements in neurons. (A) The cell body, axons, and dendrites are distinguished by the distribution of tubulin (green throughout cell) versus other cytoskeletal elements—in this case, Tau (red), a microtubule-binding protein found only in axons. (B) The strikingly distinct localization of actin (red) to the growing tips of axonal and dendritic processes is shown here in cultured neuron taken from the hippocampus. (C) In contrast, in a cultured epithelial cell, actin (red) is distributed in fibrils that occupy most of the cell body. (D) In astroglial cells in culture, actin (red) is also seen in fibrillar bundles. (E) Tubulin (green) is seen throughout the cell body and dendrites of neurons. (F) Although tubulin is a major component of dendrites, extending into spines, the head of the spine is enriched in actin (red). (G) The tubulin component of the cytoskeleton in nonneuronal cells is arrayed in filamentous networks. (H–K) Synapses have a distinct arrangement of cytoskeletal elements, receptors, and scaffold proteins. (H) Two axons (green; tubulin) from motor neurons are seen issuing two branches each to four muscle fibers. The red shows the clustering of postsynaptic receptors (in this case for the neurotransmitter acetylcholine). (I) A higher power view of a single motor neuron synapse shows the relationship between the axon (green) and the postsynaptic receptors (red). (J) The extracellular space between the axon and its target muscle is shown in green. (K) The clustering of scaffolding proteins (in this case, dystrophin) that localize receptors and link them to other cytoskeletal elements is shown in green. (A courtesy of Y. N. Jan; B courtesy of E. Dent and F. Gertler; C courtesy of D. Arneman and C. Otey; D courtesy of A. Gonzales and R. Cheney; E from Sheng, 2003; F from Matus, 2000; G courtesy of T. Salmon et al.; H–K courtesy of R. Sealock.) (A) (B) (C) (D) (E) (G) (F) (H) (I) (J) (K) Purves01 5/13/04 1:02 PM Page 6
Studying the Nervous Systems of Humans and Other Animals 7 also distinguished by their high content of ribosomes as well as specific ytoskeletal proteins that reflect their function in receiving and integrating information from other neurons. The spectrum of neuronal geometries ranges from a small minority of cells that lack dendrites altogether to neu- rons with dendritic arborizations that rival the complexity of a mature tree (see Figure 1. 2). The number of inputs that a particular neuron receives depends on the complexity of its dendritic arbor: nerve cells that lack den- drites are innervated by(thus, receive electrical signals from) just one or few other nerve cells, whereas those with increasingly elaborate dendrites are innervated by a commensurately larger number of other neurons The synaptic contacts made on dendrites(and, less frequently, on neu- ronal cell bodies)comprise a special elaboration of the secretory apparatus found in most polarized epithelial cells. Typically, the presynaptic terminal is immediately adjacent to a postsynaptic specialization of the target cell ee Figure 1.3). For the majority of synapses, there is no physical continuity between these pre- and postsynaptic elements. Instead, pre-and postsynap- tic components communicate via secretion of molecules from the presynap tic terminal that bind to receptors in the postsynaptic specialization. These molecules must traverse an interval of extracellular space between pre-and postsynaptic elements called the synaptic cleft. The synaptic cleft, however, is not simply a space to be traversed; rather, it is the site of extracellular pro- teins that influence the diffusion, binding, and degradation of molecules secreted by the presynaptic terminal(see Figure 1. 4). The number of synap tic inputs received by each nerve cell in the human nervous system varies from 1 to about 100,000. This range reflects a fundamental purpose of nerve cells, namely to integrate information from other neurons. The number of synaptic contacts from different presynaptic neurons onto any particular cell is therefore an especially important determinant of neuronal function he information convey red by synapses on the neuronal dendrites is inte. grated and"read out"at the origin of the axon, the portion of the nerve cell pecialized for signal conduction to the next site of synaptic interaction(see Figures 1.2 and 1.3). The axon is a unique extension from the neuronal cell body that may travel a few hundred micrometers(um; usually called microns)or much farther, depending on the type of neuron and the size of the species. Moreover, the axon also has a distinct cytoskeleton whose ele- ments are central for its functional integrity(see Figure 1.4). Many nerve ells in the human brain(as well as that of other species) have axons no more than a few millimeters long, and a few have no axons at all. Relatively short axons are a feature of local circuit neurons or interne- rons throughout the brain. The axons of projection neurons, however, extend to distant targets. For example, the axons that run from the human spinal cord to the foot are about a meter long. The electrical event that carries sig- nals over such distances is called the action potential, which is a self-regen- erating wave of electrical activity that propagates from its point of initiation at the cell body (called the axon hillock)to the terminus of the axon where synaptic contacts are made. The target cells of neurons include other nerve ells in the brain, spinal cord, and autonomic ganglia, and the cells of mus- cles and glands throughout the body The chemical and electrical process by which the information encoded by action potentials is passed on at synaptic contacts to the next cell in a path- way is called synaptic transmission. Presynaptic terminals(also called syn- aptic endings, axon terminals, or terminal boutons)and their postsynaptic spe. cializations are typically chemical synapses, the most abundant type of
also distinguished by their high content of ribosomes as well as specific cytoskeletal proteins that reflect their function in receiving and integrating information from other neurons. The spectrum of neuronal geometries ranges from a small minority of cells that lack dendrites altogether to neurons with dendritic arborizations that rival the complexity of a mature tree (see Figure 1.2). The number of inputs that a particular neuron receives depends on the complexity of its dendritic arbor: nerve cells that lack dendrites are innervated by (thus, receive electrical signals from) just one or a few other nerve cells, whereas those with increasingly elaborate dendrites are innervated by a commensurately larger number of other neurons. The synaptic contacts made on dendrites (and, less frequently, on neuronal cell bodies) comprise a special elaboration of the secretory apparatus found in most polarized epithelial cells. Typically, the presynaptic terminal is immediately adjacent to a postsynaptic specialization of the target cell (see Figure 1.3). For the majority of synapses, there is no physical continuity between these pre- and postsynaptic elements. Instead, pre- and postsynaptic components communicate via secretion of molecules from the presynaptic terminal that bind to receptors in the postsynaptic specialization. These molecules must traverse an interval of extracellular space between pre- and postsynaptic elements called the synaptic cleft. The synaptic cleft, however, is not simply a space to be traversed; rather, it is the site of extracellular proteins that influence the diffusion, binding, and degradation of molecules secreted by the presynaptic terminal (see Figure 1.4). The number of synaptic inputs received by each nerve cell in the human nervous system varies from 1 to about 100,000. This range reflects a fundamental purpose of nerve cells, namely to integrate information from other neurons. The number of synaptic contacts from different presynaptic neurons onto any particular cell is therefore an especially important determinant of neuronal function. The information conveyed by synapses on the neuronal dendrites is integrated and “read out” at the origin of the axon, the portion of the nerve cell specialized for signal conduction to the next site of synaptic interaction (see Figures 1.2 and 1.3). The axon is a unique extension from the neuronal cell body that may travel a few hundred micrometers (µm; usually called microns) or much farther, depending on the type of neuron and the size of the species. Moreover, the axon also has a distinct cytoskeleton whose elements are central for its functional integrity (see Figure 1.4). Many nerve cells in the human brain (as well as that of other species) have axons no more than a few millimeters long, and a few have no axons at all. Relatively short axons are a feature of local circuit neurons or interneurons throughout the brain. The axons of projection neurons, however, extend to distant targets. For example, the axons that run from the human spinal cord to the foot are about a meter long. The electrical event that carries signals over such distances is called the action potential, which is a self-regenerating wave of electrical activity that propagates from its point of initiation at the cell body (called the axon hillock) to the terminus of the axon where synaptic contacts are made. The target cells of neurons include other nerve cells in the brain, spinal cord, and autonomic ganglia, and the cells of muscles and glands throughout the body. The chemical and electrical process by which the information encoded by action potentials is passed on at synaptic contacts to the next cell in a pathway is called synaptic transmission. Presynaptic terminals (also called synaptic endings, axon terminals, or terminal boutons) and their postsynaptic specializations are typically chemical synapses, the most abundant type of Studying the Nervous Systems of Humans and Other Animals 7 Purves01 5/13/04 1:02 PM Page 7
8 Chapter One synapse in the nervous system. Another type, the electrical synapse, is far more rare(see Chapter 5). The secretory organelles in the presynaptic termi- nal of chemical synapses are synaptic vesicles(see Figure 1.3), which are generally spherical structures filled with neurotransmitter molecules. The positioning of synaptic vesicles at the presynaptic membrane and their fusion to initiate neurotransmitter release is regulated by a number of pro teins either within or associated with the vesicle. The neurotransmitters released from synaptic vesicles modify the electrical properties of the target cell by binding to neurotransmitter receptors(Figure 1.4), which are local primarily at the postsynaptic specializat The intricate and concerted activity of neurotransmitters, receptors, related cytoskeletal elements, and signal transduction molecules are thus the basis for nerve cells communicating with one another, and with effector cells Figure 1.5 Varieties of neuroglial Neuroglial Cells cells. Tracings of an astrocyte(A),an Neuroglial cells-also referred to as glial cells or simply glia-are quite dif- oligodendrocyte(B), and a microglial ferent from nerve cells. Glia are more numerous than neurons in the brain ell (c)visualized using the golgi method. The images are at approxi- outnumbering them by a ratio of perhaps 3 to 1. The major distinction is that tissue culture, labeled (red) with an ing, although their supportive functions help define synaptic contacts and antibody against an astrocyte-specific maintain the signaling abilities ons. Although glial cells also have protein.(E)Oligodendroglial cells in complex processes extending from their cell bodies, these are generally less tissue culture labeled with an antibody prominent than neuronal branches, and do not serve the same purposes as against an oligodendroglial-specific axons and dendrites( Figure 1.5) protein.(F)Peripheral axon are en- sheathed by myelin (labeled red)except t a distinct region called the node of Ranvier. The green label indicates ion channels concentrated in the node: the blue label indicates a molecularly dis- (A)Astrocyt (B)Oligodendrocyte (C)Microglial cell inct region called the paranode. (G) microglial cells from the spinal cord, labeled with a cell type-specific anti body. Inset: Higher-magnification nage of a single microglial cell labeled with a macrophage-selective marker A-C after Jones and Cowan, 1983; D ourtesy of A.S. LaMantia; Courtesy of M. Bhat; G courtesy of A. Light; inset Glial courtesy of G. Matsushima. Processes
8 Chapter One synapse in the nervous system. Another type, the electrical synapse, is far more rare (see Chapter 5). The secretory organelles in the presynaptic terminal of chemical synapses are synaptic vesicles (see Figure 1.3), which are generally spherical structures filled with neurotransmitter molecules. The positioning of synaptic vesicles at the presynaptic membrane and their fusion to initiate neurotransmitter release is regulated by a number of proteins either within or associated with the vesicle. The neurotransmitters released from synaptic vesicles modify the electrical properties of the target cell by binding to neurotransmitter receptors (Figure 1.4), which are localized primarily at the postsynaptic specialization. The intricate and concerted activity of neurotransmitters, receptors, related cytoskeletal elements, and signal transduction molecules are thus the basis for nerve cells communicating with one another, and with effector cells in muscles and glands. Neuroglial Cells Neuroglial cells—also referred to as glial cells or simply glia—are quite different from nerve cells. Glia are more numerous than neurons in the brain, outnumbering them by a ratio of perhaps 3 to 1. The major distinction is that glia do not participate directly in synaptic interactions and electrical signaling, although their supportive functions help define synaptic contacts and maintain the signaling abilities of neurons. Although glial cells also have complex processes extending from their cell bodies, these are generally less prominent than neuronal branches, and do not serve the same purposes as axons and dendrites (Figure 1.5). (A) Astrocyte (B) Oligodendrocyte Cell body Glial processes (D) (E) (F) (G) (C) Microglial cell Figure 1.5 Varieties of neuroglial cells. Tracings of an astrocyte (A), an oligodendrocyte (B), and a microglial cell (C) visualized using the Golgi method. The images are at approximately the same scale. (D) Astrocytes in tissue culture, labeled (red) with an antibody against an astrocyte-specific protein. (E) Oligodendroglial cells in tissue culture labeled with an antibody against an oligodendroglial-specific protein. (F) Peripheral axon are ensheathed by myelin (labeled red) except at a distinct region called the node of Ranvier. The green label indicates ion channels concentrated in the node; the blue label indicates a molecularly distinct region called the paranode. (G) Microglial cells from the spinal cord, labeled with a cell type-specific antibody. Inset: Higher-magnification image of a single microglial cell labeled with a macrophage-selective marker. (A–C after Jones and Cowan, 1983; D, E courtesy of A.-S. LaMantia; F courtesy of M. Bhat; G courtesy of A. Light; inset courtesy of G. Matsushima.) Purves01 5/13/04 1:03 PM Page 8